Medicinal Chemistry of Indole Derivatives

Bioorganic Chemistry 89 (2019) 103021
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Medicinal chemistry of indole derivatives: Current to future therapeutic T

prospectives
Archana Kumaria,1, Rajesh K. Singhb,
⁎
a
Rayat-Bahra Institute of Pharmacy, Dist. Hoshiarpur, 146104 Punjab, India
b
Department of Pharmaceutical Chemistry, Shivalik College of Pharmacy, Nangal, Dist. Rupnagar, 140126 Punjab, India
ARTICLE INFO ABSTRACT
Keywords: Indole is a versatile pharmacophore, a privileged scaffold and an outstanding heterocyclic compound with wide
Indole nucleus ranges of pharmacological activities due to different mechanisms of action. It is an superlative moiety in drug
Synthesis discovery with the sole property of resembling different structures of the protein. Plenty of research has been
Medicinal Chemistry taking place in recent years to synthesize and explore the various therapeutic prospectives of this moiety. This
Structure-activity relationship
review summarizes some of the recent effective chemical synthesis (2014–2018) for indole ring. This review also
Pharmacological profile
emphasized on the structure–activity relationship (SAR) to reveal the active pharmacophores of various indole
analogues accountable for anticancer, anticonvulsant, antimicrobial, antitubercular, antimalarial, antiviral,
antidiabetic and other miscellaneous activities which have been investigated in the last five years. The precise
features with motives and framework of each research topic is introduced for helping the medicinal chemists to
understand the perspective of the context in a better way. This review will definitely offer the platform for
researchers to strategically design diverse novel indole derivatives having different promising pharmacological
activities with reduced toxicity and side effects.
1. Introduction or benzo[b]pyrrole is an organic chemical compound with formula

C8H7N containing six-membered benzene ring fused to the five-mem-
Bicyclic heterocyclic structures occur widely in many biologically bered nitrogen-containing pyrrole ring reported as an important
important molecules, one of them with versatile nature is Indole. Indole building block in the field of medicinal chemistry field [1]. In 1866,
Abbreviations: 3D-QSAR, 3-Dimensional quantitative structur-activity relationship; AAPH, 2,2′-Azobis(2-amidinopropane) dihydrochloride; AbI, Abelson interactor
1; ADP, Adenosine diphosphate; AIDS, Acquired immune deficiency syndrome; Akt, Protien kinase B; ALK, Anaplastic lymphoma kinase ; ATR, Ataxia telangiectasia
and Rad3; Bcl-2, B-cell lymphoma 2; BHT, Butylatedhydroxytoluene; BVDV, Bovine viral diarrhoea virus; CC50, half maximal inhibitory compound concentration;
CD38, Cluster of differentiation 38; CDK7, Cyclin-dependent kinase 7; CHIKV, Chikungunya virus; ClogP, Calculated log P; COX-1, Cyclooxygenase-1; COX-2,
Cyclooxygenase-2; CVB-2, Coxsackievirus B-2 strain; DCFH-DA, Dichlorodihydrofluorescein diacetate; DNA, Deoxyribonucleic acid; DPPH, 2, 2-diphenyl-1-pi-
crylhydrazyl; EC50, 50% effective concentration; EI1, EZH2 inhibitor 1; ER β, Estrogen receptor beta; ERσ, Estrogen receptor alpha; EZH2, Enhancer of homology
Zesta 2; FABP, Fatty-acid-binding proteins; FAK, Focal adhesion kinase ; FGFR, Fibroblast growth factor receptors; FST, Forced swim test; GABA, gamma-
Aminobutyric acid; GSK, GlaxoSmithKline; HBV, Hepatitis B virus; HCV, Hepatitis C virus; HDACs, Histone deacetylases; HDM2, Human double minute 2; HIV-1,
Human immunodeficiency virus-1; HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A; IAP, Inhibitor of Apoptosis Protein; JAK2, Janus kinase 2; LDH, Lactate
dehydrogenase; LOX, Lipoxygenase; LP, Lipid peroxidation; LPS, Lipopolysaccharide; MCF-7, Macrophage colony-stimulating factor-7; MDM2, Mouse double minute
2; MES, Maximal electroshock; MET, Mesenchymal-Epithelial Transition; MIC, Minimum inhibitory concentration; NAADP+, Nicotinic acid adenine dinucleotide
phosphate; NAD(P)+, Nicotinamide adenine dinucleotide phosphate; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; NMDA, N-methyl-D-
aspartate receptor; NNRTIs, Non-nucleoside reverse transcriptase inhibitors; NS5B, Nonstructural protein 5B; PDGFR, Platelet-derived growth factor receptors; PERK,
PKR like endoplasmic reticulum kinase; PPARγ, Peroxisomes proliferator-activated receptor-γ; PRC2, Polycomb repressive complex 2; PYK2, Protein tyrosine kinase
2; QP Pcaco, Cell permeability; QPLogPo/w, Partition coefficient; QPLogS, Predicted aqueous solubility; RdRp, RNA-dependent RNA polymerase; RNA, Ribonucleic
acid; ROS, Reactive oxygen species; SCLC, Small cell lung cancer; ScPTZ, subcutaneous pentylenetetrazol; STAT3, Signal transducer and activator of transcription 3;
TFA, Trifluoroacetic acid; TNF-α, Tumor necrosis factor alpha; VEGFR, Vascular endothelial growth factor receptors; VZV, Varicella zoster virus; WT, Wild type;
XIAP, X-linked inhibitor of apoptosis protein ; YFV, Yellow fever virus
⁎
Corresponding author.
E-mail address: [email protected] (R.K. Singh).
1
Research Scholar, Faculty of Pharmacy, I.K. Gujral Punjab Technical University, Jalandhar, India.
https://doi.org/10.1016/j.bioorg.2019.103021
Received 27 March 2019; Received in revised form 22 May 2019; Accepted 29 May 2019
Available online 30 May 2019
0045-2068/ © 2019 Elsevier Inc. All rights reserved.
A. Kumari and R.K. Singh Bioorganic Chemistry 89 (2019) 103021
Adolf von Baeyer prepared the indole by the reduction of oxindole affording the variety of substrates with different functional groups [29].
[2,3]. It is the planar heteroaromatic molecule in which ten π electron Wu et al, give the methodology for the synthesis of indole through the
moves throughout the structure. Chemically, indole is very weakly cyclization of vinylanilines in the presence of phenyliodine bis(tri-
basic. This is due to the delocalization of nitrogen lone-pair into the π- fluoroacetate) as oxidant under mild conditions. Due to the good
electronic system which is free to circulate throughout the indole ring. compatibility of electron withdrawing and electron donating groups on
Therefore, the lone pair of the electron on nitrogen is not available for the aromatic ring and nitrogen atom of 2-vinylanilines, desired product
protonation and get protonated at the C-3 because this position due to were produced in high yield [30]. In 2015, Sayyad and colleagues re-
retention of aromaticity, is thermodynamically more stable [4,5]. Due ported the method for the synthesis of substituted indole nucleus. The
to this it is involved in various chemical reactions, i.e. electrophilic method involves the simple strategy for the formation of cyclopropyl
substitution [6], organometallic indole anion complexes [7], carbon substituted indole using thiophenol, dichloromethane, boron trifluoride
lithiation [8,9], oxidation [10], cycloaddition [11] etc, occur particu- and diethyl ether. The reaction was followed by aromatization and
larly at C-3 position. Indole is solid at room temperature. It occurs elimination of thiophenol in the presence of copper and di-
naturally in human faeces providing faecal smell. However, at a lower methylformamide under the temperature conditions of 125 °C main-
concentration, it gives the flowery smell and constituent of many flower taining for 5–24 h [31]. In 2015, Ortgies and coworkers reported the
scents, perfumes and coal tar [12]. Apart from this, indole is also in- one step cyclization method. This strategy entails the use of selenium
volved in various biochemical reactions in the occurring in the body. It catalyst for the activation of alkenes and N-flourobenzenesulfonimide
regulates various aspects of bacterial physiology, involving spore for- as terminal oxidant. It requires the temperature conditions of 100 °C
mation, plasmid stability, and resistance to drugs, biofilm formation required to maintain for 16 h. The main applications of this method
and virulence [13]. were the formation of high yield and excellent functional group toler-
ance [32]. Li and colleagues provide the scheme for the synthesis of
1.1. Chemical synthesis of the indole ring substituted indole employing the CeN bond aromatization with the
addition of N-iodosuccinimide under the mild temperature conditions
Conventional syntheses of the indole nucleus by various methods and without the use of any catalyst. The major applications of this
are mentioned in the literature. It involves a number of starting mate- method were the rapid synthesis and high yield of the products [33]. In
rials and different strategies as mentioned in Scheme 1 that includes: the same year, Michalska and colleagues introduced the hetero-
Julia indole synthesis [14], Fischer indole synthesis [15], Reissert in- cyclization of alkynylanilines with the use of the small quantity of gold
dole synthesis [16], Baeyer-Emmerling indole synthesis [17], Larock under mild conditions. The major application involves the use of a
indole synthesis [18], Bartoli indole synthesis [19], Madelung indole substrate with a variety of substituents [34]. In 2014, Nallagonda and
synthesis [20], Fukuyama synthesis [21], Leimgruber-Batcho [22]. other researchers designed an efficient strategy for the synthesis of
Recently, some novel methods using various effective catalysts have substituted indole from allylanlines through cycloisomerization with
been explored in the last five years, which have been discussed and the use of palladium acetate or triphenylphosphine as a catalyst and
presented in Scheme 2. oxygen an oxidizing agent. It illustrates the advantages of high yield
Recently, Zeidan and coworkers reported the palladium catalyzed 2- and a broad substrate scope [35]. In the same year, Jiao and others
gem-dihalovinylanilines conversion into substituted indole. Zn(TFA)2 is reported the method for the synthesis of substituted nitrogen-con-
added to prolong the catalytic activity and also Zn(CN)2 is used as a taining heterocycles i.e., pyrroles, indoles involving the palladium/
source of cyanide. The concentration of cyanide was maintained during norbornene catalyzed alkylation at the 2 carbon of these nuclei with a
the reaction due to the solubility of Zn(CN) 2 in two solvent mixtures. good yield of alkyl substituted indole. The alkyl halide was added as
Cyano indole derivatives can be seen in various plant sources and electrophile conducting the reaction smoothly. N, N-dimethylforma-
pharmaceutical drugs [23]. Shi et al, uses the strategy of CeH activa- mide acts as a good solvent which is superior in smooth conversion
tion in the rhodium catalyzed coupling reaction of butyl oxycarbonyl during the reaction [36].
hydrazones with diazodiesters under mild temperature conditions.
Trifluoroacetic acid (TFA) acts as a reaction medium, providing the 1.2. Indole in natural products
yield of about 45%, which can be further, increased to 82% with higher
temperature conditions [24]. In 2017, Yu and others introduced the This lead compound is a universal constituent of pharmacologically
scheme involving the reaction between aminoarylacetonitriles and ar- active natural products. Indole alkaloids are broadly occurring in var-
ylboronic acid with the use of palladium as a catalyst. This conversion ious plant families, i.e., Apocyanaceae, Loganiaceae, Rubiaceae and
involves the nucleophilic addition followed by intramolecular cycliza- Nyssaceae [37]. Auxin, a cell growth hormone essential for both cel-
tion. Halogens showed good compatibility providing the path for de- lular division and cellular expansion in plants, is indole-3-acetic acid
rivatization broadening [25]. Wang mentioned the formylation of in- [38]. Tryptophan (2-amino-3-(1H-indol-3-yl)propanoic acid), an es-
dole in the presence of formaldehyde and ammonia under aerobic sential amino acid, is used as a building block in protein biosynthesis. It
conditions involving the time duration of about 1–20 h. The use of is found to be a biochemical precursor for various biological com-
oxygen instead of other harmful oxidants makes this reaction eco- pounds, e.g. serotonin (neurotransmitter), melanin (a neurohormone).
nomical and environment-friendly. This method can be applied for the Indole alkaloids act on the central and peripheral nervous systems [39].
synthesis of indole on gram scale [26]. Miao and coworkers in 2016, Some indole alkaloids show interaction with the receptors, e.g. mitragy-
stated the direct use of alkynylanilines with diethyl zinc under 1 atm nine for µ-opioid receptors [40], harmala alkaloids for GABA-receptors
with CO2 for synthesis. There is the easy availability of starting material [41], ibogaine for NMDA-receptors [42] and physostigmine for acet-
providing a good chance to develop a library of bioactive indole deri- ylcholinesterase inhibitor [43] etc.
vatives. This technique is applied for the synthesis of drug “Lotronex” There are several clinically important indole alkaloids are available.
used for irritable bowel syndrome [27]. In the same year, Hu and other Some of them are (a) ergot alkaloids (ergotamine 1) (Fig. 1), ergome-
researchers reported the role of rhodium-catalyzed cascade cyclization trine, bromocriptine 2 (Fig. 1) having the action of uterine muscle
using nitrogen source N-pivaloyloxylamides for indole synthesis under contraction, migraine relief, lactation suppression, mammary carci-
mild temperature conditions. This is the novel and efficient method noma treatment [44] (b) vinca alkaloids (vincristine and vinblastine 3
used to synthesize various heterocyclic fused indole nuclei [28]. Simi- (Fig. 1)) having the hypoglycemic and cytotoxic effects [45] (c) Rau-
larly, in 2016, Mizukami and coworkers mentioned the synthesis from wolfia alkaloids (reserpine 4) (Fig. 1), reserpine etc with anti-
ethanylanilines and isocyanates using rhodium as a catalyst through the hypertensive and antiepileptic roles [46] (d) Indole alkaloids obtained
cyclization addition mechanism. It is the high yielding novel technique from Alstonia scholaris contain antibacterial activity [47] (e) Melodinus
2
Scheme 1. Chemical reactions for the synthesis of indole by old conventional methods.
cochinchinensis fruit provides various indole derivatives (melodinus A- introduced by Novartis, is used for the treatment of hypertension since
H) 5 (Fig. 1) having cytotoxic effect [48]. 1982 [53]. Indapamide 13 marketed by Servier, used in the treatment
Marine and bacterial indole alkaloids are striking molecules for drug of heart failure and hypertension [54]. Others are perindopril [55,56],
discovery as they have cytotoxic, antibacterial, antimicrobial and an- trandolapril [57] and carvedilol [58] (Fig. 2). delavirdine 14 (Fig. 2),
tineoplastic activity [49]. Topsentia sponge contains tulongicin indole approved by US FDA, used against HIV-1[59]. Indomethacin 15 (Fig. 2)
alkaloid having antibacterial activity obtained from deep water having is considered as one of the most promising anti-inflammatory and an-
anti-HIV, cytotoxic and antibiotic effect. Apart from tulongicin 6 algesic drug [60]. Yohimbine 16 (Fig. 2), is considered as an effective
(Fig. 1), fractionation gives other indole-containing compounds [50]. drug against sexual dysfunction and also reduces the risks of diabetes 2
Various other indole derivatives such as brasilidine A 7 (Fig. 1), eu- [61]. Along with this, various other marketed indole derivatives are
distomin K 8 (Fig. 1), gelliusine A 9 (Fig. 1), mitraphylline 10 (Fig. 1) illustrated in Fig. 2:
and cediranib 11 (Fig. 1) [13] are mentioned in the Fig. 1. Recently, FDA databases have revealed the significance of nitrogen-
containing heterocycles in drug designing. Among these molecules,
1.3. Indole in synthetic products indole and indole derivatives ranking in the ninth position of the top 25
molecules in 2015, involved in the synthesis of fundamental FDA ap-
The pharmacological activity of various natural indole derivatives proved drugs [62]. This class of heterocyclic compounds has great
motivated many researchers to synthesize various synthetic compounds significance in recent years due to their variety of pharmacological
containing indole. Medicinal chemists are designing various compounds activities (Fig. 3) [63].
by using the various heterocyclic nucleus with indole against various This whole information proved that indole and indole derivatives
diseases. Desai et al, synthesized pyridine and oxadiazole derivatives of are very essential in the drug discovery process and therefore, several
indole as antitubercular agents [51]. Shakuja et al, synthesized bis reviews have been published so far [64–71]. Some review on the in-
spiroindole derivatives as antibacterial agents etc [52]. Various indole volvement of the indole nucleus in Alzheimer's disease [64], as antiviral
derivatives are available in market preparations. Pindolol 12 [65] and anticancer activity [66] are accessible in the literature.
3
Scheme 2. Chemical reactions for the synthesis of indole by novel methods using various catalysts.
Silakari et al, have reviewed the chemistry of natural indole derivatives in the literature till date. Hence, in the present review, our main motive
[13]. Advancement in spirocyclization of indole [67] and synthesis of is to provide information about the recent advances in the chemistry of
phosphorous containing indole have also been published [68]. Re- indole with various pharmacological activities in the last five years. The
cently, a review on current advances in the application of indole in the changes in the indole ring substitution along with their consequences
multicomponent reaction is reported by Ziarani et al [69]. Some com- on the pharmacological activities have also been discussed.
pilations of reports on all activities associated with the indole nucleus
[70] and especially to 2‑aryl indole [71] are also reported, but in recent
2. Pharmacological profile of indole derivatives
times, no comprehensive update report on varied activities of indole
analogues along with structure–activity relationship (SAR) is available
Due to the versatile nature of indole, it had gained huge popularity
4
Fig. 1. Chemical structures of the compounds 1–11.
among the organic and medicinal chemists. A number of drug mole- targets such as histone deacetylases (HDACs), sirtuins, DNA topoi-
cules containing indole nucleus are found to be involved in the treat- somerase etc [66].
ment of various disease conditions as anticancer, antimalarial, anti- Thiazolidinediones are responsible for the activation of peroxisomes
tubercular, anti-HIV agent etc. proliferator-activated receptor-γ (PPARγ) affecting the apoptosis, cell
cycle and differentiation [73,74]. Based on this fact, Corigliano 2018,
designed and synthesized various 2, 4-thiazolidinedione substituted
2.1. Anticancer activity
indole derivatives. All the synthesized compounds were further eval-
uated against two cell line MCF-7 (human breast cancer cells) and PC3
Cancer is a life-threatening disease characterized by uncontrolled
(human prostate cancer cells). SAR study concluded that methoxy at
growth and spread of abnormal cells. According to the data of 2018,
5th position is most favorable for the activity. Compound 22
609,640 cancer deaths occur in the United States and According to
(IC50 = 5 µM) was found to be the highly potent [75].
statistics of 2006–2015 death rate declined by 1.5% in both men and
Ustundag et al, 2016, mentioned the synthesis and evaluation of
women [72]. Hence, it is required to develop novel indole derivatives
hydrazide-hydrazone, thiazolidinones derivatives of indole. SAR study
having a different mechanism of action. Various indole derivatives are
highlighted the role of methyl substitution. Compound 23
designed as an anticancer agent in recent years that act via various
5
Fig. 2. Chemical structures of the compounds 12–21.
(GI50 = 0.13–24 µM) has notable anticancer activity as compared with of indole and evaluated on K562 (erythroleukemia) and Colo-38 (mel-
standard drug 5-fluorouracil (GI50 = 0.01–79.4 µM) [76]. In 2019, anoma) cell lines. SAR studies confirmed the importance of phenol and
Demurtas and colleagues designed, synthesized hydrazone derivatives naphthol substitution. Compounds 24 (IC50 < 0.63 ± 0.05 µM) and
Fig. 3. Pharmacological signifance of indole nucleus.
6
Fig. 4. Chemical structures for indole derivatives having anticancer activity 22–35 with active pharmacophores.
25 (IC50 < 0.83 ± 0.09 µM) were found to be highly potent [77]. oxindole hybrid derivatives. Compound 28 (Fig. 4) was highly active
Parkash et al, 2018, synthesized substituted heteroannulated indole (IC50 < 5500 µM) on HL-60 cells which may be due to more interac-
derivatives and evaluated for their cervical anticancer activity. It was tions with cellular nucleophiles as compared with the standard drug
observed that electron withdrawing groups were more favorable at the [80].
C-8 position and have good interaction with the target receptor due to Microtubules are one the vital component in cell cytoskeleton par-
Van der Waal's and hydrogen bond interaction indicated by docking ticipating in mitosis, cell signalling and intracellular transport [81].
study. Compounds 26a (Fig. 4) and 26b (Fig. 4) show excellent potency Chalcone scaffold was found to be a potent microtubule inhibitor [82].
(IC50 = 13.41 µM) and (IC50 = 14.67 µM) respectively, and is close to Based on this fact, Mirzai et al, designed novel indole-based chalconoid
the activity of standard drug cisplatin (IC50 = 13.20) [78]. Bis indoles derivatives as tubulin-targeting antiproliferative agents. The com-
were synthesized and evaluated against hepatocarcinoma cells by Tocco pound, 29 (Fig. 4) (IC50 = 4.3 µg/mL) shows good potency particularly
et al, compound 27 (IC50 = 20–100 µM) was found to be more active against A549 cell compared to standard etoposide (IC50 = 7.8 µg/mL)
than standard drug indole 3-carbinol [79]. In the same year, Romagnoli and docking studies proved that it shows best binding to colchicines
and coworkers synthesized and screened a series of 3-substituted-2- binding site [83]. In another study, thiazolidine and imidazolidine rings
7
were condensed with indole moiety to obtain potent anticancer drugs. evaluated against MCF-7. SAR studies concluded that acid and aldehyde
Compound 30 (Fig. 4) exhibited significant anticancer activity on substitution on the indole and the halogen atom on coumarin ring at-
breast cancer cell lines (T47D), with IC50 value (1.93 μM), lower than tached with indole leads to an increase in activity. The compound 41
the positive control, doxorubicin (4.61 μM). The study showed that the (IC50 = 7.4 µM) (Fig. 5) showed the best results in cytotoxicity and
indole nucleus helped with the integration of molecules into the DNA docking studies, compared to standard drug vincristine
resulting in cell death [84]. Similarly, Zhou et al, studied the molecular (IC50 < 0.3 µM). Bromo group substitution was found to be favorable
hybridization of two potent molecules to synthesize various hexahy- in forming halogen bond in the docking studies [95]. Various pyrano-
dropyrrolo [2, 3-b] indole imidazolium derivatives. The compound 31 chalcone derivatives of indole were synthesized and evaluated against
(IC50 < 2.68 µg/mL) (Fig. 4) was found as most selective and potent HepG2 cancer cell line. SAR studies concluded the key role propionyl
against all the five cell lines as compared to the standard drug cisplatin substituents for the inhibitory activity. Compound 42
(IC50 = 10.45 µg/mL) [85]. (IC50 = 0.22 ± 0.03 µM) (Fig. 5) was found to be highly potent as
Chang et al, 2016, synthesized and evaluated novel series of bis- compared with the standard drug colchicine (IC50 = 2.5 µM) (Fig. 5)
(hydroxymethyl) indolizino [8,7-b] indole hybrids as anti-small cell and paclitaxel (IC50 = 2.5 µM) [96]. In the same year, Kumar and the
lung cancer agents. Hybridization of two nuclei leads to the inhibition coworkers mentioned the synthesis of chalcone substituted indole de-
of tumor cell growth via two mechanisms i.e. topoisomerase II inhibi- rivatives having the property of enhancing tubulin polymerization. SAR
tion and induction of DNA cross-linking. Compound 32 demonstrated study concluded the role of methoxy and fluoro group for the activity.
highest potency (IC50 = 0.49 µM) (Fig. 4) against the growth of SCLC Compound 43 (Fig. 5) exhibited significant potency (IC50 = 0.8 µM) as
(small cell lung cancer) H526 cells in xenograft model against cisplatin compared with the standard drug (IC50 = 0.45 µM) and selective
(IC50 = 0.63 µM) [86]. against A549 lung cancer cell line [97]. Indole-thiazolylcoumarin
Bakherad et al., also study the anticancer activity. Various thiose- analogues were synthesized and evaluated against a panel of human
micarbazone derivatives of indole were synthesized and evaluated tumor cell lines. SAR study demonstrated the role of unsubstituted
against MCF-7 (breast cancer), A-549 (lung cancer), Hep-G2 (liver thiazolylcoumarins as anticancer agents. Compounds 44 (GI
cancer) cell lines. SAR study concluded that methyl and methoxy 50 = 1.18–2.44 µM) (Fig. 5) were reported as the most active compound
phenyl substitution is favorable for the activity. Compound 33 of the series as compared with the standard drug [98]. Various sulfo-
was found to be potent against A-549 (IC50 = 12.5 µM), Hep-G2 namide derivatives of mono-indole, bis-indole, tris-indole were syn-
(IC50 = 56 ± 6.30 µM) (Fig. 4) cell lines as compared with standard thesized and evaluated against various cancer cell lines HuCCA-1,
drugs etoposide (A-549 = IC50 = 38.23 ± 1.89 µM and Hep- HepG2, A549, MOLT-3. SAR study concluded the significance of chloro
G2 = IC50 = 33.17 ± 3.19 µM) and colchicines (A-549 = IC50 substitution. Among all the synthesized compounds, 45 (IC
= 1.9 ± 0.23 µM and Hep-G2 = IC50 = 6 ± 0.49 µM) [87]. 50 < 8.74 ± 0.79 µM) (Fig. 5) was found to be most active as com-
Similarly, El-Sharief and co-workers prepared and studied isoindole pared with standard drugs etoposide (IC50 < 30.92 ± 5.35 µM) and
derivatives on three cancer cell lines. SAR study concluded that phe- doxorubicin (IC50 < 1.01 ± 0.13 µM) [99].
nylacetamide and malononitrile substitution is favorable for the ac-
tivity. Among all the synthesized compounds, 34 (IC50 < 6.67 2.2. Anticonvulsant activity
± 0.36 µM) and 35 (IC50 = 6.34 ± 0.21 µM) (Fig. 4) were found to be
highly potent as compared with standard drugs isatin (IC50 < Convulsion is a central nervous system (CNS) disorder due to par-
41.83 ± 0.67 µM) and doxorubicin (IC50 < 7.03 ± 0.21 µM) [88]. oxysmal cerebral dysrhythmia with brief episodes of seizures and /or
In the same year, Jiang and coworkers synthesized various indole loss of consciousness. Approximately 50 million people worldwide have
derivatives and evaluated against Hela, A-549, ECA-109 cell lines. epilepsy, making it one of the most common neurological diseases
Compounds 36a (IC50 < 16.65 µM) and 36b (IC50 < 14.74 µM) globally [100]. Researchers have synthesized and evaluated various
(Fig. 5) were found have more potency compared to the standard drug indole derivatives as anticonvulsant agents [101].
cisplatin ((IC50 < 30.89 µM) [89]. Halogen substitution is found to be Swathi and Saragapani in 2017 designed, synthesized and evaluated
favorable for the activity. Similarly, Yan et al, reported indole-chalcone dialkylaminoalkoxy-oxindole derivatives. SAR studies suggested that
derivatives and evaluated both by in vivo and in vitro activity. Com- semicarbazone substitution at the 3rd position of indole and alkyl
pound 37 (IC50 < 0.009 µM) (Fig. 5) was highly potent as compared substitution at the nitrogen atom present in the side chain of the indole
with the standard drug (IC50 < 0.013 µM) [90]. were favorable for the activity. Compounds, 46 (67.18 ± 0.23) (Fig. 6)
Rosuvastatins and other HMG-CoA reductase inhibitors have at- was found to be highly potent as compared with standard drug phe-
tracted enormous interest as potential anticancer agents [91]. Based on nytoin (1 0 0) [102]. The literature survey suggested that benzohy-
this fact, Kumar et al, 2016 reported various rosuvastatin based indole drazide moiety exhibits a significant anticonvulsant activity by binding
derivatives and evaluated for anticancer activities against A549, TZM- to GABA receptors [103]. This idea leads to the synthesis of benzohy-
BL cell lines. The presence of phenyl sulphonyl and fluoro substitution drazide-oxindole derivatives by Madhira et al, in 2017 [104]. Methyl
was vital for modulating cytotoxic activity. Among all the compounds, and propyl substitution at the indole ring were favorable for the ac-
38 (IC50 < 12 µM) (Fig. 5) was found to be an active compound as tivity. Compound, 47 (% protection = 83.19%) (Fig. 6) exhibited sig-
compared with standard drug gemcitabine [92]. Hu et al, 2016 devel- nificant anticonvulsant activity as compared to standard drug pheny-
oped and evaluated various novel 2, 5-disubstituted indole derivatives toin (% protection = 100%) [69]. Raju and coworkers synthesized and
as anticancer agents. SAR studies concluded that alkyl substituted conducted anticonvulsant activity of novel indole carboxylate deriva-
phenyl is favorable for the activity. Among all the compounds, 39 tives by MES method. SAR studies concluded that phenyl and piper-
(IC50 < 8.70 ± 0.11 µg/mL) (Fig. 5) was found to be an most effective azine substitution at the indole were responsible for the favorable ac-
compound as compared with the standard drug cisplatin tivity. The compound, 48 (108.3 ± 0.7) (Fig. 6) was found to be the
(IC50 < 6.10 ± 0.09 µg/mL) [93]. Various bis-indole derivatives have most effective as compared with standard drug phenytoin (100%)
been synthesized and evaluated against Hela, Colo-205, Hep G2 cell [105].
lines. Compounds 40a (IC50 < 43.1 µg/mL) (Fig. 5) and 40b A huge data suggested the pyrazole has potent anticonvulsant
(IC50 < 64 µg/mL) (Fig. 5) were found to be more active as compared properties [106–108]. This suggested the idea for Patil and Bari to
with standard drug curcumin (IC50 < 36.65 µg/mL). The activity was synthesize some novel indole derivatives having pyrazole moiety. SAR
increased by introducing 5‑bromo substituent [94]. Similarly, Kamath studies revealed that the electron withdrawing group at the phenyl ring
et al, combined the indole and coumarin moieties to synthesize indole- of indole is effective for the activity. The compound, 49a
coumarin derivatives. All the synthesized compounds were further (116.3 ± 1.54 s) (Fig. 6) and 49b (109.8 ± 2.86 s) (Fig. 6) were found
8
Fig. 5. Chemical structures for indole derivatives having anticancer activity 36–45 with active pharmacophores.
to be most effective as compared with standard drug diazepam highly potent due to the presence of amide linkage [111]. In the same
(128. ± 2.33) [109]. In 2015, Zhen and coworkers designed acetamide year, Ahuja and Siddiqui, synthesized and evaluated indole-1, 2, 4-
derivatives of oxindole. SAR studies concluded the role of halogen triazine derivatives and screened against maximal electroshock (MES)
substituent for the activity. 50a and 50b were found to be highly active test and subcutaneous pentylenetetrazole (scPTZ). Electron with-
(seizure test < 2/3) on comparing with standard drug carbamazepine drawing groups such as trifluoromethyl and chloro were more effective
(seizure test = 3/3) [110]. Indole-hydrazide derivatives were synthe- in modulating anticonvulsant activity as compared to electron donating
sized as new dual binding site cholinesterase inhibitors involving in groups i.e. thiomethyl and methoxy. On the other hand, sulfonamide
vitro and docking studies. Most of the tested compounds were found to derivatives of indole-containing halogens, CF3 showed good activity as
be actively involved in the inhibition of acetylcholinesterase and bu- compared to OCH3 and SCH3. Among the carboxamide derivatives,
tyrylcholinesterase. SAR study suggested that aryl and aryl halide compound 53 (% protection = 100%) (Fig. 6) exhibited maximum
substitution on indole enhances the activity. Compound 51 (Fig. 6) potency which studied to be due to the presence of nitro group which
(IC50 = 91.21 ± 0.06 µM) and compound 52 (Fig. 6) helps in the binding with receptor [112].
(IC50 = 68.52 ± 0.04 µM) exhibited promising acetylcholinesterase Imidazole-indole derivatives were synthesized and evaluated
inhibitory activity as compared with standard drug eserine against two seizure models viz MES (maximal electroshock seizure) and
(IC50 < 0.85 ± 0.0001). Additionally, the activity of compound 52 scPTZ (subcutaneous pentylenetetrazole. SAR studies suggest that
(Fig. 6) was also found to be due to two point attachment with acet- substitution at the N1 of imidazole substituted at the 3rd position of
ylcholinesterase. In the case of butyrylcholinesterase, 51 (Fig. 6) was indole has marked role in enhancing anticonvulsant activity. To get
9
Fig. 6. Chemical structures for indole derivatives having anticonvulsant activity 46–55 with active pharmacophores.
potential anticonvulsant agents, these derivatives can be further tai- that further amplified with an increase in antimicrobial resistance
lored. Compounds 54a and 54b (Fig. 6) were found to be highly potent [115]. The WHO's latest survey reveals that among patients suffering
in MES [113]. A series of indole derivatives were synthesized by Kumar from bacterial infection, 500,000 people are antibiotic resistant across
et al, and conducted in vivo study for anticonvulsant activity and acute 22 countries [116]. To combat the problem of antimicrobial resistance
toxicity studies. All the synthesized compounds were screened against new indole derivatives targeting microorganism through different me-
maximal electroshock-induced seizure. SAR studies concluded that 1. chanism should be developed. Various indole derivatives are diagnosed
Chloro group at the 4th position of phenyl attached to indole 3-yl is and evaluated as antimicrobial agents that are discussed below.
favorable for the anticonvulsant activity. 2. Presence of benzothiaze- Sanna and colleagues mentioned the synthesis of indole-thiourea
pine nucleus is better as compared to the benzoxapine nucleus. 3. hybrids and evaluated against about a pool of microbes containing both
Substitution of p-chloro methylene aminophenyl group at the 4th po- Gram-positive and Gram-negative type. Compound 56
sition of benzothiazepine is good for activity. Out of the entire deri- (MIC < 12.5 µg/mL) (Fig. 7) was found to be highly potent as com-
vatives, compound 55 (Fig. 6) was found to be highly potent. Whereas, pared with standard drug ciprofloxacin (MIC < 1.0 µg/mL) [117].
other compounds were also equally potent [114]. Thiazolidine is also known for its activity as an antimicrobial agent.
Various researchers are enduring to combine thiazolidine moiety with
others to design potent antimicrobial agents [118]. These prompted,
2.3. Antimicrobial activity Abo-Ashour and coworker to design and synthesize oxindole-thiazoli-
dine conjugates. All the synthesized derivatives were evaluated against
Antimicrobial resistance has been an issue since the introduction S. aureus, P. aerugenosa, E. coli, M. tuberculosis, A. fumigates, C. albicans.
into the clinical use of the first agents in the 1940 s. To curtail the SAR study concluded that chloro and methyl substitution is favorable
development and spread of antimicrobial resistance, it requires the for the activity. Compound 57 (MIC < 0.98 µg/mL) (Fig. 7) was found
preservation of current antimicrobials through their appropriate use, as to be most active with equal potency both as antimicrobial and anti-
well as the discovery and development of new agents. A higher rate of fungal as compared with standard drug ciprofloxacin (MIC < 3.90 µg/
mortality and cost is observed in the treatment of microbial disease and
10
Fig. 7. Chemical structures of the antimicrobial indole derivatives 56–62 with active pharmacophores.
mL) and amphotericin B (MIC < 1.95 µg/mL) respectively [119]. Re- role antibacterial activity of 1,2,3,5 substituted indole derivatives and
cently, Sayed et al, 2018 synthesized and evaluated various indole evaluated against S. aureus, S. pyogenes, E. coli, P. aerugenosa. Com-
derivatives containing heterocyclic nucleus as antimicrobial agents. The pounds 64 (MIC = 37.5 µg/mL) (Fig. 8) was found to be most active
presence of thiophene and imidazole rings enhances the antimicrobial [128]. Choppara et al, 2015 have designed and synthesized bis-indole
activity of synthesized compounds. It was observed that compound 58 derivatives and evaluated against B. subtilis, E. coli, K. pneumonia, P.
(MIC < 8 µg/mL) (Fig. 7) showed high antibacterial activity, whereas aerugenosa. SAR study concluded the role of prenyl system for the ac-
compounds 59 (MIC < 6 µg/mL) (Fig. 7) showed high antifungal activity. Compound 65a (Fig. 8) (zone of inhibition < 24 mm), 65b
tivity [120]. Various 5-hydroxy-indole derivatives were synthesized (Fig. 8) (zone of inhibition < 21 mm) and 65c (Fig. 8) (zone of in-
and evaluated against C. albicans, A. niger, E. coli, B. cirroflagellosus. hibition < 20 mm) were found to be the most active as compared with
Compounds 60 (zone of inhibiton = 28 mm) (Fig. 7) showed maximum standard drug ciprofloxacin (zone of inhibition < 27 mm)[94]. Gali
potency as compared with standard drug griseofulvin (zone of in- and coworkers, mentioned the synthesis of thiazolylcoumarins sub-
hibiton = 30 mm) [121]. Mane et al, 2016 synthesized and evaluated stituted indole derivatives and further evaluated against B. subtilis, E.
various indole-2-carboxamide derivatives on the basis of research that coli. SAR highlighted that the presence of unsubstituted thiazolylcou-
various ester and amide derivatives of indole-2-carboxylic acid as found marins was favorable for the activity. Compound 66 (zone of inhibi-
to be potent antioxidant and antimicrobial properties. All the synthe- tion < 18 mm) was found to be highly potent as compared to standard
sized compounds were evaluated against K. pneumonia, E. coli, P. aer- drug streptomycin (zone of inhibition < 30 mm)[98].
uginosa, S. typhi, C. albicans, C. neoformans, A. fumigates, C. parapsilosis. Hydrazone is another moiety having immense antimicrobial activity
SAR studies suggested that the alkyl and halogen substituted phenyl due to inhibition of microbial cell wall synthesis described in a large
and cyclohexylcarboxamide derivatives are favorable for the activity. literature data [129,130]. Based on this, Shirinzadeh et al, synthesized
Compound 61 (MIC < 6.25 µg/mL) (Fig. 7) exhibited maximum anti- and evaluated various indole-hydrazone derivatives to cope with the
microbial activity compared with standard drug gentamicin (MIC < problem of multidrug-resistant bacterias. SAR studies suggested that
3.0 µg/mL) [122]. activity increased with the introduction of halogen atoms into the
It is found that pyrazole and imidazole have the broad spectrum of phenyl ring especially at the ortho position. 67a (3,5-difluoro)
antimicrobial activity which may be due to the presence of nitrogen (MIC < 100 µg/mL) (Fig. 8), 67b (MIC < 50 µg/mL) (3,5-dichloro)
atom in five-membered rings which act by inhibiting cell wall synthesis (Fig. 8), showed the highest activity when compared to standard drugs
or DNA damage [123–125]. The antimicrobial activity of these het- sultamicillin (MIC < 25 µg/mL), ampicillin (MIC < 50 µg/mL), flu-
erocyclics attracted various scientists to attach pyrazole and imidazole conazole (MIC < 0.78 µg/mL) and ciprofloxacin (MIC < 0.19 µg/mL)
rings with the indole nucleus to prevent the problem of microbial re- [131]. Nassar et al, also reported the synthesis of pyrazoline, pyridine,
sistance. In 2017, Quazi and coworkers, synthesized and evaluated pyrimidine substituted indole derivatives as antimicrobial agents. All
various indole-pyrazole derivatives. Among all the compounds, 62a the synthesized compounds were evaluated against S. aureus, E. coli,
(zone of inhibition < 0.5 cm) (Fig. 7) showed good activity against P.aerugenosa, Fusarium A. niger, C. albicans. SAR study indicated the role
gram-positive bacteria and compounds 62b (zone of inhibition < of methoxyphenyl substitution. Compound 68 (Fig. 8) (zone of inhibi-
0.1 cm) (Fig. 7), has good activity against fungal strain Macrophomina tion < 34 mm) exhibited promising antibacterial activity when com-
phaseolina and Sclerotium rolfsii [126]. A series of imidazole-based in- pared to standard drug ciprofloxacin (zone of inhibition < 44 mm) and
dole derivatives were synthesized and assayed against bacterial strains nystin (zone of inhibition < 44 mm) [132].
S. aureus, S. pyogenes, Shigella flexneri, Proteus mirabilis, Vibrio cholera Recently, indole subunits have gained wide-spread concern due to
and also on fungal strains Candida albicans, C. glubrate and C. crusei. The their remarkable role as antifungal agents. In this perspective, Zhang
antibacterial activity trend of synthesized compounds were found to be et al., have done noticeable work in the area of antifungal drug de-
60 > 61 > 62 > 63. Apart from this, density functional theory, velopment. In 2012, analogues of pimpirinine, an indole alkaloid ob-
computational method, X-ray crystallographic analysis and molecular tained from streptomyces species, were synthesized and bioassay was
docking study were also performed. Compound 63 (MIC < 12.5 µg/ conducted on Pythium dissimile, Alternaria solani, Botyyotinia fuckeliana
mL) (Fig. 8) showed good chemical stability, reactivity and bond and Gibberella zeae by Zhang and coworkers. SAR study concluded that
parameters due to the presence of negative charges on oxygen and ni- bromo and acetyl chloride substitutions were favorable for the activity.
trogen atoms when compared with methicillin standard drug (MIC < Among all 69a and 69b was found to be highly potent (Fig. 8) [133].
6.25 µg/mL) (Fig. 8) [127]. In the same year, Yadav 2016, reported the Further, the same researchers in 2013, synthesized and studied the
11
Fig. 8. Chemical structures of the antimicrobial indole derivatives 63–72 with active pharmacophores.
oxadiazole derivatives of indole. All the synthesized compounds were 2.4. Antitubercular activity
evaluated against Pythium dissimile, Septoria tritici and Uromyces viciae-
fabae and also compared with pimpirine alkaloid as already reported in Tuberculosis is caused due to the infection spread by Mycobacterium
the previous article. SAR study concluded that halogen substitution is tuberculosis affecting lungs as well as other parts of the body [138].
favorable for the activity. Compounds 70a and 70b (Fig. 8) were found According to the 2016 data, among 10 million cases of TB, 1.3 million
to be potent [134]. Motivated by the promising results, this study was were died [139]. Tuberculosis is considered the most life-threatening
further extended with streptochlorin, an indole alkaloid obtained from disease that causes about 100 million deaths worldwide [140]. About
marine actinomycetes. Synthesized streptochlorin analogues were 9093 cases of tuberculosis were identified in the United States having a
evaluated against Pythium dissimile, Alternaria solani, Uromyces viciae- rate of 2.8 over 100,000 which is decreased by 1.8% from 2016 to 2017
fabae, Gibberella zeae, Alternaria solani, Phytophthora infestans, Zymo- [141]. A number of indole derivatives are mentioned here having ad-
septoria tritici and A. Solani. The introduction of chloro and bromo vanced antitubercular activity.
substitution at the 4th position of oxazole ring increases the activity. In 2018, Abo-Ashour with colleagues synthesized and evaluated
Compounds 71a and 71b (Fig. 8) were found to be highly potent various oxindole-thiazolidine conjugates active against M. tuberculosis
analogs showing 81–100% control of disease [135]. Similarly, novel bacterial strain RCMB 010126. The methoxy, ethoxy, alkyl groups were
derivatives of streptochlorin were synthesized with more active het- found to be favorable for the activity. Compounds 73a (Fig. 9)
erocycles having improved antifungal activity. All analogues were (MIC = 0.39 µg/mL) and 73b (Fig. 9) (MIC = 0.39 µg/mL) were more
studied against Pythium dissimile, Alternaria solani, Uromyces viciae- and equally potent compared to standard drug isoniazid
fabae, Gibberella zeae, Alternaria solani, Phytophthora infestans, Zymo- (MIC = 0.78 µg/mL) [119]. Various indole derivatives were synthe-
septoria tritici. SAR study marked the importance of indole moiety in sized using Knoevenagel and Michael reaction mechanism and in vitro
streptochlorin [136]. Due to the high potency of streptochlorin as an- study was conducted to evaluate the antitubercular activity against M.
tibiotic, extensive study on the derivatization of streptochlorin is also tuberculosis bacterial strain (MTCC CODE 300). Docking study was also
conducted by other researchers. Recently, Jia et al., 2018 also con- performed to further detect the affinity between the synthesized com-
ducted the study on streptochlorin, natural antifungal constituents ex- pound and enoyl-acyl carrier protein reductase using AutoDock-Vina
tracted from marine streptomyces species. Evaluation of analogues was software (Los Angeles, USA) [142]. SAR studies concluded that chloro
conducted on Pythium dissimile, Alternaria solani, Gibberella zeae, Botrytis and nitro substituent at the para and ortho positions of phenyl ring were
cinerea, Rhizoctorzia solani, Alternaria blotch and Collecterichum capsica. favorable for the activity. Compound, 74 (Fig. 9) has
Chloro and bromo substitution were favorable for the activity. Com- comparable activity (MIC = 40 µg/mL) to standard drug isoniazid
pounds 72a and 72b were found to be highly potent (Fig. 8) [137]. (MIC = 10 µg/mL) and also good binding affinity (-11.6) with target
12
Fig. 9. Chemical structures for indole derivatives having antitubercular activity 73–81 with active pharmacophores.
protein [143]. Grid–Based Ligand Docking [148]. Compounds 77a (Fig. 9) and 77b
Based on an enormous data of piperazine as antitubercular agents (Fig. 9) exhibited maximum docking in the active site of mycobacterial
[144,145], Naidu and coworkers, 2016 reported various indole-piper- enoyl reductase (InhA) [51]. Khan et al, 2016 have synthesized novel 3-
azine derivatives and evaluated against Mycobacterium tuberculosis, alkylated indole derivatives using mpCuO as a heterogeneous catalyst
bacterial strain H37Rv, Spec. 210, Spec. 192. The introduction of having high catalytic efficiency, maximum surface area and recycl-
electron withdrawing groups such as Br, CF3 leads to increase in anti- ability. Among all the synthesized compounds, 78 (Fig. 9)
tubercular activity. Compounds, 75 (MIC = 6.16 µM) (Fig. 9) was (MIC = 15 µg/mL) containing p-methoxy phenyl derivative at the 3rd
showed the highly potent antitubercular activity compared to standard position of indole exhibited significant antitubercular activity against
drug isonicotinic acid hydrazide (MIC = 91.14 µM) [146]. In the same M. tuberculosis bacterial strain (MTCC CODE 300) in comparison to the
year, Stec J, et al, designed, synthesized various indole-carboxamide isoniazid taken as a standard drug (MIC = 10 µg/mL). Docking studies
derivatives targeting MmpL3 protein and were further evaluated for were also conducted using enoyl-acyl carrier protein reductase and the
antitubercular activity by conducting in vivo and in vitro studies. Lipo- binding score was calculated for each derivative. Among all the syn-
philic compounds exhibited higher activity compared to hydrophilic thesized derivatives, 78 (Fig. 9) showed maximum binding score [149].
derivatives. The compound, 76 (Fig. 9) was found to have excellent Various organic moieties containing a hetero atom, the double bond
activity (MIC = 0.012 µM) against multidrug-resistant and extensively between carbon and nitrogen, are found to be a potent inhibitor of DNA
drug-resistant M. tuberculosis strains. Apart from this, docking studies gyrase enzyme causing the bacterial death.
were also conducted showing the maximum binding of 76 Hydrazone and thiazolidinones falling under this category are found
(MIC = 0.29 µM) (Fig. 9) with MmpL3 protein [147]. Some novel in- to be potent antitubercular agents [150–152]. Because of this, Ustundag
dole and pyridine based 1, 3, 4-oxadiazole derivatives having anti- et al, 2016 investigated and designed indole-based hydrazide-hy-
tubercular activity was reported. The in vitro studies were conducted to drazone, 4-thiazolidinones derivatives and screened for in vitro anti-
evaluate the antitubercular activity against M. tuberculosis H37Ra and tubercular activity against M. tuberculosis H37Rv. SAR studies con-
M. bovis BCG. However, the antiproliferative activities of synthesized cluded that substitutions on the phenyl ring have a major impact on the
derivatives were also evaluated using three cell lines- HeLa, A549 and activity. Substitution of F, CN, NO2, CF3 and COOCH3 at the para po-
PANC-1. According to SAR, the substitution pattern at the phenyl ring sition were favorable for the activity. Compound, 79a (MIC = 12.5 µg/
of chalcone significantly modulates the activity. At the 2nd positions of mL) (Fig. 9) and 79b (MIC = 12.5 µg/mL). (Fig. 9), 79c (MIC = 25 µg/
the phenyl ring, –OH and –NO2 functional group are favorable for the mL) (Fig. 9) demonstrated notable anti-TB activity ranging from 6.25 to
activity. Compound, 77a (Fig. 9) and 77b (Fig. 9) were recognized as 25 mg/mL compared to rifampicin as standard drug (MIC = 25 µg/mL).
the most active compounds with MIC ranging from 0.94 to 5.17 µg/mL However, anticancer activity is also evaluated using the colon cancer
compared to isoniazid (MIC = 0.037 µg/mL) and rifampicin cell line COLO 205 [76]. Various indole-2-carboxamide derivatives
(MIC = 0.017 µg/mL). Docking studies were also conducted using were also reported. SAR studies revealed that -Cl, -F, –CN substituents
13
at the 4th and 6th position of indole and methyl substitution on phenyl investigated various melatonin based indole derivatives. The synthe-
ring attached with indole leads to increase in potency. All the synthesized derivatives have an inhibitory effect on the cell cycle of P. falci-
sized derivatives were tested against M. tuberculosis H37Rv strain. The parum. The in vitro studies were conducted in P. falciparum culture and
compound, 80a (MIC50 = 0.15 µM) (Fig. 9) and 80b (MIC50 flow cytometer was used for activity calculation. SAR studies explained
= 0.23 µM) (Fig. 9) were found to be highly potent as compared to the that carboxamide at the C-3 position of indole was decisive
standard drug isoniazid (MIC50 = 0.33 µM) [153]. Later in 2014, Teh- for the activity. Compounds 84a (IC50 = 19.17 µM) and 84b
rania and colleagues, synthesized and evaluated various Schiff' base (IC50 = 19.10 µM), 84c (IC50 = 2.93 µM) (Fig. 10) exhibited maximum
based indole derivatives. All the synthesized compounds are further antimalarial activity. Alkyl and aryl substitution with carboxamide at
evaluated using a microtiter plate on gram positive and gram negative the C-3 and methoxy group at the C-5 gave maximum potency [158].
strain. SAR studies concluded that urea-based derivatives were highly Among the entire major heterocyclic nucleus, quinoline derivatives are
potent. Compounds 81 (MIC = 3.91 µg/mL) (Fig. 9) exhibited max- the well known antimalarial agents acting through the inhibition of
imum potency as compared with standard drug ethambutol DNA synthesis of microorganism [159,160]. It could be a wonderful
((MIC = 0.75 µg/mL) [154]. idea to combine this moiety with indole. This prompted Teguh et al, to
synthesize various quinoline-indole conjugates and tested against P.
2.5. Antimalarial activity falciparum using K1 strain. SAR studies concluded that the amino group
and alkyl-substituted amino group were favorable for the activity.
Malaria is an infectious disease caused by Plasmodium parasite. Compound 85 (IC50 < 0.4 ± 0.2 µg/mL) (Fig. 10) demonstrated pro-
Malaria is a chronic disease that leads to thousands of deaths annually mising antimalarial activity [161].
[155]. According to the 2016 data, among the 216 million reported Meridianin G, is an indole alkaloid obtained from marine in-
cases of malaria, 731,000 died worldwide. Maximum cases were ap- vertebrate Aplidium meridianum. It is found to be the inhibitor of cyclin-
peared in Africa [156]. It is required to develop antimalarial drugs at a dependent protein kinase, involved in the progression of malaria. Based
fast rate to combat this problem. A few of indole derivatives as anti- on this fact, Bharate et al, reported various meridianin G-based indole
malarial agents are discussed below. derivatives and evaluated against chloroquine sensitive and resistant
Yadav et al, 2016 synthesized and evaluated various novel indole clones of P. falciparum through plasmodial LDH (lactate dehydrogenase)
derivatives and evaluated against P. falciparum. SAR studies explained activity. Compound, 86 (IC50 < 4.01 µM) (Fig. 10) was found to be
that alkyl substitution with carboxylate at 1st and 2nd position and aryl most effective as compared with standard drug artemisin
at the 3rd position of indole were favorable for the activity. Compounds (IC50 < < 0.09 µM) and chloroquine (IC50 < 0.72 µM) [162].
82a and 82b (Fig. 10) showed high potency, having MIC value
not > 0.70 µg/mL on comparing to the standard drugs quinine 2.6. Antidiabetic activity
(MIC = 0.270 µg/mL) and chloroquine (MIC = 0.02 µg/mL) [128].
Various indole-based piperidine derivatives were synthesized and in Diabetes mellitus is identified by a high blood sugar level over a
vitro studies were conducted in P. falciparum culture and activity was long period of time. Diabetes is linked with the high rate of mortality
measured in terms of EC50. Lipophilicity was also calculated in terms of causes renal and eye problems [163]. The global prevalence (age-
the partition coefficient (clogP), to further access the activity of syn- standardized) of diabetes has nearly doubled since 1980, rising from
thesized derivatives. Piperidinyl moiety was found to be critical for the 4.7% to 8.5% in the adult population. According to the 2014 data, 422
activity. Compound 83 (Fig. 10) was obtained having selectivity for million adult's cases of diabetes were obtained [164]. Novel anti-
malaria parasites, no drug resistance and better activity (EC50 ∼ 3 µM, diabetic drugs are required to tackle this problem. Large pools of indole
cLogP = 2.42 and MW = 305) as compared to most of the standard derivatives are available in the literature with antidiabetic activity.
drugs chloroquine, atovaquone, amodiaquine, artesunate with EC50 Derivatives of some nitrogen-containing heterocyclic nuclei are iden-
value 285 ± 58 µM, 0.35 ± 0.14 µM, 12.30 ± 4.21 µM, tified as antidiabetic agents. Oxadiazole derivatives manage the type-II
1.97 ± 0.43 µM respectively [157]. diabetes mellitus condition through α-glucosidase inhibitory activity
Melatonin is an indole-derived hormone secreted by the pineal [165]. Another nucleus, triazole showed antiadipogenic and anti-
gland. It is involved in various signalling pathways involving the dyslipidemic activity through Wnt3a/β-catenin pathway [166].
Plasmodium cell cycle and major role in the replication of Plasmodium. Prompted by these facts, Rajan et al, synthesized and evaluated novel
Inhibition of this hormone can be used to inhibit the growth of indole-triazole derivatives. All the synthesized compounds were eval-
Plasmodium. Keeping this in mind, Schuck and coworkers have uated by the Syrian Golden Hamster model. SAR studies concluded that
Fig. 10. Chemical structures for indole derivatives having antimalarial activity 82–86 with active pharmacophores.
14
Fig. 11. Chemical structures for indole derivatives having antidiabetic activity 87–92 with active pharmacophores.
difluoro and tosyl substitution is favorable for the activity. Compound groups gave only moderate activity. Compound, 92 (Fig. 11) was found
87 (Fig. 11) was found to be the highly potent [167]. Similarly, various to have an excellent inhibitory effect (95%) that is more than standard
indole-oxadiazole hybrids were synthesized by Nazir and coworkers drug BMS309403 (85.13%) and also it was observed that oral admin-
and tested as α-glucosidase enzyme inhibitory activity. SAR study istration of compound 92 (Fig. 11) significantly reduce the levels of
concluded that 2,3 and 2,4‑dimethyl substituted phenyl were favorable plasma blood glucose, triglycerides, total cholesterol in diabetic in-
derivatives. Compounds 88a (IC50 = 9.46 ± 0.03 µM) (Fig. 11) and duced model. Docking studies were also conducted with fatty acid
88b (IC50 = 9.37 ± 0.03 µM) (Fig. 11) were found to be highly potent binding protein 4 (A-FABP) which proved that of compound 92
as compared with the standard drug acarbose (IC50 = (Fig. 11) has a good binding affinity for the protein having Ki value
37.38 ± 0.12 µM) [168]. 33Nm [172].
Srividya and Reddy, 2017 designed, synthesized and evaluated in-
dole derivatives as antidiabetic agents. In vivo study was conducted on 2.7. Antiviral activity
diabetes-induced chick model to evaluate all the derivatives. The test
compound 89 (Fig. 11) was found to have a good reduction potential of A viral infection is spread by pathogenic viruses and infectious virus
sugar level (29.6–38.6%) on comparing with the standard drug glib- particles when entering inside the body. Various antiviral drugs are
enclamide (57.10%) [169]. Combining oxadiazole with indole was available in the market against HIV, Herpes viruses, hepatitis B and C
carried out in 2017, by Taha and coworkers in which oxadiazole ring viruses. Among all the infections, viral is the fastest spreading, creating
was attached to indole to obtain a series of tris indole-oxadiazole hybrid about 60% illness in Developed countries [173]. Due to the fast re-
analogues. Synthesized derivatives showed their antidiabetic effect plication rate, it is required to design safe and efficacious antiviral
through the inhibition of α-glucosidase. Chloro substitution at R5 leads drugs. Researchers are working to design novel antiviral drugs with a
to highly potent compounds as seen in compound 90 wide range of activities [65].
(IC50 = 2.00 ± 0.001 mM) (Fig. 11) compared to standard acarbose Scuotto et al, 2016 designed a series of novel multi-target indole-3-
(IC50 = 895.09 ± 2.04 mM) (Fig. 11). High activity may be due to the carboxylate derivatives as antiviral agents. All the synthesized com-
maximum binding affinity of the chloro group to the active site of an pounds were evaluated against Chikungunya virus in Vero cell culture
enzyme. The molecular docking studies were also performed with the by a CPE reduction assay. SAR studies suggested that the hydroxyl
binding site of α-glucosidase and binding affinity is measured from the group at the 5th position is found to be most favorable. Compounds, 93
QPLogPo/w (partition coefficient), QPLogS (predicted aqueous solubi- (Fig. 12) was found to be most active (EC 50 = 6.5 ± 1) which is 10
lity), QP Pcaco (cell permeability), and Glide Score. All the synthesized fold more as compared to the standard drug arbidol. Further docking
derivatives were in the range and form hydrogen bonds with catalytic studies were also performed by using the crystal structure of CHIKV
residue. Compound 90 (Fig. 11) was completely fit into the whole glycoprotein complex. Maximum derivatives inserted into the lateral
furrow of the binding site of the protein [170]. sites of the active site whereas in compound 93 (Fig. 12) indole got
Novel indole N-glucoside derivatives were synthesized and eval- deeply inserted into the cavity and thiophenol ring occupy solvent ex-
uated on high-fat diet fed mice. SAR studies concluded that methyl and posed portions showing maximum bonding. The antiviral effect is due
halogen substitution is favorable for the activity. Compound 91 to the inhibition of an earlier viral life cycle [174].
(IC50 = 1.1 µM) (Fig. 11) was found to be highly potent [171]. A series Spiroindolines, like indole, have the property to inhibit the viral
of thiazole and indole-based derivatives were reported by Xu and protein synthesis, nucleic acid synthesis, receptor recognition. With
coworkers. In vivo study was conducted in diet-induced obese rats. All these diversified mechanisms, spiroindoline and indole combination
the synthesized compounds were evaluated for the inhibitory effect on can be the best strategy to control viral action [175]. Based on these
the production of LPS-stimulated TNF-α. A complete SAR study re- facts, Chen and other researchers, designed, synthesized and evaluated
vealed that ortho and para-substitutions on the phenyl ring at the first fused indoles and spiroindolines. All the synthesized compounds were
position showed good activity and no activity was observed at the meta further screened by in vivo and in vitro assays against Tobacco mosaic
position. Whereas, the substitution of strongly electron withdrawing virus. SAR studies concluded that in the case of fused indole derivatives,
15
Fig. 12. Chemical structures for indole derivatives having antiviral 93–107 with active pharmacophores.
phenylsulfonyl, 4-tert-butylsulphonyl, 4‑chlorophenylsulphonyl groups also reported the synthesis of amide substituted indole derivatives and
are favorable for the activity whereas C ring is crucial for the activity. In tested against human Varicella zoster virus (VZV). SAR studies con-
case of spiroindolines, electron withdrawing groups i.e., -Cl, –CN, -CF3 cluded that substitution of biphenyl ethyl moiety and acetylation at the
etc on quinolone phenyl ring were vital for activity. Derivatives 94a (% amino group of tryptamine is required for the activity against VZV.
inhibition = 48 ± 1%) and 94b (% inhibition = 56 ± 2%) (Fig. 12) Compound, 95 (CC 50 = 39 µM) (Fig. 12) was found to be highly potent
exhibited maximum potency as compared to standard drug ribavirin (% as compared with standard drug acyclovir (CC 50 = 191 µM) and biu-
inhibition = 36 ± 1%) and harmin (% inhibition = 45 ± 1%) at the vudin (CC 50 = 160 µM) [177].
concentration of 500 µg/mL [176]. Similarly, Musella and coworkers Naphthalene derivatives are also observed against a variety of viral
16
disease conditions. Inhibition of viral replication is the main me- synthesized compounds were evaluated by using HIV-1 retroviral
chanism used by these derivatives [178]. Prompted by these, Giampieri vector system. SAR studies concluded that C-1 position of propanoic
et al, in 2009 fused the indole with naphthalene nucleus to form indole- acid and amides were favorable for the activity. At the C-2 position,
naphthyl derivatives. All the synthesized derivatives were screened cyclic groups, i.e., phenyl and thiophene enhance the activity and fi-
against a variety of viruses i.e., HIV-1 (human immunodeficiency virus- nally, at the C-3 position, Cl and Br groups are favorable. Compounds
1), BVDV (bovine viral diarrhoea virus), YFV (yellow fever virus), CVB- 103a (IC50 = 0.085 µM) and 103b (IC50 = 0.065 µM) (Fig. 12) were
2 (coxsackie virus B-2 strain). Presence of carboxylate, indole and highly potent on the basis of the comparison with standard drug ne-
naphthol were found to be imperative for the antiviral activity. Com- virapine (IC50 = 0.087 µM). Docking studies were also conducted to
pound 96 (CC50 = > 57 µM, SI = < 5) (Fig. 12) was quite active further evaluate the activity using HIV non-nucleoside reverse tran-
among all the compounds and compared to the standard drugs acy- scriptase enzyme which confirmed that compound 103b (Fig. 12) well
clovir, mycophenolic acid, ribavirin, 6-azauridine (CC50 = > 100, accommodated within the active site [187].
SI = < 50) [179]. Various indole-piperazine derivatives were also synthesized and
AIDS is a very dreadful disease occurring due to the infection by screened using various molecular computational techniques, i.e., com-
human immunodeficiency virus (HIV) [180]. According to 2016 data, bined docking, molecular dynamics and 3D-QSAR study. SAR studies
36.7 million people are diagnosed with HIV worldwide in 2016 [181]. suggested that small bulky substituents were required for the activity
Thus, the advancement of anti-HIV drugs should emphasize on the fa- and also smaller substituents having balanced steric and electrostatic
vorable structural modifications and its mechanism of action. Some properties are highly desirable at 7 positions of the indole ring.
novel indole derivatives as anti-HIV agents are mentioned here. However, activity reduced in the order of primary > secondary >
In 2018 Sanna, with other researchers mentioned the synthesis of tertiary amine. Compounds, 104a (EC50 = 0.006 nM) and 104b
novel indole-thiourea hybrids and evaluated against HIV-1. SAR studies (EC50 = 0.005 nM) (Fig. 12) were found to be highly potent, having
reported the importance of 4‑bromophenyl moiety. Among all the good binding affinity with receptor [188]. In the same year, indole-7-
synthesized compounds, 97 (EC50 = 8.7 ± 0.4 µM) (Fig. 12) was found carboxamide derivatives were synthesized by Yeung and coworkers. All
to be highly potent as compared with standard drug efavirenz the synthesized compounds were evaluated by cell-based assay against
(EC50 = 0.002 ± 0.0002 µM) [117]. In 2016, Doussan with other re- a pseudotype virus expressing a JRFL envelope. SAR studies concluded
searchers, synthesized and evaluated various indole derivatives for anti- that 4‑fluoro substitution is favorable for the activity. Among all the
HIV activity. Compounds, 98 (EC50 < 0.011 µM) (Fig. 12) was found compounds, 105 (EC50 = 0.29 nM) (Fig. 12) was found to be highly
to be highly potent as compared [182]. Various indole-7-carboxamide potent [189]. Regina et al, 2012 synthesized and evaluated nitrogen-
derivatives were also reported by Ravichandran. Computational tech- containing indole 2-carboxamide derivatives. All the synthesized deri-
niques were used to screen the synthesized derivatives, thereby calcu- vatives were evaluated against mutant Y181C, Y188L, K103N, K101Q,
lated various properties to evaluate the indole-7-carboxamide analo- IRLL98 AND G190A HIV-1 strain. SAR studies concluded that pyridine-
gues i.e., physicochemical, steric, electrostatic and hydrophobic 4-yl methyl substituent is favorable for the activity. Compound 106
properties. SAR studies revealed that bulky and electronegative groups (EC50 = 2.0 ± 0.2 nM) (Fig. 12), as compared with standard drug zi-
were favorable at the 3rd position of indole-7-carboxamide groups dovudine (EC50 = 2.0 ± 0.2 nM) and efavirenz (EC50 = 6.3
present on benzamido and pyrazine nucleus contribute hydrogen ac- ± 3.2 nM) was found to be highly potent [190]. Regina et al, also
ceptance property which facilitates binding with HIV-1. Compound 99 studied the synthesized and evaluated indole 2-carboxamide deriva-
(Fig. 12) was found to be highly potent [183]. Ashok et al, 2014, stu- tives with different substitutions. All the synthesized compounds were
died and reported the synthesis and evaluation of various indole-pyrido further evaluated against mutant L100I and K103N RT HIV-1 strains.
derivatives. In vitro study was conducted on HIV-1 infected cells and SAR studies concluded that nitro and pyrrole substituted carboxamide
molecular properties were also calculated to further screen the syn- is favorable for the activity. Compound 107 (EC50 = 1.3 ± 0.0 nM)
thesized analogues. SAR studies were conducted on the basis of sub- (Fig. 12) was found to be highly potent than standards, nevirapine
stitutions present on the phenyl ring attached to piperazine which is (EC50 = 19.2 ± 0.2 nM) and efavirenz (EC50 = 1.5 ± 0.3 nM) [191].
further attached with indole. The studies concluded that ortho and para
directing substitutions on 4th position of phenyl ring leads to no anti- 2.8. Antiinflammatory activity
HIV activity. Whereas, the 2-3rd position of phenyl favors the activity.
Replacement of phenyl with benzyl moiety leads to increase in potency. Inflammation is a complex body response towards the harmful sti-
The compound, 100 (EC50 = 0.53 µM) (Fig. 12) was found to be highly muli, i.e., pathogens, damaged cells, irritants. Inflammation is involved
potent whereas others have moderate activity compared to standard in tissue repairment. But in the chronic form, it has negative effects on
drug zidovudine (EC50 = 0.002 µM) [184]. In the same year, tri- the body. Antiinflammatory agents treat inflammation reducing swel-
fluoromethyl-indole derivatives having improved drug resistance with ling and pain. The indole is found to be a major inhibitor of cycloox-
anti-HIV-1 NNRTIs were reported by Jiang and coworkers. All the ygenase [192].
synthesized derivatives were screened against WT (wild-type) HIV-1 In 2018, Mukthung and coworkers developed various capsaicins
strain. SAR studies revealed that the presence of Cl or Br at C-5 im- based indole and nitroindole derivatives and evaluated against the
proved the activity and presence of nitro at C-7 reduced the activity. proinflammatory kinase TNF-α. SAR study highlighted the role of
Substitution of alkyl chain substituted with halogen at C-3 leads to capsaicin alkyl chain system and nitro substitution for favorable ac-
potent compound 101 (EC50 < 133.33 µM) (Fig. 12) on basis of the tivity. Compound 108a (relative % inhibition = 47.65%) and 108b
comparison with standard drug nevirapine (EC50 = 0.4 µM) and efa- (relative % inhibition = 51.95%) (Fig. 13) were the highly potent as the
virenz (EC50 = 0.08 µM). Further docking analysis gave the idea about relative % inhibition compared with standard drug capsaicin [193]. In
the binding mode of various derivatives with HIV reverse transcriptase the same year, Bhat and colleagues reported the acetohydrazide-indole
enzyme [185]. Ferro et al, 2014 designed, synthesized and evaluated hybrids for COX-2 inhibitory activity. SAR studies suggested the role of
indole derivatives by performing the docking study with HIV-1 in- nitrophenol substituent favorable for the activity. Docking studies re-
tegrase. Docking studies concluded that bulkier substituent on the vealed that compound 109 (potency = 0.79%) (Fig. 13) found to be a
benzyl group, i.e. tert-butyl, trifluoromethyl group, is favorable for the most selective inhibitor and also potent as compared to standard drug
interaction with HIV-1 integrase protein. Compound, 102 indomethacin (potency = 1.0%) [194]. Similarly, Shaker and collea-
(IC50 = 0.4 mM) (Fig. 12) was found to be highly potent [186]. Hassam gues discussed the synthesis and evaluation of COX-2 inhibitory activity
and coworkers synthesized and evaluated cylopropyl indole derivatives of indole derivatives having methylsulphonyl and aryl substituted de-
as HIV non-nucleoside reverse transcriptase inhibitors. All the rivatives. SAR highlighted the importance of halogen substitution.
17
R2
O
O
R1 N
N n OCH3 N O
H R2 N NH S
HO O2N R1 O
108a-b N
H 110a-b
108a=R1=NO2, R2=NO2, n= 4
108b=R1=NO2, R2=NO2, n= 5 109 110a=R1=H, R2= Cl
110b=R1=F, R2= Cl
R
HN
R2
N H
N N
NH N F N
R1
O N
111a-b N NH2
F3C N
111a=R1=H, R2=4-NO2-C6H4 112 113a-b
111b=R1=H, R2= -C6H5
113/a=R=Furan-2-carbonyl
113b=R= N,N-
dimethylaminocarbonyl
Fig. 13. Chemical structures for indole derivatives having antiinflammatory activity 108–113 with active pharmacophores.
Compound 110a (IC50 = 0.11 µM, SI = 107.63) and 110b mechanisms involving different pathways can be the best approach to
(IC50 = 0.15 µM, SI = 76.6) (Fig. 13) showed maximum anti-in- design potent anti-inflammatory agents [203]. Based on this concept,
flammatory activity as compared to standard drug indomethacin Shaveta et al, designed, synthesized and evaluated various chromone
(IC50 = 0.49 µM, SI = 0.079) [195]. substituted oxindole derivatives. All the synthesized compounds were
Indole derivatives such as indomethacin and melatonin reduce the evaluated against COX-1, COX-2 and 5-LOX. SAR studies concluded that
inflammation and oxidation process [196–198]. Hence, it is required to halogen substituted chromone derivative was favorable for the
develop novel indole derivatives with potent antiinflammatory activity. activity. Compounds 115a (IC50 = 9.5 ± 0.8 µg/mL) and 115b
Shroff and Daharwal, synthesized and evaluated novel indolyl-pyrazo- (IC50 = 10.0 ± 4.2 µg/mL) (Fig. 14) demonstrated maximum potency
line derivatives as anti-inflammatory agents. In vivo study was con- as compared with standard drug indomethacin (IC50 = 0.7 ± 0.2 µg/
ducted using carrageenan-induced paw edema method. SAR studies mL) [204]. Sharath and colleagues also reported various pyrazole
concluded that phenyl and p-nitro phenyl substitution at C-3 and unsubstituted indole derivatives. All the synthesized compounds were
substitution at N1 gave best results. Compounds 111a (%inhibi- evaluated by the anti-lipoxygenase assay. SAR studies concluded that
tion = 63.97%) and 111b (%inhibition = 57.46%) (Fig. 13) were the anisole substituted pyrazole is favorable for the activity. Compound
highly potent when compared to standard drug indomethacin (%in- 116 (IC50 = 18 ± 0.45) (Fig. 14) was found to be highly potent as
hibition = 61.36%) [199]. Similarly, Fatahala et al, in 2017 reported a compared with standard drug ascorbic acid (IC50 = 10 ± 0.11) [205].
series of indole derivatives and screened for antiinflammatory activity A series of isoxazole-fused indole derivatives were synthesized and in
using rat paw edema method and docking analysis. The addition of vivo study was conducted for anti-inflammatory activity using carra-
hydrophobic ring coplanar with the original ring, the substitution of p- geenan-induced rat paw edema model. SAR studies concluded that C-3
fluorophenyl leads to increased activity. Compound, 112 (%inhibi- substituted indole derivatives have a significant role. i.e., 4-chlor-
tion = 92%) (Fig. 13) showed maximum activity to standard drugs ophenyl, 4‑trifluoromethyl phenyl and 4-iodo phenyl substituted iso-
ibuprofen (%inhibition = 69.84%) and indomethacin (%inhibi- xazole, phenyl. Compounds, 117a (paw edema volume = 1.51 ±
tion = 78.58%) [200]. 0.08 mL) and 117b (paw edema volume = 1.47 ± 0.05 mL) (Fig. 14)
In 2016, Liu et al, studied and designed indole-2-carboxamide de- were found to be highly potent as compared to indomethacin standard
rivatives. Further, in vivo study was conducted for screening the bio- (paw edema volume = 1.31 ± 0.06 mL) [206]. Various indole-imida-
logical activity resulted in the identification of potent compounds. SAR zolidine derivatives were synthesized and evaluated using an air pouch
concluded that oxazole and amine substitution through carboxamide at and carrageenan-induced, acetic acid induced vascular permeability
C-5 has a marked effect on activity. With the increase in methoxy models. Compound 118 (percentage inhibition = 72.1%) as compared
substitution leads to an increase in activity. Substitution of 2, 6-di- with standard drug indomethacin (percentage inhibition = 86.7%)
chlorobenzyl, 3-fluorobenzyl, 4-chlorobenzyl, 4‑bromobenzyl and (Fig. 14) was found to be potent [207]. A series of carboxyphenyl imino
4‑trifluoromethylbenzyl at N1 leads to the compounds having good indole derivatives were mentioned by Chandra and coworkers. Sub-
anti-inflammatory activity. Compounds 113a (%inhibition < 2.90 ± stitution of the halogen group on phenyl ring was found to be favorable
0.73%) and 113b (%inhibition < 2.67 ± 0.76%) (Fig. 13) were for the activity. All the synthesized compounds were further evaluated
found to be highly potent [201]. In 2015, indole-chalcone derivatives by carrageenan-induced paw edema. Among all the synthesized com-
were reported by Ozdemir and other researchers. All the synthesized pounds, 119 (% inhibition = 67.9%) (Fig. 14) showed maximum po-
compounds are evaluated against COX-1, COX-2. SAR studies con- tency as compared with standard drugs, phenylbutazone (% inhibi-
cluded that methoxy, bromo groups and sulphonyl substituted chalcone tion = 65.6%) and indomethacin (% inhibition = 92.3%) [208].
derivative is favorable for the activity. Among all the synthesized
compounds 114a and 114b (Fig. 14) were found to be the highly potent 2.9. Antidepressant activity
[202].
Chromone derivatives are found to be potent inhibitors of ROS de- Depression affects the person's thought, behavior, tendencies, po-
pendent activation of TRAF6-ASK1-p38 pathway which is particularly tential feelings characterized by the low mood [209]. Depression is the
involved in the inflammation process. A combination of two leading cause of ill health and disability worldwide. At this time about
18
Fig. 14. Chemical structures for indole derivatives having antiinflammatory activity 114–119 with active pharmacophores.
300 million people are suffering from depression and there is the in- phenyl, 4-Br-phenyl, 3-CF3‑phenyl and benzyl group attachment with
crement of 18% between 2005 and 2015 [210]. Recent data shows that acetamide gives potent compounds. Compounds, 121a (65.77 ± 17.8)
8.1% American adults over had depression in the 2-week period. and 121b (75.77 ± 18.7) (Fig. 15) exhibited good potency when
Women are suffering more as compared to men [211]. Researchers are compared to standard drug fluoxetine (58.5 ± 9.3) [110].
involved in the discovery of drugs with advanced structural modifica- Another mechanism involved in the treatment of depression is
tions having a potent effect on the brain. Various indole derivatives are MAO-A inhibition. This mechanism is particularly seen in dihydropyr-
reported as antidepressant agents. azole derivatives [214]. Hence, potent indole-dihydropyrazole deriva-
Latest literature survey finds out azetidinone and derivatives have tives can be synthesized to inhibit depression. Patil and Bari et al, 2016,
potent antidepressant acting via cholinergic and NMDA receptor in- synthesized and screened a series of indole derivatives bearing dihy-
hibition [212]. This finding motivated to combined derivatives of in- dropyrazole moiety and evaluated for antidepressant activity using FST.
dole and azetidinone. Kerazare et al, 2017 synthesized oxindole deri- The presence of electron donating groups on the phenyl ring of indolyl-
vatives bearing azetidinone moiety and conducted in vivo study using a pyrazoline has marked role in the activity. Finally, it was concluded
forced swim test (FST). Finally, SAR study concluded that –NO2 and -Cl from the in vivo study that 122a (116.3 ± 1.54) and 122b molecules
group substitution at the ortho position of the phenyl ring system are (109.8 ± 2.86) (Fig. 15) were found to be highly potent when com-
better for potency. Also, highly lipophilic group, i.e., para-substituted pared to standard drug fluoxetine (immobility reduced to 77.4%) and
hydroxyl, dimethylamino, trimethoxy and dimethoxy group in the imipramine (immobility reduced to 75.5%) [109]. The same group
phenyl ring, leads to the compounds with good hydrophobic interaction previously synthesized the isoxazoline fused indole derivatives, as an-
with the enzyme. Compounds 120a (immobility reduced to 66.82%). tidepressant agents. A detailed SAR was also conducted which proved
and 120b (immobility reduced to 65.61%). (Fig. 15) were found to be that the activity of these compounds is due to the presence of hetero-
highly potent on comparing with standard drug fluoxetine (immobility cyclic rings i.e., pyridine, pyrrole. Also, the substitution of electron
reduced to 70.93%) [213]. Further molecular docking studies were also withdrawing system (F, Br, Cl) at the para position resulted in the good
conducted which identify the potent compound 120a and 120b on the activity. Similarly, electron releasing groups (CH3, OH, OCH3) de-
basis of the maximum binding score. Both the compounds showed creases the activity. Compounds 123a and 123b (Fig. 15) were found to
binding with the enzyme through a hydrogen bond, hydrophobic and be the highly potent [215].
Van Der Waal's interactions [213]. In 2015, Zhen and coworkers in-
troduced a series of 2-(5-methyl-2, 3-dioxoindolin-1-yl) acetamide de- 2.10. Antioxidant activity
rivatives. All the synthesized compounds were further screened for
antidepressant activity using FST. SAR study concluded that only 3-Br- Antioxidant agents inhibit the oxidation reactions ultimately
Cl HN
O O O
N
O
R N H3C
N N O R NH R
NH
HN R N NH 123a-b
O
120a-b 121a-b 122a-b 123a=R=
N
120a=R=2-NO2-C6H4- 121a=R=3-Br-C6H4- 122a=R=4-Cl-C6H4-
120b=R=2-Cl-C6H4- 121b=R=3-CF3-C6H4- 122b=R=4-NO2-C6H4- 123b=R=
N
H
Fig. 15. Chemical structures for indole derivatives haviing antidepressant activity 120–123 with active pharmacophores.
19
prevent the free radical formation and cell damage. Thiols and ascorbic (Fig. 16) were found to be highly potent as compared with standard
acid are found to be responsible for the termination of these reactions. drug butylatedhydroxytoluene (BHT) [220]. In the same year, Suzen
Apart from this, antioxidants have also effect on the neurodegenerative et al, investigated the antioxidant activity of indole-based melatonin
diseases, i.e. Alzheimer’s disease, Parkinson’s disease, amyotrophic derivatives and evaluated by LP (lipid peroxidation) inhibition and
lateral sclerosis etc [216]. Indole derivatives are found to be very ef- DPPH radical scavenging activities. SAR studies concluded that ben-
fective antioxidizing agent protecting biomolecules from the perox- zoylpyrrolidine is favorable for activity. The compound, 127 (Fig. 16)
idation [217]. showed better results [221].
Melatonin, found in almost every cell, promotes the synthesis of In another study, various aminomethyl-indole derivatives were
superoxide dismutase, glutathione peroxidase which acts as antioxidant synthesized and evaluated for superoxide radical scavenging activity
enzymes. It scavenges various reactive oxygen species such as peroxyl and anti LP (lipid peroxidation) activities. Electron withdrawing
radical, peroxynitrite anion etc. Orhan et al, 2016 synthesized and groups, phenyl and pyrrole substitution were found to be favorable for
evaluated indole-based melatonin derivatives. SAR studies concluded the activity. Among all the synthesized derivatives, 128a and 128b
that hydrazone derivatives of indole bearing o-halogenphenyl and 3, having % inhibition of 36–42%, as compared with standard drug bu-
5‑difluorophenyl substituents are favorable for the activity. All the tylated hydroxyl toluene (Fig. 16) were found to be highly potent
synthesized derivatives were screened against ROS-induced DCFH-DA [222]. Melatonin based indole derivatives were also synthesized by
oxidation. Compounds, 124a (IC50 = 38.3 ± 8.9 µM) and 124b Shirinzadeh et al, and screened by evaluating their reducing effect
(IC50 = 37.0 ± 2.0 µM) (Fig. 16) were found to be the highly potent against the oxidation of the redox-sensitive fluorescent probe, by ex-
antioxidant and cytoprotective in neuronal and non neuronal cells as amining their protective effect against H2O2 and by determining the
compared with standard drug melatonin [218]. In 2013, Silveira and inhibitory effect on AAPH. SAR studies disclosed that halogen sub-
colleagues reported the study on the antioxidant activity of C-3 sulfenyl stitution impacts a marked effect on activity, i.e., o- and m- halogens in
indoles. SAR studies concluded that increased potency is due to the the aromatic side chain increase the antioxidant activity. Substitution of
presence of bis-indole system connected through sulfide group at the C- methyl at indole nitrogen and halogenated side chain leads to highly
3 position. The substitution at the C-3 position leads to the better sta- potent compounds. Among all the entire series, 129a and 129b
bilization of indole ring and delocalization of electrons. Compounds, (Fig. 16) were found to be the most promising compounds [223]. In the
125 (activity < 96.8%) (Fig. 16) exhibited the highly potent anti- same year, Estevao et al, synthesized and evaluated tryptophan and
oxidant activity [219]. Various triazole substituted indole derivatives tryptamine derivatives of indole with the prenylated system. The
were synthesized by Baytas and coworkers and were tested for DPPH scavenging activity of all the synthesized compounds was checked
and superoxide radical scavenging activities. SAR studies concluded against superoxide, hydrogen peroxide, hypochlorous acid radical. SAR
that unsubstituted 1, 2, 4-triazole-5(4H)-thione ring attached at the 2nd studies reveal that carbomethoxy group, free amine group in the side
position of indole is found to be favorable for the activity. Compounds, chain and free indolic nitrogen are favorable for the activity. Com-
126a (% inhibition = 87 ± 3) and 126b (% inhibition = 88 ± 4) pounds, 130 (IC50 = 4.13 0.17 mM) and 131 (IC50 = 4.56 0.48 mM)
Fig. 16. Chemical structures for indole derivatives having antioxidant activity 124–131 with active pharmacophores.
20
(Fig. 16) were found to be highly potent [224]. and coworkers reported the synthesis of indole-3-carboxamide and
screened against HCV genotype. SAR studies concluded that t-bu-
tylsulfonamide substitution as compared to n-propyl sulfonamide was
2.11. Antihepatitis activity
favorable for the activity. Further alkyl and alkoxy group substitution at
the 6th position leads to the analogues having good activity. Among all,
Hepatitis involves the inflammation of liver tissues due to the in-
compound 135 (EC50 < 831 μM) (Fig. 17) showed the maximum po-
fection by Hepatitis C virus characterized by yellow coloration of the
tency [232].
skin, the whiteness of the eyes, poor appetite, vomiting, tiredness, ab-
Various pyridine based indole derivatives synthesized and evaluated
dominal pain, and diarrhea. Estimated 325 million people were living
using pharmacophore modelling and 3D-QSAR study as hepatitis C
with chronic hepatitis infections i.e., hepatitis B virus (HBV) or hepa-
virus NS5B polymerase inhibitors by Varun G and coworkers. All the
titis C virus (HCV) worldwide in 2015. Globally, 1.34 million people
synthesized derivatives were evaluated as using pharmacophore mod-
died of viral hepatitis in 2015 [225–227]. Only a few vaccines are
elling and 3D-QSAR study. Compounds, 136 (PIC50 = 4.67) (Fig. 17)
available in the market as anti-hepatitis agents which are not much
having –OH group at the C-5 position of indole with pyridine at C-1 and
more effective [228]. Thus, the development of anti-hepatitis drugs is
C-3 position was found to be highly potent [233]. In the same year, Jin
required at a fast pace. Some of the newly synthesized anti-hepatic
and colleagues, synthesized and evaluated various chemical genetics
indole derivatives with the structure–activity relationship are discussed
based indole derivatives. All the synthesized compounds were eval-
below.
uated against HCV NS5B polymerase. SAR studies concluded that ac-
In 2016, annulated indole derivatives were studied against influ-
rylamide and cyano group substitution were favorable for the activity.
enza endonuclease and HCV by Zoidis G and colleagues. SAR studies
The compound, 137 (CC50 = 61.8 µM) (Fig. 17) was found to be highly
concluded that substitution of N-hydroxyimides resulted in the com-
potent as compared with standard drug clemizole (CC50 = 8.0 µM)
pounds having potent activity against PA endonuclease. Fluoro and
[234].
chloro group substitution leads to active derivatives whereas, removal
of hydroxyl group from imido nitrogen leads to the compounds with
complete loss of activity. Docking studies were also conducted between 2.12. Antileishmanial agents
the active site HCV polymerase and ligands and it was found that
compound, 132a (EC50 = 83.8 ± 4.8 µM) and 132b Leishmaniasis is a parasitic disease spread by female Sandfly be-
(EC50 = 10.5 ± 3.1 µM) (Fig. 17) show better hydrophobic interaction longing to genus Leishmania which can be appeared in the visceral,
with the active site of the protein. Compounds, 132aand 132b (Fig. 17) cutaneous, diffuse and mucocutaneous form [235]. According to the
were found to be highly potent whereas other compounds have the least recent data by WHO, nearly 88 developing and developed countries are
activity towards HCV as compared with standard drug 2,4-dioxo- affected with leishmaniasis. Every New Year, nearly 1.5–2.0 million
4‑phenylbutanoic acid (EC50 > 200 µM) [229]. In the same year, var- cases are reported [236]. As Leishmania causes a wide range of health
ious indole-pyrazole derivatives as antihepatitis agents were also re- problems, it is imperative to develop effective drugs.
ported by Han and coworkers. SAR studies concluded that substitution Recently, Porwal et al, synthesized and evaluated gem-dithioace-
of p-Me-phenyl, p-MeO phenyl, p-flouro phenyl and m-fluoro phenyl tylated indole derivatives. All the synthesized compounds were
attached with indole at C-3 through pyrazole increases the activity. R- screened through in vivo study against Leishmania donovani. SAR study
enantiomer of compound 133 (EC50 = 1.02 ± 0.10 µM) (Fig. 17) was revealed that the presence of H2S at the C-3 and p-cyanophenoxy, N-
found to be the highly potent [230]. In another study, Andreev et al, phenyl, pentyl chain at nitrogen atom and dimethylsulphoxide at 3rd
2015 synthesized and evaluated indole-phenyl derivatives. All the position of indole were most important for the activity. Compound, 138
synthesized compounds were screened for anti-hepatitis activity using (% inhibition = 96–99%) (Fig. 18) showed maximum activity [237].
NS5B RdRp assay ns5b. SAR studies revealed that N-benzyl substitution Felix and coworkers reported the synthesis of thiophene-indole hybrids
at the tetrahydroindole core, found to be favorable for the activity, and evaluation against L. donovani. SAR study concluded the role of 5-
whereas para-fluorophenyl substitution at the nitrogen atom leads to cyano, 5‑methyl were found to be favorable for the activity. Compounds
3–4 fold reduction in activity. Compound 134 (EC50 < 7.9 μM) 139a (IC50 = 2.1 μg/mL, SI. > 193.2), 139b (IC50 = 2.3 μg/mL,
(Fig. 17) was found to be highly potent [231]. In the same year, Zang SI. > 172.4), and 140 (IC50 = 3.2 μg/mL, SI. > 124.6) (Fig. 18) were
Fig. 17. Chemical structures for indole derivatives having antihepatitis activity 132–137 with active pharmacophores.
21
O O
NC
S S N
NC
R N
S
N HN S
HN
139a-b
O N
138 139a=R=-CN
139b=R=H 140
R
N N NO2
NH
S n O
Cl I
N I
N N
N
R'
141a-b
HN NH N
141a=R=H, R'=H, n=2
141b=R=H, R'=CH3, n=2 142
143
Fig. 18. Chemical structures for indole derivatives having antileishmanial activity 138–143 with active pharmacophores.
found to be highly potent with as compared to standard drug ampho- applied to screen the synthesized compounds. SAR studies concluded
tericin B (IC50 = 0.2 μg/mL, SI. > 124.5) [238]. In 2014, triazino in- that substitution of pyridine, and aryl halide, alkyl chain through
dole-quinoline hybrid derivatives were synthesized and evaluated by carboxamide at 5th position and phenyproipionyl moiety were required
Sharma and coworkers. All the synthesized compounds were screened for the activity of indole. Compounds, 144a (IC50 = 4.7 µM) and 144b
through in vitro study against L. donovani. SAR studies suggested that at (IC50 = 52 µM) (Fig. 19) showed moderate activity [243].
the nitrogen atom of indole hydrogen, methyl, ethyl, isopropyl, iso-
butyl, allyl, benzyl were favorable for the activity. Alkyl chain length 2.13.1.2. Tyrosinase inhibition. For the past few decades, tyrosinase
connecting triazino indole and quinoline should contain a maximum of inhibitors have been a great concern solely due to the key role of
two carbons. Compounds, 141a (IC50= 1.11 μM) and 141b (IC50= tyrosinase enzymes in both mammalian melanogenesis and fruit or
0.36 μM) (Fig. 18) were found to be highly potent as compared with fungi enzymatic browning [244]. Based on this, Ferro et al, in 2016,
standard drug miltefosine (IC50= 8.10 μM) [239]. The antileishmanial synthesized and evaluated various indole derivatives. All the
activity of 3,3‑diindolylmethane was investigated by Bharate and synthesized compounds were assayed by in vitro technique. SAR
coworkers. All the synthesized compounds were screened through in studies concluded that a fluorobenzyl derivative at the nitrogen atom
vitro study against L. donovani. Pharmacophore model was also devel- of indole was found to be highly potent. The compound, 145
oped for diindolyl methane derivatives showed excellent statistical (IC50 = 224 ± 1.23 µM) (Fig. 19) was found to be highly potent as
parameters. SAR studies concluded that 4‑nitroaryl substitution was compared with standard drug Kojic acid (IC50 = 17.76 ± 0.18 µM)
favorable for the activity. Compound 142 (IC50 < 8.37 μM) (Fig. 18) [245].
was found to be highly potent as compared with pentamidine
(IC50 < 8.39 μM) and amphotericin B (IC50 < 0.17 μM) [240]. 2.13.1.3. Lysozyme inhibition. Lysozyme is part of the immune system.
Leishmania cysteine protease is essential for the growth, differ- Lysozyme inhibition leads to the prevention of cell lysis [246].
entiation and multiplication of parasite. Azetidine derivatives are one of Shinitzky et al, evaluated various indole derivatives and concluded
the prominent inhibitors of this enzyme. Based on this fact, Singh and that inhibition is due to bond formation between histidine and lysine
colleagues synthesized and evaluated azetidine-indole derivatives. All residue of lysozyme and indole. Two indole derivatives, i.e. 146a and
the synthesized compounds were screened through in vitro study using 146b (Fig. 19) were evaluated against lysozyme and found to be active
Leishmania major promastigotes. SAR studies concluded that methyl [247].
substitution to the imine attached to the indole enhanced the activity.
Conversion of imine into azetidin-2-one resulted in the drastic increase 2.13.1.4. Hyaluronidase inhibitor. Hyaluronidase enzyme is responsible
in the activity. Among all, compound 143 (0.56 ± 0.06 µg/mL) for the degradation of hyaluronic acid and increasing cell permeability.
(Fig. 18) was found to be highly potent as compared with standard drug Hyaluronidase inhibitors are responsible for the antiinflammatory,
amphotericin B (0.56 ± 0.001 µg/mL) [241]. antiaging, antimicrobial, anticancer and antivenom properties [248].
The hyaluronidase inhibiting effect of various amino methyl indole
2.13. Miscellaneous activity derivatives was reported by Olegan et al. The synthesized compounds
were evaluated by using stain-all assay method. SAR studies concluded
2.13.1. Enzyme inhibitory activity that a compound with piperazine derivative and phenyl group at the
2.13.1.1. CD38 enzyme inhibition. CD38 (cluster of differentiation 38) is 5th position of indole was favorable for the activity. For better results,
a multifunctional enzyme which is ubiquitously distributed in more lipophillic compounds were required. Compound 147 (%
mammalian tissues. It is involved in the conversion of NAD(P)+ into inhibition = 23%) (Fig. 19) was found to be highly potent [249].
cyclic ADP-ribose, NAADP+ and ADP-ribose and the role of these Previously, the same group also synthesized various novel indole
metabolites in multiple Ca2+ signalling pathways makes CD38 a novel derivatives and evaluated various parameters by turbidimetric,
potential pharmacological target. The dire lack of CD38 inhibitors, viscometric and colorimetric methods. SAR studies concluded that
however, renders the search for new molecular tools are highly substitution of choro and fluoro at the para position of benzamide
desirable [242]. Wu et al, 2013 synthesized and evaluated novel attached at the 3rd position of indole were favorable for the activity.
indole derivatives. In vitro studies and docking procedures were Compounds, 148a (% inhibition = 23%) and 148b (%
22
Fig. 19. Chemical structures of the enzyme inhibitors indole derivatives 144–148 with active pharmacophores.
Fig. 20. Chemical structures of the anticholinergic indole derivatives 149–150 with active pharmacophores.
Fig. 21. Chemical structures of the indole derivatives with other activities 151–155 with active pharmacophores.
inhibition = 23%) (Fig. 19) were found to be highly potent at the 7 pH, derivatives using cholinesterase enzyme. SAR studies concluded that
as compared with standard drug vcpal (6-palmitoyl-L-ascorbic acid) (% carbonyl and biphenyl substitutions are favorable for the activity. The
inhibition = 23%) [250]. compound, 149 (Fig. 20) was found to be the highly potent [252].
Farani et al, synthesized and evaluated oxindoline derivatives by in vitro
2.13.2. Anticholinergic activity and docking analysis. SAR studies concluded that Cl, F, NO2, at the ortho
An anticholinergic agent is the inhibitor of acetylcholine present in and para position and methoxy at the meta position of phenyl were
the central and peripheral nervous system [251]. Parveen et al, 2018 favorable for the activity. Compound, 150 (IC50 = 1.1 ± 0.25 μM)
synthesized and evaluated indole derivatives. In vitro study and mole- (Fig. 20) was found to be highly potent compared with standard drug
cular docking, the study was conducted to screen the synthesized donepezil (IC50 = 0.41 ± 0.12 μM) [253].
23
Table 1
Chemical structure and mechanism of action of indole containing drugs which are in advanced stages of development.
S. No. Indole drugs Structure Mechanism of action/Use References
1 Panobinostat Panobinostat inhibits multiple histone deacetylase enzymes (HDAC), [262]

leading to apoptosis of malignant cells via multiple pathways. Developed
by Novartis for treatment of various cancers and recently approved by
FDA and European medicines Agencies in 2015.
156
2 Dacinostat (LAQ- It is hydroxamate HDAC inhibitor with potential anticancer activity. [263]
824) When tested on a variety of solid tumour cell lines, NVP-LAQ824
exhibited selective anti-proliferative effects, inducing cell growth
inhibition in some, while inducing cell death in others.
157
3 PCI-34051 It selectively inhibit HDAC8 and treat T-cell malignancies. [264]
158
4 EI1 It inhibits histone-lysine-N-methyltransferase enzyme which inhibits the [265]
methyltransferase activity of the EZH2 (Enhancer of zeste homolog 2)
/PRC2 (Polycomb repressive complex 2) thereby blocking tumor cells
proliferation.
159
5 GSK 126 GSK126 is a potent, highly selective EZH2 methyltransferase inhibitor. It [266]
block proliferation in in vitro and in vivo models of diffuse large B-cell
lymphoma.
160
6 EPZ005687 It is a potent and selective inhibitors of lysine methyltranferase EZH2 to [267]
control non-Hodgkin’s lymphoma and other cancers.
161
7 IN461 Suppress the spontaneous motor activity and act as anticonvulsant. [268]
162
8 IN399 Suppress the spontaneous motor activity and act as anticonvulsant. [269]
163
(continued on next page)
24
Table 1 (continued)
9 AZ20 AZ20 is the first reported inhibitor of ATR(ataxia telangiectasia and Rad3) [270]
protein kinase demonstrating tumor growth inhibition in vivo. It is a
promising anticancer agent.
164
10 CPI-169 Potent and selective EZH2 inhibitor having microsomal stability and treat [271]
lymphoma xenograft, bladder cancer.
165
11 CPI-1205 CPI-1205 is a highly potent and selective inhibitor of EZH2. This decrease [272]
in histone methylation, alters gene expression patterns associated with
cancer pathways and results in decreased proliferation of EZH2-expressing
cancer cells.
166
12 CPI-360 CPI-360 is a potent, selective, and SAM-competitive EZH1 inhibitor. [273]
Effective against non-Hodgkin’s lymphoma.
167
13 RG-108 This oxoindole derivative is DNA methyltransferase inhibitor and [274]
promsing anticancer agent.
168
14 Orantinib This oxoindole derivative is VEGFR2 (Vascular endothelial growth [275]
factor receptors type 2), PDGFR (Platelet-derived growth factor
receptors), FGFR(Platelet-derived growth factor receptors) inhibitor and
treat hepatocellular carcinoma.
169
15 Motesanib This indoline [276]
170 derivative is VEGFR2, PDGFR, stem cell factor receptor and used to treat
breast cancer.
16 PF-00562271 This oxoindole derivative is FAK (Focal adhesion kinase) and PYK2 [277]
(Protein tyrosine kinase 2) inhibitor and treat hepatocellular carcinoma.
171
25
Table 1 (continued)
17 Sotrastaurin It acts through protein kinase C (PKCs) inhibition. PKCs are vital in the [278]
activation of nuclear factor-kappaB (NF-kB) mediated signaling and treat
B-cell lymphomas.
172
18 Obatoclax It acts through Bcl-2 (B-cell lymphoma 2) inhibition. It induces apoptosis [279]
(GX15-070) in cancer cells thereby preventing tumor growth. Effective in various
cancerous conditions.
173
19 JNJ-26854165 It acts through the inhibition of HDM2 (Human double minute 2) [280]
(Serdemetan) ubiquitin ligase. It inhibits cell growth and induces apoptosis in leukemia
cell lines and treat solid tumors.
174
20 TL32711 It is a potent antagonist for XIAP (X-linked inhibitor of apoptosis protein) [281]
(Birinapant) and IAP (Inhibitor of apoptosis protein) family proteins, with potential
antineoplastic activity. It also inactivate the nuclear factor-kappa B (NF-
kB)-mediated signaling and treat myelogenous leukemia.
175
21 GSK2606414 The first selective inhibitor discovered for the enzyme protein kinase R [282]
(PKR) like endoplasmic reticulum kinase (PERK), which is involved in
various processes related to cancer and neurodegenerative disorders.
176
22 GSK2656157 It is a selective first in class PERK inhibitor and stop the tumor growth [283]
177
23 Enzastaurin It is as selective Protien kinase C β inhibitor an enzyme involved in the [284]
induction of vascular endothelial growth factor (VEGF) and developed as
an antiangiogenic cancer therapy
178
26
Table 1 (continued)
2+
24 Go6976 Potent, selective PKC inhibitor. Selectively inhibits Ca -dependent PKC [285]
isoforms over Ca2+-independent. Promising antitumor agent.
179
25 Rucaparib It is first-in-class pharmaceutical drug targeting the DNA repair enzyme [286]
i.e. poly (ADP-ribose) polymerase enzyme and treat breast, ovarian
cancer.
180
26 Indole-3-carbinol It prevents the development of estrogen-enhanced cancers including [287]
breast, endometrial and cervical cancers
181
27 ARQ-197 It is the first selective non-ATP-competitive c-MET inhibitor and treat [288]
(tivantinib) hepatocellular, coloreactal, breast, prostate cancer.
182
28 AZD-3463 ALK (Anaplastic lymphoma kinase) has been shown to promote cell [289]
survival and growth. AZD-3463 is potent ALK inhibitor and therefore
effective against drug resistance cancer cell lines.
183
29 YH-239-EE P53-MDM2 (Mouse double minute 2) antagonist and treat myeloid [290]
leukemia.
184
30 THZ1 It selectively inhibit CDK7 (Cyclin-dependent kinase 7) dependent [291]
transcriptional addictions in pancreatic cancer
185
31 Atervirdine It is novel nonnucleoside reverse transcriptase inhibitor (NNRTI) and acts [292]
as antiviral drug.
186
27
Table 1 (continued)
32 Oglufanide Inhibit vascular endothelial growth factor which may inhibit angiogenesis [293]
and acts against hepatitis C.
187
33 Indalpine Indalpine, recently entered in the market, acts through serotonin reuptake [294]
(LM-5008) inhibiton. Potent antidepressant..
188
34 LU 28-179 It acts as sigma2 receptor agonist and used as anticancer, antidepressants. [295]
(Siramesine)
189
35 Roxindole Acts as dopamine D2 receptor agonist and treat depression. [296]
190
36 GSK2248761 GSK2248761 is a novel, next-generation NNRTI with activity against [297]
efavirenz-resistant strains. Promising anti-HIV agent.
191
37 Golotimod (SV- Inhibit the STAT3 transcription factor. STAT-3 transcription factor [298]
07) upregulated in many cancer cell types, tumor cell growth and survival and
immunosuppression.
192
38 BILB-1941 Acts as non-nucleoside inhibitor of HCV-NS5B (Hepatitis C virus [299]
Nonstructural protein 5B) polymerase. Promising anti-HCV agent.
193
39 BMS-791325 It acts as HCV NS5B RNA dependent polymerase inhibitor and acts as [300]
potent antihepatitis agent.
194
28
Table 1 (continued)
40 MK-8742 HCV-NS5A (Hepatitis C virus Nonstructural protein 5A) inhibitor. Acts [301]
against genotype 1a, 1b, and 2a. Promising antihepatitis agent.
195
41 TMC647055 Non-nucleoside inhibitor of the hepatitis C virus NS5B polymerase. [302]
Promising antihepatitis agent.
196
42 YQ36 Antiproliferative agents and acts through the caspase dependant apoptosis [303]
induction.
197
2.13.3. Antihistaminic agents estrogen. It is used in the treatment of infertility and breast cancer
Mast cells secrete the histamine which increases the cell perme- [260]. Ji et al, designed, synthesized and evaluated indole derivatives
ability that causes the hypersensitivity reactions. Hence antihistaminic as antiestrogen agents acting on uterine and mammary tissues. All the
agents are used to treat various allergic conditions [254]. synthesized derivatives were evaluated by examining binding affinity
Santillan et al, synthesized and evaluated various indole derivatives. with estrogen receptors (ERσ, ER β). Effect on mouse uterus and bone
SAR studies concluded that alkylpiperdinyl substitutions are most fa- were also evaluated. SAR studies concluded that substitution of piper-
vorable for antihistaminic activity. Also, the substitution of indole ni- idine at the nitrogen atom and hydroxy at the 5th position of indole
trogen with methyl and methyl sulphonyl leads to a decrease in activity. were favorable for the activity. Among all the synthesized compounds,
Human H3 binding affinity data showed that compounds, 151a 155 (Fig. 21) was found to be the highly potent [261].
(affinity = 1.9 ± 1.8 nM) and 151b (affinity = 15 ± 10 nM) (Fig. 21)
were highly potent [255]. Various novel indole derivatives were re- 3. Indole containing drugs under advanced stage of developments
ported by Madasu et al. All the derivatives are synthesized on the basis
of the basic scaffold of eletriptan having antimigraine activity i.e. The clinical trial is to effectively prevent, diagnose and treat disease.
compound 152 (Fig. 21) [256]. Swathi and coworkers have designed, A large pool of data is available of the FDA approved and under clinical
synthesized and evaluated various oxindole derivatives. SAR studies trial indole containing drugs. Along with indole, various other isoforms
concluded that substitution of dimethyl and diethyl amino ethyl chain of indole i.e. oxindole and indoline, due to similar mechanism of action,
at the fifth position of indole was favorable for the activity. All the have distinct biological significance in the variety of disease conditions.
synthesized derivatives were evaluated by the histamine chamber They are, therefore, also among the potential drug candidates which are
method. Derivatives, 153a (% protection = 74%) and 153b (% pro- under clinical trial. Maximum drugs have successfully passed the var-
tection = 80%) (Fig. 21) were found to be highly potent as compared ious phases of clinical trial considered to be very effective. However, a
with standard drug chlorpheniramine (% protection = 83%) [257]. few of them, having serious side effects are not further screened. These
indole containing drugs are under study and proper structural mod-
2.13.4. Antifertility agents ifications are applied to bring them under clinical trial. Some of these
A vast increase in population is a barrier for the social, economic drugs are mentioned below in Table 1.
and technological development of the human race and country [258].
Hence, various synthetic and natural products are designed as anti- 4. Conclusion
fertility agents. Bhowal et al, designed, synthesized and evaluated in-
dole derivative. Synthesized compounds were evaluated by measure- A large pool of drugs posses’ indole nucleus involved in the treat-
ment of level sexual hormones and spermatogenesis by in vivo method. ment of various diseases conditions from acute to the chronic state. This
Compound 154 (Fig. 21) has shown good activity [259]. ring can be traced in a commercially available marketed drug approved
by FDA which are being therapeutically utilized. A number of drugs
2.13.5. Antiestrogen activity with indole nucleus obtained from natural origin and synthetic process
An antiestrogen agent acts as the inhibitors of the sex hormone, are under clinical trial. Researchers are still working on non-marketed
29
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Medicinal Chemistry of Indole Derivatives

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Bioorganic Chemistry 89 (2019) 103021

Contents lists available at ScienceDirect

Medicinal chemistry of indole derivatives: Current to future therapeutic T

ARTICLE INFO ABSTRACT

1. Introduction or benzo[b]pyrrole is an organic chemical compound with formula

Fig. 1. Chemical structures of the compounds 1–11.

Fig. 2. Chemical structures of the compounds 12–21.

Fig. 3. Pharmacological signifance of indole nucleus.

1 Panobinostat Panobinostat inhibits multiple histone deacetylase enzymes (HDAC), [262]

S. No. Indole drugs Structure Mechanism of action/Use References

S. No. Indole drugs Structure Mechanism of action/Use References

S. No. Indole drugs Structure Mechanism of action/Use References

S. No. Indole drugs Structure Mechanism of action/Use References

S. No. Indole drugs Structure Mechanism of action/Use References

(2012) 867–884. derivatives as hyaluronidase inhibitors, Z. Naturforsch. C. 65 (2010) 445–450.

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