1,2,4 Triazoles PDF

Journal of Molecular Structure 1274 (2023) 134487
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Journal of Molecular Structure

journal homepage: www.elsevier.com/locate/molstr
An updated review on diverse range of biological activities of

1,2,4-triazole derivatives: Insight into structure activity relationship
Ojasvi Gupta, Tathagata Pradhan, Gita Chawla∗
Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
a r t i c l e i n f o a b s t r a c t
Article history: Since its discovery 1,2,4-triazole ring has emerged as a prominent heterocyclic scaffold in medic-
Received 10 January 2022 inal chemistry. It possesses a wide spectrum of biological activities such as antimicrobial, anti-
Revised 28 September 2022
cancer, antiepileptic, anti-inflammatory, antiviral, antihypertensive, sedative-hypnotic, etc. Its wide bio-
Accepted 2 November 2022
logical profile has always been a subject of interest that have attracted researchers to investigate the
Available online 6 November 2022
pharmacophoric features of this skeleton. In the past few years, significant progress has been made in
Keywords: the medicinal chemistry of 1,2,4-triazole-based derivatives. The current review summarizes the synthetic
1,2,4-Triazole approaches that have been designed along with the diverse biological activities of 1,2,4-triazole-based
Heterocyclic chemistry compounds reported in the last decade. We hope that this review will be highly beneficial for the re-
Biological activity searchers and medicinal chemists engaged in exploring 1,2,4-triazole as a potential lead for drug design
Structure-activity relationship and discovery.
Drug design
© 2022 Elsevier B.V. All rights reserved.
Synthesis
1. Introduction diunsaturated ring system containing three nitrogen atoms. Tri-

azoles can exist in two isomeric forms namely 1,2,3-triazole and
Nitrogen-based heterocyclic chemistry has recently piqued 1,2,4-triazole differing in the position of nitrogen atoms (Fig. 1)
the interest of medicinal chemists looking forward to the de- [18]. Since the last decade, 1,2,4-triazole based derivatives have
sign of novel and effective medicinal compounds. In this regard, driven the interest of medicinal chemists because of their fas-
an ample amount of literature has been reported dedicated to cinating pharmacophoric features [19]. The electron-rich nature
the heterocyclic-based discovery of small molecules [1–7]. An of the 1,2,4-triazoles helps in the binding with the various bi-
overview of the FDA database reveals that approximately 75% of ological targets and enzymes thus showing a broad range of
the heterocyclic drugs contain the nitrogen-based core. Various biological activities including antibacterial, antifungal, antitumour,
nitrogen-based heterocycles such as pyrroles, pyrazoles, imida- anti-inflammatory, antitubercular, hypoglycaemic, antidepressant,
zoles, triazoles, pyridine, pyrazine, pyrimidine, etc. have been anticonvulsant, analgesic, antiviral, anticancer, antimalarial, antiox-
reported in the scientific databases possessing multiple physio- idant, etc. (Fig. 2) [15,16,20–23]. The scope of 1,2,4-triazoles in
logical and pharmacological properties [1,2,8–12]. Among these designing the novel compounds has been rapidly increasing over
heterocyclic frameworks, triazoles have recently gained a hot spot time. Different triazole-containing drugs are available in the mar-
in medicinal chemistry [13–17]. The unique structural features of ket which have wide array of applications (illustrated in Table 1).
the five-membered triazole moiety distinguish it as a remarkable Also, some of the approved patents based on 1,2,4-triazoles have
heterocyclic motif. Triazoles also known as pyrrodiazoles are a been described in Table 2.
Despite several research findings related to 1,2,4-triazoles, there
are very few review articles which covers the systematic compila-
Abbreviations: PFU, Plaque-forming unit; MIC, Minimum inhibitory concentration of the different biological activities of 1,2,4-triazoles. Recently,
tion; MTT, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide.; FST,
Sathyanarayana et al. have reported the various biological appli-
Forced swim test; VEGFR-2, Vascular endothelial growth factor receptor 2; HD50 ,
hypnotic dose; PLK1, Polo- like Kinase 1; PARP-1, Poly (ADP-ribose) polymerase - cations of 1,2,4-triazoles [24]. Xu and co-workers also described
1; SAR, Structure activity relationships; MPAK, Microtubule associated protein ki- the recent development in the triazole derivatives as inhibitors of
nase; TNF, Tumour necrosis factor; EAC, Ehrlich Ascites Carcinoma; LSD1, Lysine- Alzheimer’s disease [13]. Apart from these there have not been
specific histone demethylase 1; FLT-3, Fms-like tyrosine kinase 3; IC50 , Half high- much reviews published lately focusing on the advancements in
est inhibitory concentration; MMP, Matrix metalloproteinases; BRCA1/BRCA2, Breast
the synthesis and medicinal chemistry of 1,2,4-triazoles. Therefore,
Cancer gene1/2.
∗
Corresponding author. in the present review authors have tried to summarize the medic-
E-mail address: [email protected] (G. Chawla). inal importance of 1,2,4-triazole based derivatives reported in the
https://doi.org/10.1016/j.molstruc.2022.134487
0022-2860/© 2022 Elsevier B.V. All rights reserved.
O. Gupta, T. Pradhan and G. Chawla Journal of Molecular Structure 1274 (2023) 134487
Fig. 1. Structural isomers of triazoles.
scientific databases in the last decade. Also, an attempt has been

made to conclude the structural activity relationships (SARs) of
the reported molecules possessing antidiabetic activity. We believe
that this comprehensive compilation will serve as a useful tool for
medicinal chemists and the researchers involved in drug discovery
and development.
Fig. 2. Pharmacological applications of 1,2,4-triazole based compounds.
2. Synthetic approaches for 1,2,4-triazoles

Hence, the usage of CuBr2 (30% mol) in the DMSO solvent at
1,2,4-Triazoles occur as white to pale yellow crystals soluble in 80°C originated to be ideal, and the substrate possibility study
polar solvents like water and alcohol and slightly soluble in nonpo- was attained by these conditions (scheme 1, fig. 3) [26]. In an-
lar solvents, having a melting point of about 120°C [25]. Synthesis other approach, one-pot synthesis of two nitriles and hydroxy-
of 1,2,4-triazoles have been reported by different methods reported lamine hydrochloride in the presence of triethylamine (TEA), DMSO
by various researchers as depicted in Fig. 3 (schemes 1-10). and catalyst Cu(OAc)2 at 80°C was carried out to yield correspond-
Gogoi et al., reported the synthesis of 1,2,4-triazoles from aryli- ing 1,2,4-triazoles (scheme 2, fig. 3) [27]. A simple and efficient
dene aryl thiosemicarbazones in presence of the CuBr2 catalyst method for synthesis of 1,2,4-triazoles (scheme 3, fig. 3) [28].
and DMSO solvent at 80°C. It is to be noted that high temper- An efficient catalytic system involving copper catalyst, K3 PO4 and
ature was not appropriate for the formation of triazole-thiones. O2 has been developed for the synthesis of 1,2,4-triazoles from
Fig. 3. Various methods for the synthesis of 1,2,4-triazole ring (schemes 1-10).
2
Table 1
Triazole-based drugs available for clinical use.
S. No. Drug name Structure Uses References
1. Fluconazole Antifungal [40,41]
2. Itraconazole Antifungal [42]
3. Voriconazole Antifungal [43]
4. Posaconazole Antifungal [44–46]
(continued on next page)
3
Table 1 (continued)
5. Isavuconazole Antifungal [47]
6. Primaconazole# Antifungal [48]
7. Tebuconazole Antifungal
8. Ribavirin Antiviral [49]
9. Maraviroc Anti-retroviral [50]
10. Rizatriptan Anti-inflammatory [51]
4
Table 1 (continued)
11. Rilmazafone Anxiolytic [52]
12. Estazolam Sedative-hypnotic [53]
13. Nefazodone Antidepressant [54]
14. Trazodone Antidepressant [55]
15. Etoperidone Antidepressant [56]
16. Trapidil Antihypertensive [57]
17. Alprazolam Tranquillizer [58]
5
Table 1 (continued)
18. Letrazole Antiestrogen [59]
19. Vorozole Anti-neoplastic [60]
20. Anastrozole Antineoplastic [61]
#
Primaconazole going through clinical trials (phase-II).
amidines and trialkylamines in presence of DMF (scheme 4, fig. 3)

[29]. Another synthetic route to obtain 1,2,4-triazoles was estab-
lished by Guido Pellizzari in 1894 from the reaction of formamide
and hydrazide and the reaction was named after him (scheme 5,
fig. 3) [30,31]. Another one pot synthesis of 3,4,5-trisubstituted
1,2,4-triazoles was devised from the reaction of secondary amides
and hydrazides in presence of trifluoromethane sulfonic anhy-
dride (Tf2 O) and 2-fluoropyridine (2-FPyr) as a base followed by
the microwave-induced cyclodehydration (scheme 6, fig. 3) [32].
A microwave-assisted approach has been developed which in-
volves the oxidative cyclization of amidrazones and aldehydes us-
ing ceric ammonium nitrate and polyethylene glycol (was utilized
to synthesize 1,2,4-triazoles from alkyl hydrazines with imides at
160°C, 250 psi, and 230 W for 10 min (scheme 7, fig. 3) [33]. Fig. 4. Quinoline clubbed 1,2,4-triazole hybrids as antibacterial agents.
A general method for the synthesis of 1,3,5-trisubstituted 1,2,4-
triazoles was developed from reaction of carboxylic acids, primary
amidines, and monosubstituted hydrazines via sequential reac- medicinal chemistry. Several marketed drugs have been reported
tion in presence of HATU (2-(7-Aza-1H-benzotriazole-1-yl)−1,1,3,3- to possess triazole-based structure. Research has also shown that
tetramethyluronium hexafluorophosphate), DIPEA (diisopropylethy- triazole derivatives holds a broad spectrum of pharmacological at-
lamine), DMF and ethylacetoacetate (scheme 8, fig. 3) [34]. Syn- tributes which is being discussed in the following sub-sections.
thetic route for substituted 1,2,4-triazoles from acylhydrazines with Various researchers have portrayed the importance of a triazole
CS2 in ethanolic potassium hydroxide solvent was also reported nucleus by their recent developments in the discovery of triazole
(scheme 9, fig. 3) [35]. The synthesis of 1,2,4-triazoles from ni- containing compounds.
triles and 2-aminopyridines via copper-catalyzed reaction in pres-
ence of 1,2-dichlorobenzene (DCB), CuBr2, and ZnI2 solvent was 3.1. Antimicrobial activity
also reported (scheme 10, fig. 3) [36]. Some other methods in-
clude multicomponent synthesis such as, Tam et al. reported ni- 3.1.1. Antibacterial activity
trile imine cycloaddition, B. Wong et al. [37] reported the syn- Hofny and colleagues reported the design, synthesis and an-
thesis from 1,3,4-oxadiazolium hexafluorophosphates, Chen et al. tibacterial evaluation of some quinoline clubbed 1,3,4-oxadiazole
[38] reported iodine catalyzed oxidative coupling reactions, Yin et and 1,2,4-triazole hybrids as DNA gyrase and topoisomerase IV
al. [39] reported the synthesis from cyanidation of aldehydes. inhibitors (1 and 2, Fig. 4). Twenty-four new quinoline-1,3,4-
oxadiazole and quinoline-1,2,4-triazole hybrids were synthesized
3. Biological significance of 1,2,4-Triazoles including SAR and tested against DNA gyrase and topoisomerase IV obtained from
Escherichia coli and Staphylococcus aureus. All the title compounds
The recent decade has witnessed remarkable advancement in were screened for DNA gyrase inhibitory activity against E. Coli
the development of the 1,2,4-triazole nucleus as a potential lead in wherein compounds 1a, 1b, 1c, and 2a displayed the strongest in-
6
Table 2
Patents published on 1,2,4-triazole possessing different biological activity.
S.no Patent no. Date Inventor Description References
1. US10975139B1 13, Apr 2021 Robert Babb, Regeneron Pharmaceutical Inc. Anti SARS CoV 2 spike glycoprotein antibodies [62]
and antigen-binding fragments
2. US10918624B2 16, Feb 2021 Ayhan Bozkurt, Imam Abdulrahman Bin, Faisal Anti-cancer azole compound [63]
University
3. US20210205311A1 08, Jul 2021 Hui Wang, Incyte Corporation Combination therapy comprising A2B/A2B and [64]
PD-1/PD-L1 inhibitor
4. US20210015822A1 21, Jan 2021 Marzena MAZUR, Oncoarendi Therapeutics Substituted amino triazoles useful as [65]
S.A. chitinase inhibitors
5. US20200281931A1 10, Sep 2020 Richard L. Schuub, Incyte Corporation Jak 1 pathway inhibitors for treatment of [66]
chronic lungs allograft dysfunction
6. US20200270244A1 26, Sep 2021 Taisheng Huang, Incyte Corporation Pyrazolo pyridines and triazolopyridines as [67]
A2A/A2B inhibitors.
7. US20200399264A1 24, Dec 2020 Ashish Kumar Pathak, Corinne E., Augellis 4-Substituted-2-thiazole amides as antiviral [68]
szafran, Syed Kaleem Ahmed, Atefeb Garzam, agents.
Daniel Streblow, Nicole Haese
8. US10292391B2 21, May 2019 P. J. M. Jung, M. Muehlebach, A. Buchholz, A. Pesticidally active 1,2,4-triazole derivatives [69]
Edmunds, through sulfur enclosing substituents.
D. EMERY.
9. US20190127338A1 02, May 2019 J. SHI, Z. Zhang, Q.SHENG, J. Wang, X. Du, B. Method of synthesizing 1,2,4-triazole-3-thione [70]
Chen. compounds and intermediates.
10. US9540379B2 10, Jan 2017 B. Langen, H.J. Lankau, U. Egerland, C. 1,2,4-Triazolo[4,3- quinoxaline derivatives as [71]
Grunwald, N.Hoefgen, H. Stange, R.Dost. inhibitors of phosphodiesterase’s.
.
11. US9573936B2 21, Feb 2017 Z. Ma, J. C. Medina, S. H. Olson, X. Chen, Y. Triazole agonists of the APJ receptor. [72]
Chen, A. C. Cheng, J. Houze, R.V. Connors, J.
Deignan, P.J. Dransfield, X. Du, Z. Fu, J. A.
HEATH, D. B. Horne, M. R. Kaller, A.Y. Khakoo,
D. J. KOPECKY, S.J. Lai, N. Chen,
L. R. McGee, J. T. Mihalic, N. Nishimura, V.
Pattaropong, G. Swaminath, X. Wang, K. Yang,
W.C. Yeh, M. V. DeBenedetto, R. P. Farrell, S. J.
Hedley, T.C. Judd, F. Kayser.
12. US9376402B2 28, Jun 2016 A. P. Likhite, A. Khan, D. SARKAR, S. R. 1,2,4-Triazole derivatives, and their [73]
Deshpande, anti-microbial activity.
S. Sarkar, P. M. Chaudhary, S. P. Maybhate, S.
R. Chavan.
13. US8685987B2 01, Apr 2014 D. Strobaek, U. S. Sørensen, B. L. Eriksen, C. Substituted [1,2,4]triazolo[1,5-a]pyrimidines [74]
Hougaard, and their use as potassium channel
P. Christophersen. modulators
14. US8802696B2 12, Aug 2014 B. F. Molino, S. Liu, K. Nacro. 7-([1,2,4] Triazolo[1,5-a] pyridin-6-yl)−4-(3,4- [75]
dichlorophenyl)−1,2,3,4-tetrahydroisoquinoli
and use.
15. US8658669B2 25, Feb 2014 D. Goff,R. Singh, J. Zhang, S.Holland, J. Litvak, Bridged bicyclic heteroaryl substituted [76]
T. J. Heckrodt. triazoles useful as Axl inhibitors.
16. US8871760B2 28, Oct 2014 R. S. Stabler, B. E. Loe, C. E. B. Pleiss, R.N. [1,2,4] Triazolo[3,4-C]s [1,4] oxazines as P2×7 [77]
Harris, III, F.J. L.Tapia, P. D. Rege, D. B. Repke, modulators.
K. A.M. Walker.
17 US8349878B2 08, Jan 2013 M. P. G. Laza, A.D. Zueras, N. Jagerovic, J. M. C. 1,2,4-Triazole derivatives as sigma receptor [78]
Montanchez, inhibitors.
M. R. C. Altisent.
18. US8435994B2 07, May 2013 J. M. Harris, A. W. Stamford, B. R. Neustadt. Substituted [1,2,4] triazolo[4,3-alpha] [79]
quinoxalines as adenosine A2A receptor
antagonists.
19. US8546394B2 01, Oct 2013 L. J. Kennedy, J. A. Robl, J. Li, J. J. Li, S. P. Substituted [1,2,4] triazolo[4,3-A]pyrazine [80]
O’Connor, H. Wang, L. G. Hamann 11-beta-hydroxysteroid dehydrogenase
inhibitors.
20. US8501946B2 06, Aug 2013 R.E. A. Thewlis, D. K. Dean, J. M.Muriedas, M. 5,6,7,8-Tetrahydro [1,2,4] triazolo[4,3-a] [81]
Sime, D. S. Walter, J. G. A. Steadman, G. Trani. pyrazines derivatives equally P2×7
modulators.
21. US20120225904A1 06, Sep 2012 J. A. Bosch, I. C. Moruno. Novel 7-Phenyl- [1,2,4] triazolo[4,3-a] [82]
Pyridin-3(2H)-One Derivatives.
22. US7888380B2 15, Feb 2011 S. A. Middleton, S. Huang, R.Lin, S. L. Emanuel, 1,2,4-Triazolylaminoaryl (heteroaryl) [83]
R. H. Gruninger, P. J. Connolly, S.K. Wetter. sulfonamide derivatives.
7
Fig. 5. Antibacterial activity of some pyridine fused 1,2,4-triazolopyrimidinone hybrids.
hibitory efficacies with IC50 values of 34, 26, 32, and 90 nM, re- PASS prediction of antifungal activity was carried out for all the
spectively as compared to reference novobiocin (IC50 = 170 nM). designed analogs among which fourteen compounds were selected
These potent compounds were further screened on S. aureus DNA for synthesis and biological testing. Predicted antifungal activity
gyrase where the tested compounds showed favourable activity (Pa) for all the selected compounds lied in the range of 0.43–0.53.
but weaker than E. coli where the tested compounds showed Selected compounds were screened for antifungal activity using
favourable activity but weaker than E. coli gyrase. Compounds 1a, bifonazole and ketoconazole as reference drugs. Among the tested
1b and 1c displayed IC50 values in the sub micromolar range derivatives, compound 4d displayed the highest activity with
against S. aureus DNA gyrase from (IC50 = 0.79, 0.24, and 0.49, re- MIC ranging between 22.1–184.2 μM while the reference drug,
spectively), which was higher than novobiocin (IC50 = 0.041 μM). ketoconazole exhibited MIC in the range of 480–640 μM. All the
These compounds also displayed promising results against topoi- compounds showed better antifungal effect than ketoconazole
somerase of both the strains having IC50 in sub micromolar and bifonazole. Docking studies were performed with lanosterol
range. Antibacterial activity was also tested for the most active 14α -demethylase of C. albicans and DNA topoisomerase IV. Results
compounds taking ciprofloxacin as standard where compound 1b revealed that the docked compounds showed higher free binding
demonstrated strongest antibacterial activity having MIC value of energy than CYP15. Thus, indicating that inhibition of this enzyme
10 ng/ml against S. aureus as compared to standard ciprofloxacin could be a putative mode of action of the analyzed compounds.
(30 ng/ml). Further the tested compounds did not show any sign Moreover, in silico studies suggested that the target compounds
of cytotoxicity in cell viability assays. Docking simulations also val- possessed drug-likeness and none of the compounds violated any
idated the present biological activity where compounds 1b sug- Lipinski’s rule. All the screened compounds were predicted to pass
gested the good fitting and favourable binding with key amino the blood-brain barrier except for compounds 4c and 4e. To ensure
acids [84]. the safety of the title compounds, cytotoxicity was determined in
Sanad and colleagues synthesized pyridine fused 1,2,4- both cancerous breast cancer cell line MCF7 and non-cancerous
triazolopyrimidinone hybrids as promising MRSA and VRE cell line HK-2 where results indicated that few compounds on
inhibitors (3, Fig. 5). Synthesized compounds were tested initial screening showed little toxicity at 100 μM concentration.
in vitro for antibacterial efficacies against Staphylococcus au- But at a 50 μM, tested compounds displayed higher survival as
reus (ATCC6538), Enterococcus faecalis (ATCC29212), Klebsiella compared to 100 μM results. From the above findings, it can be
pneumoniae (ATCC10031) and E. coli (ATCC9637) strains tak- concluded that compound 4a, 4b, 4d, 4f and 4g were considered
ing ciprofloxacin as a standard drug. Among all the screened as potential candidates for further drug development [86].
derivatives, hybrids 3b and 3d bearing 4-methoxyphenyl moiety Wu et al. designed and synthesized three series of analog of
displayed the highest antibacterial activity against S. aureus with voriconazole bearing triazole core (5, 6, and 7, Fig. 7). All the syn-
MIC values of 1.6 and 1.5 μM, respectively which was even better thesized derivatives were tested for three selected fungal strains
than the standard, ciprofloxacin (MIC=2.7 μM). Compounds 3a and (C. abl SC5314, C. neo, A. fum) compared to standard references,
3c showed the second-best antibacterial activity with MIC values fluconazole and voriconazole. The MIC80 values for the all the
of 3.4 and 3.3 μm, respectively against S. aureus. Remaining com- screened compounds were found in the sub-micromolar ranges
pounds displayed lower MIC values in the range of 28.3–54.9 μM. against Candida albicans, Cryptococcus neoformans, and Aspergillus
Encouraged from the findings of antibacterial evaluation against S. fumigates. Target compounds 5 displayed higher antifungal activ-
aureus and E. faecalis, potent analogs 3a-d were further screened ity among the three series except 5f wherein compounds 5a-
against four different MRSA (ATCC33591 and ATCC43300) and e displayed MIC80 values in the range of 0.125–1 μg/mL against
VRE (ATCC51299 and ATCC51575). Results suggested that hybrids A.fum. strain which was better than standard, fluconazole (illus-
3b and 3d displayed higher MIC value of 3.3 and 3.2 μM against trated in Table 3). Excellent activity was observed for compounds
ATCC33591 MRSA or ATCC51299 VRE strains, respectively, while 5a-e against C.neo strain (MIC80 = 0.5–0.0156 μg/mL). Compounds
they gave MIC values of 1.6 and 1.5 μM against ATCC43300 MRSA 5a and 5b were selected as representative compounds among all
or ATCC51575 VRE strains, respectively. Hence, the potent hits and were also tested for other fungal strains where compound 5b
identified from the present investigation could be utilized as an was found to be the most active in the in vitro investigations. Se-
important lead for further drug development [85]. ries 6 and 7 were synthesized through the structural modifica-
tion of compound 5a where both the series failed to demonstrate
3.1.2. Antifungal activity potent antifungal activity against all the tested strains. The se-
Antifungal evaluation of some new 1,2,4-triazole based lected compound 5b was also tested for in vivo evaluation where it
chromenols was reported by Zveaghintseva et al. (4, Fig. 6). A showed inferior activity in the mice. Docking studies also validated
8
Fig. 6. Antifungal potential of some new 1,2,4-triazole based chromenols.
Fig. 7. Triazole-based compounds derived from voriconazole.
Table 3
Biological evaluation of compounds 5a-f.
MIC80 (μg/mL)
Compound
Candida albicans Cryptococcus Aspergillus
SC5314 neoformans fumigatus
5a 0.0156 0.0156 1
5b 0.03125 0.0156 0.125
5c 0.125 0.125 1
5d 0.03125 0.125 1
5e 0.0156 0.125 0.5
5f 0.5 0.5 8
Fluconazole 1 2 >64
Voriconazole 0.03125 0.03125 0.25
the biological activity suggesting the formation of key interactions

of 5b within the 3D model of Aspergillus CYP51 [87].
In search of potential antifungal agents, Çavusoglu et al. synthe-
sized a new series of triazole appended oxadiazole compounds and
evaluated them for antifungal and apoptotic effects (8, Fig. 8). All
the synthesized compounds were evaluated for anti-candidal ac- Fig. 8. Oxadiazole appended 1,2,4-triazoles as promising antifungal agents.
tivity against panel of Candida species [C. albicans (ATCC 90028), C.
glabrata (ATCC 90030), C. krusei (ATCC 6258), C. parapsilosis (ATCC
22019)] taking ketoconazole and clotrimazole as standard refer-
ences. Among the tested compounds, eight compounds were found 8b on four fungal strains were found in between 36.7 and 42.3%
to possess moderate activity against the tested fungal strains. Com- which were even more than the standard drugs. The late apoptotic
pounds 8a and 8b were identified as the most potent antifungal effects of compound 8a (MIC90 μg/ml) on C. glabrata, C. krusei and
agent among all the screened derivatives against C. albicans and C. C. parapsilosis were 36.7%, 42.3% and 41.8%, respectively. Compound
glabrata with MIC90 value of 62.5 μg/ml. Moreover, apoptotic ef- 8a also showed significant apoptotic activity on C. albicans which
fects of the potent compounds 8a and 8b were analyzed on the was found as 13.9% at tested MIC90 μg/ml concentration, while its
tested fungal strains based on Annexin V-PI binding capacities us- necrotic effect was determined as 7%. All these results confirmed
ing flow cytometry assays after 24 h incubation period. Results that the target compounds were safe and effective as antifungal
demonstrated that early and late apoptotic ratios for compound and apoptotic agents in the tested concentrations [88].
9
Fig. 9. Isoxazole incorporated triazole analogs as antifungal agents.
Fig. 10. SYN-2869 inspired triazole derivatives as promising antifungal agents.
Table 4
Antifungal evaluation of compounds 9a, 9b and 9c.
MIC80 (μg/mL)
Compounds
C.alb Y0109 C. alb SC5314 C.par 22,019 C.neo32,609 C.gla 537 A.fum 7544 T.rub cmccftla M.gyp cmccftla
9a 0.0625 0.0313 0.125 0.125 0.0313 2.0 0.0625 0.5

9b 0.0625 0.0625 0.25 0.125 0.125 2.0 0.125 0.5
9c 0.0625 0.0625 0.125 0.125 0.0313 2.0 0.0625 0.5
Fluconazole 0.25 0.5 1 1 2 >64 8.0 32
Ravuconazole 0.0625 0.0625 0.25 0.125 0.125 2.0 0.125 1.0
Xie et al., reported the design, synthesis, and antifungal evalu- A library of compounds bearing pyridine was synthesized in-
ation of new triazole analogues of ravuconazole and isavuconazole spired from an orally active antifungal agent, SYN-2869 and tested
(9, Fig. 9). All the synthesized compounds were evaluated for an- for antifungal activity by Cao and co-workers (10 and 11, Fig. 10).
tifungal activity against a panel of eight fungal strains. Majority of All the target compounds were tested for in vitro antifungal evalu-
the screened compounds were found potent having MIC80 in the ation using serial dilution method taking fluconazole and voricona-
sub-micromolar range against a panel of tested fungal cell lines zole as standard references. Among the evaluated compounds,
(C.alb: Candida albicans; C.par: Candida parapsilosis; C.neo: Crypto- compounds 11 possessed better inhibitory profile compared to
coccus neoformans; C.gla: Candida glabrata; A.fumi: Aspergillus fu- compounds 10 against six tested fungal strains. Compounds 10a
migatus; T.rub: Trichophyton rubrum; M.gyp: Microsporum gypseum). and 11a were found to possess better activity than standard against
Among which compounds 9a, 9b and 9c exhibited the most po- Candida parapsilosis and A. fumigatus. Potent compounds (10a and
tent antifungal activity in comparison to standard ravuconazole 11a) observed in the in vitro testing were selected for further test-
(depicted in Table 4). Rest of the compounds also displayed good ing of aqueous solubility wherein all the tested compounds were
antifungal activity [89]. found to possess better solubility than SYN-2869 [90].
10
Fig. 11. Pyrazole and triazole based antifungal agents. Fig. 13. Quinazolinone based triazolothiadiazole possessing antimicrobial proper-
ties.
Bendaha and co-workers described the synthesis and antifun- 3.1.3. Dual antibacterial and antifungal activity
gal evaluation of new series of tridentate ligands based on pyra- Sekhar et al. synthesized series of pyrimidinyl clubbed oxa-
zole and triazole (12 and 13, Fig. 11). Two series of compounds diazoles, thiadiazoles and triazoles using conventional and ultra-
bearing bipyrazolic and bitriazolic moiety were tested for antifun- sonication methodologies (14–16, Fig. 12). Final target compounds
gal activity against S.cerevisiae. Results suggested that the hydrox- 14, 15, and 16 were screened for antimicrobial activity against a
ymethyl functional group was important for anti-fungal activity. panel of bacterial and fungal cell lines via zone inhibition method
Cell cycle analysis was also undertaken by measuring DNA content at different concentrations (12.5, 25, 50 and 100 μg/well). Results
using flow cytometry to determine whether compound 12 caused revealed that compounds bearing pyrimidinyl fused thiadiazoles
cell cycle perturbation. Results revealed that compound 12 led to exhibited better antimicrobial activity in comparison to series of
delay in the G1 phase of the cell cycle. In addition, mode of action compounds having pyrimidinyl bis oxadiazoles 14 and pyrimidinyl
of compound 12 was investigated which illustrated that compound bis triazoles 16. All the tested compounds were found to inhibit
12 and 13 caused DNA damage that necessitated the function of spore germination against tested fungal strains. Among all the
double-strand break repair pathways and the SKI complicated, as screened compounds, analog 16a and 16b displayed comparable
well as impairing PKC1 roles in DNA metabolism. These potent antifungal activity as compared to standard, ketoconazole. While,
compounds cause DNA damage hence acting by a different mecha- target compounds 15a and 15b showed significant antibacterial ac-
nism as compared to other azole derivatives. As a result, these two tivity [92].
compounds 12 and 13 may resemble potential lead molecules for Lv et al. reported the design, synthesis and antimicrobial
the further progress of antifungal medications for human medicine evaluation of new series of 1,2,4-triazole fused thiadiazole moiety
[91]. (17, Fig. 13). All the synthesized compounds were screened for
Fig. 12. Pyrimidinyl clubbed oxadiazoles, thiadiazoles and triazoles as potent antimicrobial agents.
11
(GF) based on the method of mycelial growth rate. Results of the

antifungal evaluation elucidated that majority compounds did not
exhibit appreciable antifungal activity except compounds 17e, 17f,
17g, 17h and 17j against the GZ (>78%). The above findings showed
that quinazolinone derivatives containing a 1,2,4-triazole clubbed
thiadiazole moiety can be utilized as lead compounds for the
development of new and more efficient antibacterial agent [93].
Puthiyapurayil et al. reported to synthesis and biological evalu-
ation of series of 1,2,4-triazole clubbed thioridazines as anticancer-
ous, anthelmintic, antibacterial and antifungal agents (18, Fig. 14).
All the synthesized compounds were tested in vitro for cytotoxic
activity by trypan blue exclusion method using Ehrlich Ascites Car-
cinoma (EAC) cell lines and MTT assay method using different can-
cer cell lines (EAC, MCF-7 and A549). Results of the in vitro cyto-
toxicity testing indicated that the compounds 18a, 18d, 18e, 18f,
18g, 18i, 18j, 18k and 18l were found to be active in MTT as-
say with IC50 values in the range of 12.24–29.42 μM in EAC cell
lines. The results of the study revealed that compounds 18a, 18c-
g, 18i-l also showed moderate to good cytotoxic activity in MCF-7
cells. Among all, compound 18j was the most promising cytotoxic
Fig. 14. Thiadiazines fused triazoles as potential lead molecules for multifarious ap-
plications. agent with IC50 value of 10.54 μM. The target compounds were also
assessed for anthelminthic properties where compounds 18k, 18l,
18p-r showed good anthelmintic activity almost similar with stan-
antimicrobial activities wherein all the compounds were found to dard drug, albendazole. The determination of antibacterial and an-
possess good to moderate potencies. Among the title compounds tifungal activities unfolded that all the tested compounds except
17, analogs 17c-e and 17j demonstrated more than 90% inhibitory 18b, 18h and 18n showed good to moderate inhibition against the
capacity towards the Xoo bacterium at 100 μg/mL, which was tested bacterial (E. Coli, S. aureus, P. aeruginosa, B. subtilis) and fun-
better than control BMT (52.8%). Furthermore, compounds 17a gal strains (R. oryzae, A. fumigates, A. niger, T. mentagrophytesa) [94].
and 17b were found to possess more potent inhibition capabilities Kumari et al. discussed Synthesis and biological evaluation
against the pathogen Xac (89.2% and 99.4%, respectively) at the of heterocyclic 1,2,4-triazole scaffolds as promising antimicrobial
concentration of 100 μg/mL, relative to control BMT (68.5%). agents (19, Fig. 15). All the synthesized scaffolds were in vitro eval-
Inspired from the above encouraging results, EC50 values of the uated for antimicrobial potential against panel of gram-positive
potent compounds was investigated against Xoo and Xac bacterium strains (Bacillus subtilis, Pseudomonas aeruginosa), gram-negative
via serial dilution method where compounds 17d, 17c, 17e and strain (E. coli) and fungal strains (Candida albicans and Aspergillus
17j displayed EC50 values of 28.2, 34.8, 41.5 and 42.5 μg/mL, re- niger). Results revealed that compounds 19c (MICBS ,EC = 24.7 μM,
spectively in comparison to control BMT (95.8 μg/ml). While, com- MICPA ,CA = 12.3 μM) and 19e (MICAN = 27.1 μM) were found
pounds 17a and 17b showed EC50 values of 29.5 and 20.7 μg/ml, to be the most potent antimicrobial compounds among the se-
respectively as compared to control BMT (53.8 μg/ml). Additionally, ries when compared with the standard drug ciprofloxacin, amox-
antifungal potential of the target compounds was also determined icillin and fluconazole. All the synthesized motifs were evalu-
against six phytopathogenic fungi (Botrytis cinerea Pers. (BC), Phy- ated further for in vitro antioxidant assay using DPPH free rad-
tophthora infestans (PI), Verticillium dahliae (VD), Cytospora mand- ical scavenging method where analog 19a (IC50 = 34.83 μg/ml)
shurica (CM), Gibberella zeae (GZ) and Gloeosporium fructigenum and 19b (IC50 = 34.38 μg/ml) displayed the most potent inhibi-
Fig. 15. Structural activity of 1,2,4-triazole containing derivatives.
12
Fig. 16. 1,2,4-triazol-3-yl]-naphthyridinones as promising DNA-gyrase inhibitors.
tion of enzyme in comparison with reference drug ascorbic acid. of 0.78 μg/ml when compared with the standard drug etham-
Moreover urease inhibition evaluation was performed using Jack butol. Further, compounds were examined for cytotoxicity assay
Bean Urease by Indophenol method which revealed that com- against monocyte macrophage cell lines (RAW 264.7) which re-
pound 19b (IC50 = 54.01 μg/ml) was the most potent when com- vealed that all compounds had very low toxicity which could be
pared with the standard drug thiourea. In addition, compounds 19a used as promising hits for further development of anti-tubercular
(IC50 = 3.84 μM) and 19d (IC50 = 3.25 μM) also exhibited signifi- agents [97].
cant anticancerous activity against HCT116 cell line (human colon
cancer cells) using 5-fluorouracil as standard reference [95]. 3.1.5. Antileishmanial activity
Mohamed et al. reported the synthesis and antimicrobial Patil et al. reported the synthesis and biological evaluation
evaluation 3-(5-Amino-(2H)−1,2,4-triazol-3-yl]-naphthyridinones of pyrazine clubbed triazoles as promising antileishmanial agents
as promising DNA-gyrase inhibitors (20 and 21, Fig. 16). All the (23 and 24, Fig. 18). All the synthesized compounds 23 and 24
synthesized compounds were evaluated in vitro for antimicrobial were tested for in vitro antileishmanial activity against a cul-
assay using modified cup diffusion method against gram positive ture of Leishmania donovani promastigotes using a modified 3-(4,5-
(S. aureus and B. subtilis), and gram-negative (E. coli, P. aeruginosa dimethylthiazol-2-yl)−2,5-diphenyl tetrazolium bromide (MTT) as-
and A. actinomycetemcomitans) strains where results revealed that say. Results revealed that compounds 23a and 24a were found to
among all tested series, compounds 20a-c, 21a-b showed good be most promising compounds exhibiting IC50 values of 79.0 μM
antibacterial activity against A. actinomycetemcomitans with zone each when compared with the reference sodium stibogluconate.
of inhibition ranging from 16 to 22 mm and MIC values in the Further, cytotoxic study was also performed with HeLa cell line
range of 4.25–6.3 μg/ml. Compound 20d showed good activity wherein the potent compound 23b showed no cytotoxicity ef-
against E. coli DNA-gyrase with IC50 value of 6.93–9.8 μg/mL fect against HeLa cell line when tested at different concentrations.
followed by compound 20e showing IC50 values of 3.78 μg/mL. Moreover, molecular docking study was performed to understand
Moreover, molecular docking study was performed which illus- the binding interactions with Pteridine reductase 1 (PTR1) enzyme
trated that 1,2,4-triazole ring is bioisosteric to the COOH group of L. donovani (PDB ID: 2XOX). Results revealed that all the docked
that retains the necessary binding interaction with DNA-gyrase compounds displayed good binding affinity exhibiting strong non-
cleavage complex same as the co-crystallized ligand, moxifloxacin. covalent interactions such as hydrogen bond interaction, van der
Additionally computational studies were performed which showed Waal’s interaction, Pi-anion interaction, Pi-Pi shaped interaction,
that synthesised compounds have good intestinal absorption, and alkyl interaction. In silico ADME and metabolic sites prediction
bioavailability, and blood–brain barrier penetration and possess studies also suggested that target compounds showed good drug-
drug-likeness properties which establish them as potential lead likeliness which indicate that these compounds had the potential
for further development [96]. to act as good oral drug candidate. Additionally, title compounds
were evaluated for antioxidant activity using free radical scaveng-
3.1.4. Antitubercular activity ing activity DPPH method which elucidated that all compounds
Pogaku et al. reported the synthesis of new potent antitubercu- showed high to moderate percentage of inhibition as compared to
losis 1,2,4-triazol-1-yl-pyrazole via the ultrasonication-ionic liquid ascorbic acid where compound 23a showed excellent activity with
synergy and evaluated for anti-TB activity (22, Fig. 17). All the syn- IC50 value of 13.96 μM equivalent to standard drug ascorbic acid
thesized derivatives were obtained in shorter reaction time with (IC50 = 14.0 μM) [98].
good yields and well characterized by various spectroscopic meth-
ods, single-crystal X-ray diffraction. All the synthesized compounds 3.1.6. Antimalarial activity
were investigated for in vitro anti-tuberculosis activity against My- Thakkar et al. reported the synthesis and biological evaluation
cobacterium tuberculosis H37Rv (ATCC27294) by employing the Mi- of some new 1,2,4-triazole (25a-e) and 1,3,4-oxadiazole analogs
croplate alamar blue assay method. Among all the screened com- (26a-e) as DHFR inhibitor as well as for antimicrobial potential
pounds, analog 22 was the most potent compound with MIC value (25 and 26, Fig. 19). All the synthesized compounds were evalu-
13
Fig. 17. Antitubercular activity of 1,2,4-triazol-1-yl-pyrazoles.
density. All the compounds possessed good to moderate inhibitory

potencies against bacterial strains and did not possess any anti-
fungal efficacy. The cytotoxicity studies were also performed us-
ing bioassay on S. pombe cells at the cellular level wherein it was
observed that cytotoxicity increased on increasing the concentra-
tion of compounds. The outcomes from cytotoxicity analysis mo-
tivated for genotoxicity studies to check the effect of compounds
on integrity of DNA where the results displayed that analogs af-
fected the integrity of DNA of S. pombe cells. Moreover, in vitro
antimalarial activity was investigated against P. falciparum strain.
All the compounds showed good activity when compared with
standard drug pyrimethamine wherein compounds 25b-d and 26d
were found to possess the highest anti-malarial activity. Dock-
ing study was also performed to determine the potency of active
compounds against P. falciparum dihydrofolate reductase (PDB ID:
4DPD). All the compounds interacted with the active sites (amino
acids) of receptor 4DPD through conventional hydrogen bonds, van
der Waals, π -cation, π -anion, π -alkyl, π -donor hydrogen bond, π -
Fig. 18. Pyrazine clubbed triazoles as promising antileishmanial agents. sulfur, carbon-hydrogen bond, and π -sigma. Compounds showed
high binding affinity showing binding energy in the range of −7.20
to −9.06 kcal/mol which was better than standard drugs, Chloro-
ated for in silico pharmacokinetic studies where results revealed quine and Pyrimethamine. Additionally, DHFR inhibition assay was
that all the analogues agreed to Lipinski’s rule of five except 25d performed with the active compounds (25b-d and 26d) against P.
and 25e. Further, in vitro antimicrobial activity was performed falciparum strain and inhibitiory efficacy against bovine liver DHFR
against different bacterial and fungal strains, analogues were sub- enzyme, The IC50 values of 25b-d & 26d indicated that all com-
jected to DFT and PM6 calculations to examine the anti-bacterial pounds were potent DHFR inhibitors when compared to standard
activity. It was found that the antibacterial activity could be cor- drugs [99].
related to energies of the LUMO and maximum LUMO electron
Fig. 19. 1,2,4-triazole and 1,3,4-oxadiazole bearing analogs as antimalarial agents.
14
Fig. 20. Ribavarin analogues of 1,2,4-triazole having antiviral activity.
3.2. Antiviral activity in the range of 43.78 to 108.65 μM as compared to the standard,
quercetin (4.86 μM) and balcalein (2.24 μM). Further, toxicity was
Isosteric ribavirin analogues bearing triazole ring were syn- determined for the synthesized series of compounds on lympho-
thesized and evaluated for antiviral activity by Zhurilo et al. cytes from MNCs using flow cytometry analysis where compounds
(27 and 28, Fig. 20). Final target compounds 27 and 28 were 30f-h were found to be least toxic among all series 30 while in
screened for in vitro antiviral activity on influenza A virus H5N1 series 31, compounds 31a was the least toxic with 93.26% cellular
(A/duck/Novosibirsk/56/05) and HCV in SPEV cells as well as in viability followed by analogs 31c and 31g. Compounds from series
Vero E6 cells infected with herpes simplex virus (type 1, L2 strain). 30 were found to comparatively more toxic in comparison to series
Among the tested compounds, analog 27c displayed significant se- 31 compounds. The target compounds 30 and 31 also possessed
lectivity against HCV with IC50 value of 8.8 μg/ml as compared to drug-likeliness properties without violating any Lipinski’s rules.
12.5 μg/ml of ribavarin and cytotoxicity Compound 27a demon- In addition, molecular docking studies were performed with the
strated potent activity against HSV-1 with IC50 of 250 μg/ml com- synthesized series of compounds to calculate the binding affini-
parable to the ribavirin activity. Whereas, compounds 27b and 28a ties against human 5-LOX, human 15-LOX and soybean 15-LOX
exhibited no antiviral activity. Cytotoxicity was also determined us- enzymes. Results showed that compound 31c expressed the best
ing optical methods where none of the tested compounds were binding affinity against 5-hLOX with a score of −8.8 kcal/mol com-
found toxic except compound 27c displaying moderate cytotoxic- pared to standard quercetin −8.4 kcal/mol whereas compounds
ity (CC50 =380 μg/ml) [100]. 31g, 30g and 31h displayed higher binding affinities of −9.7, −9.7
and −9.3 kcal/mol, respectively compared to standard quercetin
3.3. Anti-inflammatory activity (−9.0 kcal/mol) against 15-hLOX. The lead compounds obtained
from the present research work could be used as template for
In search of new and effective anti-inflammatory agents, further discovery of anti-inflammatory agents [102].
Muzaffar et al., synthesized a series of phenylcarbamoylazinane- Khan et al., synthesized and biologically evaluated hydra-
1,2,4-triazole amides conjugates and were evaluated for 15-LOX zone derivatives of 1,2,4-triazole as anti-inflammatory agents
inhibitory potential (29, Fig. 21). Results of the in vitro 15-LOX inhi- (32, Fig. 23). All the synthesized analogs were initially evaluated
bition indicated that all the tested compounds showed significant for in vitro antioxidant activity through DPPH assay, total reduc-
inhibitory activity with IC50 values in the range of 9.25–56.35 μM tion capability (TRC) assay, NO radical scavenging assay. In vitro
in comparison to standard quercetin (IC50 = 4.86 μM). Among all investigations demonstrated that among all the tested derivatives,
the screened compounds, 29a and 29d displayed the highest activ- compounds 32e and 32c displayed the highest DPPH scavenging
ity having IC50 values of 9.25 and 9.54 μM, respectively followed activity of 95.45 and 95.31%, respectively followed by 32d (91.67%),
by 29b and 29e. In order to further evaluate the cytotoxicity of 32a (88.69%) and 32b (80.98%) in comparison to ascorbic acid
the title compounds 29 cell viability studies were carried out as standard (95.36%). While, TRC for compounds 32d (2.205),
using mononuclear cells purified from fresh blood. The outcomes 32e (1.924), 32a (1.079), 32b (0.697) and was found to be the
revealed that compound 29c was found to possess least toxicity best among all the compounds compared to the standard ascor-
followed by compound 29b showing 83.5 and 78.4% cell viability, bic acid (2.602). Results of nitric oxide scavenging activity of
respectively. In contrast, compound 29f was found to exhibit max- tested compounds also showed that compounds 32a, 32b, 32d
imum toxicity with 28.5% cell viability. Computational methods and 32e displayed remarkable inhibitory effect of 57.29, 60.49,
including ADME and docking studies also favoured the biological 32.40, 36.33 μg/ml. Six potent compounds 32a, 32c, 32d and 32e
outcomes. Analysis of docked compounds suggested the strong identified in the in vitro investigations were assessed for in vivo
binding of the target compounds within the crystal structure of anti-inflammatory activity wherein compound 32c exhibited the
soybean 15-LOX and human 5-LOX. Hence, these investigations most potent inhibition of 64.44% at 20 mg/kg dose. Rest of the
suggested the potential of the active molecules (29a, 29b, 29d and compounds also showed significant reduction in edema. Moreover,
29e) as promising anti-inflammatory agents [101]. docking studies were carried out with the potent analogs 32a-e
Inspired from the previous research findings, Shahid et al., against the crystal structure of COX-1 (PDB ID: 3KK6) and COX-2
synthesized a series of phenylcarbamoylazinane-1,2,4-triazole (PDB ID: 5KIR) to rationalize the above biological outcome. Results
thioethers conjugates and were evaluated for 15-LOX inhibition revealed that all the analogs exhibited significant binding energy
(30 and 31, Fig. 22). Among the screened compounds, analogs in which compound 32c exhibited the highest binding energy of
30a, 30c, and 31c demonstrated potent inhibitory activity against −10.5 and −11.2 kcal/mol in comparison to standard celecoxib
soybean 15-LOX enzyme having IC50 values of 12.52, 17.82 and [103].
35.64 μM, respectively followed by the compounds 31b, 31 g, 31d, Encouraged from the literature reportings, Tariq et al., synthe-
31a, 30b, 30e, 30d, 30g, 30h, 30f and 31h showing IC50 values sized and evaluated some new 1,2,4-triazole-based benzothiazole-
15
Fig. 21. Series of phenylcarbamoylazinane-1,2,4-triazole amides conjugates as anti-inflammatory agents.
Fig. 22. Phenylcarbamoylazinane-1,2,4-triazole thioethers conjugates as anti-inflammatory agents.
16
Fig. 23. Hydrazone derivatives of 1,2,4-triazole as promising anti-inflammatory agents.
Fig. 24. 1,2,4-triazole-based benzothiazole-2-amines as anti-inflammatory agents.
2-amines as anti-inflammatory agents (33, Fig. 24). The synthe- ther assessed for p38α MAPK mediated ATF-2 phosphorylation.
sized series of analogs were subjected to in vitro evaluation of anti- The results were found favourable as the tested compounds dis-
inflammatory activity by inhibition of albumin denaturation tech- played activity in the range of 35.23–68.05% as compared to stan-
nique. In vitro outcomes showed that the tested compounds pos- dard SB203580 (65.64%). Compound 33c was found to be potent
sessed anti-inflammatory activity in the range of 51.18 to 86.34%. with 68.05% enzyme inhibition. Based on the in vitro findings,
Among all the assayed compounds, analog 33c displayed the high- seven compounds were identified displaying good inhibitory effi-
est anti-inflammatory potential of 86.34% as compared to stan- cacies and were tested for in vivo anti-inflammatory activity. The
dard drug, diclofenac (81.79%). All the title compounds were fur- tested compounds demonstrated good to potent activity ranging
17
Fig. 25. Anti-inflammatory potential of 1,2,4-triazole based pyrimidines.
Fig. 26. Quinoline incorporated 1,2,4-triazole/oxime hybrids as potential anti-inflammatory agents.
from 60.84 to 85.31% whereas standard drug diclofenac displayed tent compounds, in vivo xylene-induced-ear-edema test was car-
83.68% inhibition. Like the in vitro outcomes, compound 33c pos- ried out with compounds 34d and 34e. Results from the in vivo
sessed the highest in vivo efficacy with 85.31% inhibition. The se- studies revealed that compounds 34d and 34e significantly pre-
lected compounds 33a-g were also evaluated for acute ulcerogenic vented the edema at 25 and 50 mg/kg dose where compound 34e
activity where the tested compounds significantly caused reduc- exhibited the strongest inhibition of 49.26% as compared to the
tion in ulcerogenic activity showing better GI safety profile in com- ibuprofen (28.13%) and indomethacin (49.36%) at 50 mg/kg dose.
parison to standard diclofenac. Docking studies also validated the Further, docking studies of compound 34e within the active site
anti-inflammatory potential of the target compounds where the of 3NT1 has been done where the outcomes suggested that the
most potent compound 33c showed good binding mode within docked compound could shrink the cavity space thus enhancing
the active site of p38α MAPK. Thus, compound 33c emerged the interaction force. To further validate the effect of compound
as an important lead for further development as potential anti- 34e on COX-2, expression of COX-2 was evaluated where significant
inflammatory agents [104]. decrease has been marked in the value of COX-2/GAPDH. All these
Zhang et al., illustrated the design, synthesis and anti- findings supported the fact that the some of the designed com-
inflammatory evaluation of new series of 1,2,4-triazolopyrimidines pounds 34d and 34e could act as potent anti-inflammatory agents
(34, Fig. 25). The synthesized compounds were evaluated in vitro [105].
for anti-inflammatory activity using LPS-stimulated inflammation Mohassab et al. reported the synthesis of quinoline contain-
model. In vitro results showed that compounds 34a, 34b and 34c ing 1,2,4-triazole hybrids as promising anti-inflammatory agents
reduced the cell viability in RAW264.7 cells to a greater extent (35–38, Fig. 26). The synthesized compounds were subjected to
than rest of the compounds. TNF-α and IL-6 concentrations were in vitro determination of NO release by using modified Griess
also determined at a dose of 50 μg/ml where compounds 34d and colorimetric method. Results displayed that compounds 36a, 36b,
34e were found to lower the concentration of concerned inflam- 36c, and 38f bearing oximes release small amounts of NO in phos-
matory factors. The compound 34d and 34e were selected for fur- phate buffer. Biological screening of all the target compounds was
ther testing of dose-dependent decrease in levels of TNF-α and done in vivo using carrageenan-induced paw edema in rats where
IL-6. To further establish the anti-inflammatory action of the po- all the tested compounds expressed promising anti-inflammatory
18
further validate the potency of the potent compound 38e, enzyme

kinetics studies were performed where results indicated the com-
pound 38e showed non-competitive inhibition of COX enzyme.
All these findings conclude that the introduction of quinoline
incorporating the 1,2,4-triazole/oxime hybrids holds promising
anti-inflammatory activity [106].
Paprocka et al. synthesized and evaluated series of new 1,2,4-
triazole based derivatives for anti-inflammatory activity (39 and
40, Fig. 27). The synthesized compounds were evaluated for viabil-
ity of peripheral blood mononuclear cells (PBMC) at rest, and ac-
tivated by monoclonal antibody anti-CD3 (aCD3), phytohemagglu-
tinin P (PHA) or E. coli lipopolysaccharide (LPS) where all the com-
pounds except 39d and 39e displayed toxicity at 50–100 μg/ml.
Rest of the compounds that were nontoxic in the above assay were
Fig. 27. 1,2,4-Triazole based anti-inflammatory derivatives. screened on mitogens-induced proliferation in short term culture.
Results indicated that among all the tested compounds, analogs
39g and 40b significantly lowered the proliferation of aCD3 and
action compared to standard indomethacin. Among all the tested PHA-induced PBMC. Compound 39a-c, 39f-g and 40a-b were also
series of compounds, compounds 35a-c, 36a-c, 37a-e, 37g, 37h, assessed for LPS-induced cytokine (TNF-α , IL-6 and IL-10) produc-
38b and 38e elicited excellent anti-inflammatory action with tion. It was found that compounds 39c, 40a and 40b has signifi-
>100% relative potency to standard. These potent compounds cant impact on reduction of cytokine levels. Based on these find-
were further subjected to in vitro evaluation of COX inhibitory ings, it was concluded that all the tested compounds possessed
activity on both ovine COX-1 and human recombinant COX-2 immunomodulatory activity where compounds 39c, 40a and 40b
isoenzymes using SC-560 and DuP-697 as reference compounds. have shown excellent inflammatory potential [107].
Results revealed that most of the tested compounds displayed Derived from naproxen a series of novel thiazole clubbed 1,2,4-
significant inhibition of COX-1 with IC50 values ranging from 0.48 triazoles were synthesized and evaluated for anti-inflammatory
to 15 μM while some of the tested compounds exhibited weak properties by Sarigol et al. (41, Fig. 28). All the synthesized com-
or no inhibition of COX-2 isoenzyme. Among all the screened pounds were evaluated for analgesic and anti-inflammatory activ-
compounds, compounds 38b and 38e were found potent showing ity. Results showed that all the tested compounds exhibited mod-
IC50 values of 0.54 and 0.48 μM, respectively. Apart from these erate to high analgesic activity (tail flick test) in the range of 11–
some of the other tested derivatives also showed sub-micromolar 52% at 50 mg/kg dose. Among all the compounds, hybrids 41a,
inhibition of COX-1. These results also agreed with the in vivo 41b, 41d, 41e, 41g, 41h and 41i exhibited higher analgesic activities
outcomes along with the docking results where majority of the than the other compounds of the series. Analgesic activity for ana-
derivatives were showing similar bonding interaction like the log 41e was higher than that of the standard drugs naproxen [48%
standard drug. Moreover, safety profiles for the title compounds (50 mg/kg); 49% (100 mg/kg)] and indomethacin [47% (10 mg/kg),
was investigated by histopathological studies where compounds 46% (50 mg/kg)]. All these potent compounds were also tested
36c and 38g were observed to have gastro-protective effects. To for hot plate test where again compounds 41d (42%) and 41e
Fig. 28. Thiazole clubbed 1,2,4-triazoles having analgesic/anti-inflammatory properties.
19
Fig. 29. Diaryl-1,2,4-triazoles bearing N-hydroxyurea moiety as dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase.
(40%) were found to be more efficacious than standard naproxen tent in vivo activity at a dose of 30 mg/kg owing to the low
[39% (50 and 100 mg/kg)] and indomethacin [35% (10 mg/kg); 41% bioavailability. While, N-hydroxyurea bearing compound 43c dis-
(50 mg/kg)]. In addition, all the synthesized compounds were as- played the most potent anti-inflammatory activity (inhibition:
sayed for anti-inflammatory activity where all the compounds in- 54.1% at a dose of 30 mg/kg), comparable to the reference drug,
duced significant inhibition of edema especially compounds 41b-g, celecoxib (inhibition: 46.7% at a dose of 30 mg/kg. In addition,
41i and 41j were observed to be favourable. Few compounds hav- analgesic activity was investigated both by chemical and ther-
ing good analgesic as well as anti-inflammatory activity with low mal method for 43c where it was found to increase the pain
ulcerogenic scores (41a, 41b, 41d, 41e, 41h and 41i) were further threshold towards the thermal source as well as increased the
selected for evaluation of their ability to inhibit COX-1 and COX- writhe latency and reduced the number of abdominal constric-
2 enzymatic activity. Results indicated that compounds 41a, 41e, tions and stretching of hind limbs induced by the injection of
41h and 41i were relatively selective for COX-2, whereas 41b ex- acetic acid may contribute to analgesic activity. Further, molecu-
hibited higher selectivity for COX-1. Docking studies also supported lar docking studies were done within the active sites of COX-2
the biological activity suggesting the strong binding interactions of and 5-LOX which validated the anti-inflammatory action of 43c
the potent compounds within the key amino acid residues. Further, by exhibiting strong binding interactions with the key amino acid
acute toxicity studies also constituted the designed analogs to be residues [109].
relatively safer and potent analgesic/ anti-inflammatory molecules Almasirad et al. reported the synthesis and biological evalua-
[108]. tion of new series of methyl-imidazolyl-1,3,4-oxadiazoles and 1,2,4-
In search of novel potential anti-inflammatory agents, diaryl- triazoles as analgesic and anti-inflammatory agents (45, Fig. 30).
1,2,4-triazoles bearing N-hydroxylurea moiety were designed In vivo investigations were performed for analgesic activity (Acetic
and evaluated as dual inhibitors of cyclooxygenase-2 and 5- acid writhing test) and anti-inflammatory activity (carrageenan in-
lipoxygenase by Jiang et al. (42–44, Fig. 29). A series of hy- duced rat paw edema). The outcomes of writhing test revealed
brids were synthesized and initially evaluated in vitro for anti- that majority of the synthesized compounds displayed signifi-
inflammatory activity by measuring COX-2 and 5-LOX inhibitory cant antinociceptive effect as compared to indomethacin standard.
capacities. In vitro results showed that all the compounds displayed The compounds tested potent in analgesic activity were screened
moderate to potent inhibition of COX and LOX. Among all, analogs for anti-inflammatory activity where the target compounds were
42a-f and 43c showed potent COX-2 inhibition (IC50 = 0.13– found active with 33–43% inhibition comparable to the standard
0.19 μM) comparable to that of the standard drug, celecoxib indomethacin. Compounds 45a and 45b were found to be the most
(IC50 = 0.14 μM). While compounds 42c-f, 43a-f, and 44a-e exhib- potent derivative and were further evaluated for acute ulcerogenic
ited equipotent 5-LOX inhibitory capacity (IC50 = 0.74–0.89 μM) activity. A remarkable reduction in the stomach ulcerogenic activ-
to that of the reference, zileuton (IC50 = 0.82 μM). Compounds ity was recorded with a score between 0.50 and 0.58 as compared
found potent in the in vitro findings were further investigated to the standard, indomethacin (1.67). In silico drug-likeliness was
in vivo through xylene-induced ear edema in mice model. Re- also in favor of the title compounds hence suggesting that these
sults suggested that compounds having hydroxamic acid moiety compounds could be selected as lead compounds for further de-
showing potent in vitro efficacy did not exhibited similar po- velopment [110].
20
Fig. 30. 1,2,4-Triazole based anti-inflammatory agents.
Fig. 31. Triazole clubbed quinolinones as antidepressant and anticonvulsant agents.
3.4. Antidepressant activity sized and evaluated for antidepressant and antimicrobial activ-
ity by Jubie and co-workers (48, Fig. 33). All the synthesized li-
Deng et al. reported the design, synthesis and evaluation of tri- brary of compounds were screened for antidepressant properties
azole based quinolinones as promising anticonvulsant and antide- by FST methods taking diazepam as standard drug. Results sug-
pressant agents (46, Fig. 31). Synthesized series of hybrids were gested that all the screened series significantly reduced immo-
tested for antidepressant activities using FST (forced swimming bility time (p<0.01) where compound 48c displayed the most
test) wherein compounds 46a, 46c, 46e and 46f displayed re- potent antidepressant activity. In order to further validate the
markable reduction in the duration of immobility time as com- antidepressant activity, dopamine levels of midbrain region was
pared to reference drug fluoxetine (dose=50 mg/kg). Potent com- determined where compound 48c elevated the dopamine levels
pound 46c was selected for validation of the antidepressant activ- whereas compounds 48a and 48b lowered the dopamine levels.
ity using FST where it significantly reduced the immobility time Antimicrobial investigations also revealed that all the tested com-
in TST when administered with dose 50 and 25 mg/kg. Addition- pounds were found to possess good to moderate antibacterial
ally, anticonvulsant properties of all the target compounds were in- activity [113].
vestigated using maximal electroshock seizure (MES) method. Re-
sults revealed that compound 46a and 46b were found to be the 3.5. Antihypertensive activity
most potent hybrids showing 100% protection against seizures at
100 and 300 mg/kg dose, respectively. Moreover, title compounds Perokhoda et al., reported the synthesis and in silico antihy-
did not display any signs of neurotoxicity at a maximum dose pertensive potential of new mannich bases incorporated 1,2,4-
of 300 mg/kg. Hence, the above findings conclude the lead com- triazoles. The target compounds were synthesized by using one-
pounds as potential antidepressants [111]. pot multicomponent mannich reaction (49, Fig. 34). The synthe-
Synthesized and evaluation of some new aryl substituted 1,2,4- sized compounds were screened through computer prognosis of
triazoles as antidepressants was described by Radhika et al. acute rat toxicity using online program Acute Rat Toxicity of the
(47, Fig. 32). All the synthesized derivatives were tested for gross GUSAR software package wherein results indicated that all the
behavioral studies where all the screened compounds displayed tested compounds 49a-j were promising angiotensin converting
alertness. Antidepressant activity was performed using tail suspen- enzyme inhibitors (ACE) belonging to the toxicity class 4 and 5.
sion method where compounds 47f, 47d and 47e displayed signifi- In addition, molecular docking studies were also carried out us-
cant decrease in immobility time while rest of the compounds ex- ing three different crystal structures (PDB ID: 1R4L, 3NXQ, 4BZR)
hibited slightly lower activity except compounds 47a, 47b, 47c, 47g where the best binding affinity was observed in PDB ID: 1R4L. The
and 47h which were devoid of any activity. All the title compounds outcomes of the docking analysis suggested that majority of the
were free from toxicity even at a high dose of 20 0 0 mg/kg [112]. docked compounds 49a-j showed binding affinity more than the
Derived from natural sources, stearic acid analogues bear- co-crystallized ligand indicating the potent binding of the com-
ing 1,3,4-oxadiazole, 1,2,4-triazole and thiadiazole were synthe- pounds within the crystal structure [114].
21
Fig. 32. Aryl-1,2,4-triazoles possessing antidepressant action.
Table 5
Mean arterial blood pressure results of compounds 52.
Mean arterial blood pressure % Reduction

Compounds MABP (mean ± SEM) in MABP
52a 94.41 ± 7.32 41.84

52b 95.8 ± 3.93 40.98
52c 93.96 ± 6.61 42.11
Propranolol 95.12 ± 4.68 41.40
Hydralazine 96.16 ± 4.70 41.76
al. (52, Fig. 36). A series of compounds were synthesized and eval-
uated for antihypertensive activities by the non-invasive methods
Fig. 33. Fused 1,2,4-triazolothiadiazole having antidepressant activity. using the Tail Cuff method. Among all the derivatives, compounds
52a, 52b and 52c were found to exhibit significant reduction in
mean arterial blood pressure but at a higher dose than the stan-
dard, hydralazine and propranolol as depicted in Table 5 [116].
Ali et al. synthesized 1,2,4-triazole substituted pyrimidine-based
derivatives as antihypertensive agents (53, Fig. 37). Acute toxic-
ity was determined for the screened compounds by calculation
of LD50 . From the observed findings, it has been concluded that
many of the newly tested compounds demonstrated significant an-
tihypertensive activity in comparison to standard, captopril. More-
over, diuretic activity was determined by using KAU method us-
ing furosemide as standard drug. All the tested derivatives showed
Fig. 34. Antihypertensive potential of new mannich bases incorporated 1,2,4- potential diuretic activity. Among all the tested compounds, hy-
triazoles. brids 53a-d showed the highest observed activities (displayed in
Table 6). Hence, these compounds can be considered as potential
antihypertensive lead compounds [117].
Based on previous research findings, Liu et al. designed and
synthesized new series of 1,2,4-triazole bearing 5-substituted
biphenyl-2-sulfonamide derivatives and evaluated for antihyper- 3.6. Anti-epileptic activity
tensive activity (50 and 51, Fig. 35). The target compounds were
screened for radio-ligand binding assay by displacement of [125 I] Lingappa et al., synthesized series of 4-amino-4H-1,2,4-triazoles
Ang II from AT1 receptors in rat liver membranes and from AT2 as potential anticonvulsant agents (54 and 55, Fig. 38). Two series
receptors in pig uterus membranes. The natural substrate Ang II of compounds 54 and 55 were synthesized and evaluated in vivo
and the selective AT1 receptor antagonist losartan were used as for antiepileptic activity at a dose of 100 mg/kg via MES model. Re-
reference drug. Results indicated that maximum compounds from sults demonstrated that among all the screened compounds, com-
series 50 displayed potent affinities for AT2 receptor and none pounds 54b and 55a displayed the significant protection of 64.42
showed any affinity for AT1 receptor. Among series 50, compound and 65.43%, respectively through induced convulsions as compared
50a (IC50 = 0.4 nM) and 51a (IC50 = 5.0 nM) displayed potent AT2 to standard phenytoin (75.80% protective effect). Remaining com-
receptor affinity and selectivity in binding assays. In vivo findings pounds also showed moderate protective effect. Neurotoxicity for
suggested that 50a was more potent and efficacious than losar- the synthesized compounds was also determined using rotarod
tan in RHRs, but had no significant impact on heart rate. While, method at 100 mg/kg dose. All the compounds were found non-
compounds from series 51 neither showed any affinity for AT1 nor toxic except 54a and 55b which demonstrated 25% toxicity after 2
AT2 . Above findings concluded that combining unsubstituted 1,2,4- hr of oral administration [118].
triazole with biphenyl sulfonamide scaffold yielded selective non- Inspired from the previous reported literatures, development
peptide AT2 receptor agonists [115]. of some new 1,2,4-triazole based anticonvulsant drugs acting on
Design, synthesis and biological evaluation of triazole appended voltage-gated sodium channels have been described by Kapron
pyridazinones as antihypertensive agents was carried by Siddiqui et et al. (56, Fig. 39). All the synthesized compounds were inves-
22
Fig. 35. 1,2,4-Triazole bearing 5-substituted biphenyl-2-sulfonamide derivatives as potential antihypertensive agents.
Fig. 36. Triazole incorporated pyridazinones as antihypertensive agents.
Table 6
Biological evaluation results of compounds 53a-d.
Antihypertensive Diuretic
Compounds
Relative potency ED50 [mg/kg] Relative potency ED50 [mg/kg]
53a 6.17 4.38 20.14 0.10

53b 5.87 4.60 18.45 0.11
53c 5.55 4.86 16.61 0.12
53d 6.58 4.10 21.87 0.12
Captopril 1 – – –
Furosemide – – 1 –
tigated for in vivo anticonvulsant efficacy using MES (maximal lower MolDock score than the representative compounds. Among
electroshock-induced seizure) mice model. Results indicated that all the synthesized compounds, 56f and 56g has showed the best
newly synthesized compounds 56a-h did not show appreciable anticonvulsant potential which was further tested to investigate
ED50 values in comparison to previous reported analogs 56i and the mechanism of action. Results elucidated that compound 56f
56j-m by their research group [119,120] indicating that introduc- acted as a weak positive allosteric modulator of GABAA receptors.
tion of branched alkyl chains reduced the anticonvulsant activ- Cytotoxicity studies were carried out with human and murine hep-
ity. Additionally, the synthesized compounds were also screened atic cells wherein tested compounds 56f and 56g were found to be
for neurotoxicity by rotarod test where they displayed higher tox- less toxic than 56l. These derivatives also did not show any sign
icity than previously reported compounds 56i and 56j-m. Dock- of genotoxicity in HepG2 cells. Hence based on these observations
ing score also supported the biological activity through exhibiting it was concluded that previously reported compounds seem to be
23
good pharmacokinetic properties except hERG inhibition that can

optimized by further modifications [122].
Luszczki et al. studied and determined the anticonvulsive prop-
erties of a new S-triazole derivative on the protective action of four
classical antiepileptic drugs (carbamazepine, phenobarbital, pheny-
toin, and valproate) (58, Fig. 41). Animal models were used for
induction of electro-convulsions by maximal electroshock seizure
threshold test and maximal electroshock seizure test. These test
were first utilized to evaluate the antiepileptic property of com-
pound 58 administered alone at an increasing dose (12.5, 25, 37.5,
50, 75 and 100 mg/kg) until the threshold for electro-convulsions
of compound 58 administered animals were statistically differ-
ent from control animals. Those doses of 58 that did not affect
the threshold were selected for testing in combination with the
Fig. 37. Triazole fused pyrimidine as antihypertensive and diuretic agents. antiepileptic drugs. Results of the animal studies clearly displayed
a significantly improved impact on the anticonvulsant action when
administered along with the antiepileptic drug. Hence, establishing
compound 58 as a novel and potential anticonvulsant agent that
could be extrapolated to further clinical studies [123].
3.7. Antioxidant activity
Shakir et al., discussed the synthesis and antioxidant activity

of 1,2,4-triazole and their corresponding fused rings containing
2-methylphenol (59–61, Fig. 42). All the synthesized compounds
were examined for anti-oxidant activity using DPPH assay and
FRAP assay. Among all the synthesized compounds 61a, 61c and 60
showed good antioxidant activity with IC50 values of 80.82, 81.11,
Fig. 38. 4-Amino-4H-1,2,4-triazoles as potential anticonvulsant agents. and 73.57 μg/ml, respectively for DPPH assay when compared with
the reference drug ascorbic acid whereas compounds 59, 61b and
61c showed good activity towards FRAP assay having IC50 values
most promising for further development as anticonvulsant agents of 27.37, 81.11, and 80.54 μg/ml, respectively. Moreover, the synthe-
[121]. sized compounds were tested for tubulin binding affinity with the
Sari et al., reported the synthesis and anticonvulsant screen- aid of docking studies which revealed that compound 61b showed
ing of 1,2,4-triazole derivatives (57, Fig. 40). The synthesized com- the best binding affinity with a value of −6.89 kcal/mol within the
pounds were tested for anticonvulsant properties by performing crystal structure [124].
Epilepsy Therapy Screening Program (ETSP) in mice using maxi- Saadaoui et al. designed, synthesized and biologically eval-
mal electroshock (MES) and rotarod tests. Results inidicated that uated Schiff bases of 4-amino-1,2,4-triazole derivatives as po-
most of the tested compounds showed significant protective effects tent angiotensin converting enzyme inhibitors and antioxidants
against MES-induced seizures where compounds 57a-c were found (62, Fig. 43). The in vitro anti-oxidant study was performed with
to be active at 100 mg/kg. Compound 57c emerged as most active all the synthesized compounds 62a-h using DPPH assay which re-
compound without having any signs of neurotoxicity. All the tar- vealed that all the tested derivatives showed excellent to moderate
get compounds were predicted to possess drug-likeliness and have activity with 71.22 − 96.42% inhibition but among all, compound
Fig. 39. 1,2,4-Triazole based anticonvulsant drugs acting on voltage-gated sodium channels.
24
Fig. 40. 1,2,4-triazole derivatives as anti-epileptic agents.
calculated and X-ray z-matrix coordinates. The compounds 63a-c

were evaluated for anti-oxidant activity using two different meth-
ods [1, 1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging
activity and ferric reducing capacity of extracts (FRAP)] which re-
sulted that compound 63a exhibited the excellent free radical scav-
enging activity (DPPH) and good reducing power showing IC50 val-
ues of 0.80 mg/ml (DPPH) and 0.35 mg/ml (FRAP), whereas com-
pound 63b possessed IC50 of 12.47 mg/ml (DPPH) and 15.65 mg/ml
(FRAP) whereas, analog 63c displayed the lowest antioxidant activ-
Fig. 41. Anticonvulsant property of 1,2,4-triazole based compounds. ity with IC50 values of 24.24 and 39.70 mg/ml in DPPH free radical
scavenging and ferric reducing antioxidant power assays [126].
62f showed excellent radical-scavenging activity when compared

with the standard BHT. Moreover in vitro ACE inhibition assays 3.8. Antidiabetic activity
were performed with all the target compounds using colorimet-
ric method where results elucidated that analog 62e was the most Synthesis and antidiabetic evaluation of some new coumarin
effective having 95.17% inhibition when compared with the stan- appended triazole hybrids was carried by Basappa et al.
dard drug, captopril. In vitro cytotoxic study was also performed (64, Fig. 45). Intermolecular interactions for the synthesized
against human HeLa cell lines which unveiled that all the syn- analogs were studied using Hirshfeld surface analysis and the DFT
thesized compound showed good inhibition effect on human cell method was employed to optimize the molecular geometry. After
growth in a dose-dependent manner. Additionally docking studies that all the synthesized compounds were screened for α -amylase
on ACE active site also validated the discussed biological activity inhibition activity which displayed that all the synthesized com-
demonstrating good fit for all the compounds within the catalytic pounds showed good inhibition wherein compounds 64a and 64b
cavity of the enzyme and showed strong inhibition of the enzyme were the most potent compounds having IC50 values of 5.43 and
through competitive mode [125]. 5.98 μM, respectively when compared to the standard drug lisino-
Lahmidi et al. unfolded the synthesis and antioxidant evaluation pril. Moreover, statistical analysis was performed to analyze their
of some new 1,2,4-triazole fused pyrimidine hybrids (63, Fig. 44). ability to inhibit α -amylase enzyme at four different concentra-
All the synthesized compounds were characterized through NMR, tion levels by two–way analysis of variance (ANOVA). The results
FT-IR, and single crystal X-ray diffraction techniques. The theoret- showed that the compound 64a exhibited more α -amylase inhibi-
ical structure of 63a-c was obtained by DFT calculations at the tion activity compared to that of 64b. Additionally, molecular dock-
B3LYP/6–31+G(d,p) level in a solvent model which showed ex- ing and ADME prediction were performed wherein results demon-
cellent agreement between the experimental and calculated data, strated that compounds 64a and 64b possessed high affinity to-
the agreement is confirmed by very good correlation between the wards the catalytic site of α -amylase and showed better ADME
Fig. 42. 1,2,4-triazoles as potential antioxidant agents.
25
Fig. 43. Structure and SAR of 4-amino-1,2,4-triazole derivatives.
over DPP8 of compounds 65a and 65b (>1984-fold) was better

than Sitagliptin. Additionally, 65a-c was docked against the crys-
tal structure of DPP-4 protein (PDB ID: 1×70) which revealed that
compounds 65a and 65c provided stronger π –π stacking interac-
tion with key residue Phe357 than compound 65a and Sitagliptin.
The compounds 65a and 65c could be promising lead compounds
for further development of DPP-4 inhibitor [128].
Sever et al., reported synthesis of effects of new 4 H −1,2,4-
Fig. 44. 1,2,4-triazole fused pyrimidine hybrids as antioxidants. triazole derivatives as aldose reductase inhibitors (66, Fig. 47). All
the synthesized compounds were evaluated for aldose reductase
inhibition and enzyme kinetics studies which revealed that all the
compounds possessed IC50 values in the range of 0.205–0.346 μM
profiling with majority analogs showing zero violation of Lipinski’s
and Ki ranging between 0.04–0.81 μM where compounds 66b and
rule [127].
66g were identified as most potent AR inhibitors having Ki val-
Fuh et al., reported the design, synthesis and biological eval-
ues of 0.04 and 0.08 μM, respectively compared to that of stan-
uation of glycolamide, glycinamide, and β -amino carbonyl 1,2,4-
dard quercetin (IC50 =3.86 μM and Ki =5.66 μM). Moreover, MTT
triazole derivatives as DPP-4 inhibitors (65, Fig. 46). All the syn-
assay was performed with L929 mouse fibroblast cell line to de-
thesized compounds were biologically evaluated for in vitro DPP-
termine the cytotoxic effects of compounds which revealed that all
4 inhibition by disk diffusion method and the measurement of
the compounds were found nontoxic except compounds 66a and
the zone of growth inhibition which revealed that all the tested
66c-f were nontoxic against healthy cells. Additionally, molecular
compounds showed good to moderate activity where compounds
docking studies were performed to study the essential binding in-
65a-c exhibited potent DPP-4 inhibitory activity with IC50 val-
teractions with the key residues such as Trp219, Phe122 and Trp111
ues of 49.9, 34.4 and 50.4 nM, respectively. Further, selectivity of
within the active site of AR where compounds 66b and 66g were
compounds 65a-c for DPP-4 over DPP-7, DPP-8, and DPP-9 sug-
displaying highest binding affinity with the target protein. In silico
gested that the tested compounds displayed excellent selectivity
ADME study was also performed which displayed that all the com-
for DPP-4 whereas 65b showed lower selectivity. The selectivity
Fig. 45. Coumarin appended triazole hybrids as antidiabetic agents.
26
Fig. 46. 1,2,4-triazole derivatives as DPP-4 inhibitors.
Fig. 47. 1,2,4-triazole derivatives as aldose reducatse inhibitors.
Fig. 48. Pyrano-triazolo-pyrimidine derivatives as α -amylase inhibitor.
pounds possessed good pharmacokinetic profile. Therefore in vitro that compounds 67a, 67d, and 67e showed the lowest values of
and in silico studies concluded that compounds 66b and 66g will chemical hardness, energy gap, and the three highest softness val-
attract a great notice as drug-like AR inhibitors for further investi- ues, in comparison with the other molecules which made them the
gations [129]. most reactive compounds among the series [130].
Hajlaoui et al., designed and synthesized a novel series of Gani et al., synthesized some novel indole based 1,2,4-triazole
pyrano-triazolo-pyrimidine derivatives as α -amylase inhibitors (67, derivatives as potent α -glucosidase and α -amylase inhibitors
Fig. 48). Initially in silico pharmacokinetic parameters were pre- (68, Fig. 49). All the synthesized hybrids initially underwent dock-
dicted which showed that all synthesized compounds were com- ing simulations on α -glucosidase obtained from the human intes-
pliant with Lipinski’s rule of five. All the compounds displayed tine (PDB ID: 3CTT) which displayed that synthesized compounds
easy transportation, absorption, diffusion, and good permeability were well accommodated in the binding pocket of α -glucosidase
across the cell membrane and blood-brain barrier. The plasma pro- enzyme where compounds 68a and 68b showed the best binding
tein binding results also suggested the excellent binding of com- interactions with the key amino acid residues within the active
pounds 67a-b and 67d-e. Moreover, no compounds were found site. Further, in vitro α -amylase inhibitory activity also unveiled
to possess any toxic risks on predictions. Further the designed that all synthesized compounds showed moderate to low in-
compounds were tested for in vitro α -amylase inhibitory activity hibitory potential when compared to standard acarbose but among
which revealed that compounds 67a-e showed good α -amylase in- all compound 68a displayed the best α -amylase inhibitory activity
hibitory activity displaying IC50 in the range of 2.78 - 9.58 μg/ml. in a dose-dependent manner with 30.05% inhibition at 20 μg/ml
Moreover, molecular docking studies were performed (PDB: 2QV4) and 63.14% inhibition activity at 100 μg/ml. Compound 68b also
where compound 67b displayed the highest binding affinity among showed similar α -amylase inhibitory potential with% inhibition
all the docked compounds with a binding energy of −8.0 kcal/mol. of 30.08 at 20 μg/ml and 71.29% inhibition activity at 100 μg/ml.
A theoretical DFT/B3LYP study was also carried out to explain the Moreover, in vitro α -glucosidase inhibitory activity revealed that
reactivity of the target compounds where the results demonstrated compounds 68a and 68b were the most active compound observed
27
Fig. 49. Indole based 1,2,4-triazole derivatives as potent antidiabetic agents.
Fig. 50. 1,2,4-Triazole and 1,3,4-thiadiazole clubbed with different heterocyclic rings as anticancer agents.
having% inhibition of 30.07 and 30.40 at 20 μg/ml concentration toxic activities against all the tested cell lines including MGC-803
[131]. (9.7–10.3 μM), MCF-7 (9.6–10.2 μM), CNE2 (9.5–10.1 μM) and KB
(9.4–9.9 μM). Apart from these compounds, other compounds pos-
3.9. Anticancer activity sessed moderate activities against tested cancer cell lines. Hence
these potent compounds establish them as potential leads for fu-
Abu-Hashem et al., designed and synthesized a series of ture development as anticancerous agents [132].
new 1,2,4-triazole and 1,3,4-thiadiazole clubbed with different Mansury et al., synthesized and biologically evaluated series
heterocyclic rings and evaluated for their anticancer activities of 3-mercapto-1,2,4-triazole derivatives as antiproliferative and an-
(69, Fig. 50). The synthesized compounds were evaluated for in tioxidant agents (70–74, Fig. 51). Two series of compounds as
vitro cytotoxicity against a panel of four cancer cell lines MGC- combertastatin analogs were synthesized and assessed for antipro-
803, MCF-7, CNE2 and KB cells using MTT colorimetric method. liferative activity against colon cancer cell line (SW480). The in
Among all the tested compounds, few analogs such as 69a-e dis- vitro cytotoxicity activity showed that compounds 70 demonstrated
played the highest anticancer activity even better than the stan- cell growth inhibition between 13.46 – 33.84% at 50 μM where
dard 5-fluorouracil. These analogs demonstrated significant cyto- compound 70b displayed the highest activity of 33.84%. Whereas
28
Fig. 51. 3-Mercapto-1,2,4-triazole derivatives as antiproliferative and antioxidant agents.
Fig. 52. 1,2,4-Triazole-3-thiols as anticancer agents.
compounds 71a and 71b showed cell growth inhibition of 57.74 activity against three human cancer cell lines including A549, U87
and 52.53%, respectively against SW480 cell line. In vitro results and HL60. All the tested compounds exhibited moderate to high in
of another series of compounds 72 and 73 showed that com- vitro antiproliferative activity against the tested cancer cell lines.
pounds 72a and 73a expressed the highest inhibition of 35.16% and Compound 75d displayed the most potent activity against all the
54.14%, respectively among their respective series. However, the tested cell lines A549, U87 and HL60 with IC50 values of 3.8, 4.1,
most significant cytotoxicity of 60.70% was showed by compound 17.5 μM, respectively followed by compounds 75a and 75b. Dock-
74 against the tested cell line. Additionally, synthesized compounds ing studies were also conducted with the crystal structure of p53-
were also evaluated for antioxidant potential wherein compounds MDM2 (PDB ID: 1YCR) which helped to establish a hypothetical
70a and 72a displayed the best antioxidant activity of 75 and 71%, binding model that justified the potency of all the synthesized
respectively. Hence, the mercapto containing 1,2,4-triazole could compound screened through in vitro assays. From docking analy-
imply as potential lead for discovery of novel anticancer agents as sis, it was observed that compounds 75a, 75b and 75d were found
well as antioxidants [133]. to be the most potential hits among all the designed compounds.
Patel et al., reported the design, synthesis and biological evalu- Further, molecular dynamics and in silico ADME profile also vali-
ation of novel series of 1,2,4-triazole-3-thiols as anticancer agents dated the above biological activity and indicated that compounds
(75, Fig. 52). Three-finger pharmacophore model was utilized for 75e and 75c were found with zero violation of Lipinski’s rule while
the designing of p53-MDM2 inhibitors since it was based on strat- rest of the compounds violated octanol-water partition coefficient.
egy to mimic three crucial hydrophobic pockets: Phe19, Trp23 and Naaz et al., described the design, synthesis and biological eval-
Leu26. The synthesized molecules 75 were evaluated for anticancer uation of series of 1,2,4-triazole and 1,3,4-oxadiazole as promising
29
Fig. 53. Series of 1,3,4-oxadiazole and 1,2,4-triazole based anticancer agents.
anti-proliferative agent (76 and 77, Fig. 53). A multistep synthetic

pathway was used to synthesize series of topsentin based 1,3,4-
oxadiazole and 1,2,4-triazole analogs. All the synthesized com-
pounds were screened against a panel of 60-human cancer cell
lines among which two cancer cell lines, colon (HCC-2998) and
breast (MCF-7) were found to be more susceptible. Among all the
screened derivatives, compounds 76a-c and 77a-b, exhibited good
anti-proliferative activity against various cancer cell lines. Com-
pounds 76b, 77a and 77b displayed highest activity showing IC50
values of 2.42 μM, 3.06 μM, and 3.30 μM, respectively against MCF-
7 human cancer cell line compared to standard drug doxorubicin
(IC50 = 6.31 μM). Cell cycle analysis was performed with potent
compound 76b which showed that it arrested the cell cycle at
G0/G1 phase and reduced the cell migration potential of MCF-7
cells by disrupting mitochondrial membrane potential. In vitro mi-
crotubule polymerization assays indicated that compound 76b dis-
rupted tubulin dynamics by inhibiting tubulin polymerization dis-
playing IC50 value of 3.89 μM in comparison to standard nocoda-
zole (IC50 = 2.49 μM). In silico docking studies for compound 76b
also supported the reported biological activity by exhibiting strong
binding at colchicine binding site of β -tubulin. All these findings
suggested compound 76b as an important lead molecule that may
Fig. 54. MMP-10/13 inhibition by pyrimidine fused triazoles.
serve as a template for further drug discovery as anticancer agents
[134].
Structure-based drug design and optimization of pyrimi- 7777 nM. Moreover, ligand efficiency metrics were also determined
dine fused 1,2,4-triazole-based matrix metalloproteinase-10/13 in- for comparing and assessing the drug likeness of the synthesized
hibitors was reported by Ashry et al. (78–81, Fig. 54). The compounds where all the compounds passed the acceptable limit
synthesized derivatives were screened for MMPs (metallopro- (0.3) against all the tested MMPs. The most active MMP inhibitors
teinase) inhibitory activity in comparison to N-Isobutyl-N-(4- 81b and 81c were selected further to evaluated their anticancer
methoxyphenylsulfonyl) glycyl hydroxamic acid (NNGH) as a ref- potential against three cancer cell lines including triple negative
erence MMP inhibitor. In vitro evaluation revealed that all the breast cancer (MDA-MB 231), liver cancer (HepG-2), and colon can-
compounds displayed selectivity towards MMP-10 compared to cer cell (Caco-2) taking quercetin as a reference anticancer MMP
MMP-13 except compound 79a which displayed inhibition against inhibitor. Both the tested compound showed superior or compa-
both the enzymes. Among the screened derivatives, compounds rable anticancer activities against the tested cell lines. Moreover,
81b, 79b, 78 and 81a were found to be the most potent MMP- docking studies were performed with the active isomers 80 and
10 inhibitor with IC50 values of 24, 53, 62 and 93 nM, respec- 81b to observe the possible binding mode and justify the selectiv-
tively. Whereas, compound 81c displayed the highest IC50 value of ity of MMP-10 over MMP-13. Results showed that compound 81b
294 nM against MMP-13 which was even more than the reference chelated with the catalytic zinc ion via the triazolopyrimidine core
however, rest of the compounds showed IC50 in the range of 538– and the nearby acetyl oxygen. Additionally, it exhibited hydrogen
30
Fig. 55. Triazole fused pyridine analogues as potent antitubulin agents.
bonding with Ser179 residue that binds one of the calcium ions at IC50 values of 29.94, and 45.69 μM, respectively. Moreover, some
the catalytic site. Hence, explaining its selectivity towards MMP-10 of the potent analogs displaying excellent antiproliferative activ-
[135]. ity on HeLa cells were additionally tested against three different
Yang et al. designed and synthesized 1,2,4-triazole fused pyri- cancer cell lines, including A549, MCF-7 and T47D. Among all the
dine analogues as antitubulin agents (82 and 83, Fig. 55). In vitro screened derivatives, compound 85i was found to be the most po-
screening of the antiproliferative activities of all the synthesized tent analog against the tested strains suggesting its potential for
hybrids was performed against three cancer cell lines A549 (hu- further investigation. Cell cycle analysis also demonstrated that
man alveolar epithelial cells), HeLa (human cervical cancer cells), compound 85i arrested at the G2/M phase. To further determine
and HCT116 (human colon cancer cell lines). Results showed that the potential of these compounds in microtubule system, seven
most of the tested derivatives displayed moderate to good antipro- highly active compounds 85a, 85b, 85f, 85h, 85i, 85j, and 85p
liferative activities against A549 and HeLa cell lines while majority were initially selected to evaluate their in vitro tubulin polymer-
compounds were found inactive against HCT116 cell lines (IC50 > ization inhibition at the concentration of 10 μM. Results indicated
100 μM). Among all the tested compounds, compound 83b showed that most of the tested compounds significantly inhibited tubulin
the strongest inhibition of all the screened cell lines HeLa, A549, polymerization where analog 85a, 85b and 85i showed 77, 68 and
and HCT116 cancer cell lines with IC50 values at 0.75, 1.02, and 81% inhibition, respectively suggesting it to be a most likely target
10.91 μM, respectively. In order to evaluated the toxicity of tar- of these compounds [137].
get compounds, five potent compounds (82a-b and 83a-c) were Zhang et al., discussed the design and synthesis of novel 1,3-
selected and evaluated against non-cancer cell line HEK-293. Com- diaryl-1,2,4-triazole-capped histone deacetylase 6 inhibitors with
pound 83b was further subjected to cell cycle analysis to deter- potential anti-gastric cancer activity (87, Fig. 57). All the syn-
mine the mechanism of action where results clearly indicated that thesized compounds were in vitro evaluated for enzyme inhibi-
it induced significant cell cycle arrest at G2/M phase. Additionally, tion towards HDAC6 and HDAC1 wherein results revealed that
compound 83b was also investigated for inhibition of microtubule among all the tested compounds, analog 87a showed the best in-
formation where it showed favourable activity. To further explore hibitory activity towards HDAC6 (IC50 = 30.6 nM), with 128-fold
the potential of the title compounds on tubulin polymerization, selectivity over HDAC1. Further, the synthesized compounds were
five potent compounds were selected and assayed for inhibition studied for HDAC6 inhibition through inhibit of cell growth in
of tubulin polymerization where results demonstrated that com- MGC803 cells which revealed that compound 87a was the most
pound 83c displayed the best inhibitory activity (56%), while CA-4 potent compound with selectivity towards HDAC6 exhibited im-
exhibited a 79% inhibition at the tested concentration. Therefore, pressive antiproliferative activity against MGC803 cells with IC50
analog 83c was evaluated for antitubulin activities relative to that value of 8.45 nM. Moreover, compound 87a was also assayed for in
of CA-4 at a 1.5 μM concentration where it displayed anti-tubulin vitro HDAC isoform selectivity against HDAC2, HDAC3 and HDAC8,
activity with an IC50 value of 9.9 μM, comparable to the reference where it displayed similar inhibition effect on the three isoforms,
compound CA-4 (IC50 =4.2 μM) [136]. with IC50 values of 224, 235 and 349 nM. Specific binding of com-
Inspired from the previous research findings, series of 1,2,4- pound 87a to HDAC6 was studied afterwards to explore the inter-
triazole fused pyridine analogs were synthesized and evaluated as action between biological macromolecules with small molecules.
tubulin polymerization inhibitors by Yang et al. (84–86, Fig. 56). Results revealed that compound 87a had strong binding affin-
The synthesized compounds were first screened against human ity with human recombinant HDAC6 which leads to the accu-
cervical cancer cells (Hela) wherein majority of the tested com- mulation of acetylated a-tubulin (Ac-a-tubulin) in a dose depen-
pounds displayed remarkable antiproliferative activities in sub- dent manner without significantly increasing acetylation of his-
nanomolar range. Among all the assayed compounds, compounds tone H3 in MGC803 cells. Molecular docking studies also (PDB ID:
85a-j and 85n-q showed better IC50 values in the range of 0.012– 5EF7) showed that compound 87a fitted well into the hydrophobic
0.651 μM compared to the previously reported compound 84 pocket and exhibiting a unique monodentate hydroxamate-Zn2þ
(IC50 = 0.75 μM). Some of the highly active compounds were fur- coordination geometry related to phenylhydroxamate HDAC6 in-
ther selected and explored for cytotoxic activities against a normal hibitors. Additionally, apoptosis of compound 87a on MGC803 cell
human embryonic kidney cell line (HEK-293) where compounds growth suggested that 87a could enhance the apoptosis rate of
85a, 85c, 85f-j and 85p having potent antiproliferative efficacy MGC803 cells in a dose-dependent manner. The safety evaluation
were found nontoxic (IC50 > 100 μM) on the normal human em- and acute toxicity assay were performed with 87a that displayed
bryonic kidney cells, HEK-293, while both the parent compound no toxic effects on tissues at 2 g/kg in vivo, which fully proves
84 and reference CA-4 displayed significant cytotoxicity showing the accuracy of a series of anti-tumor activity. Compound 87a also
31
Fig. 56. Triazole fused pyridine analogues as potent tubulin polymerization inhibitors.
Fig. 57. 1,3-diaryl-1,2,4-triazole as HDAC6 inhibitors with potential anti-gastric cancer activity.
showed promising anti-gastric cancer activity and could be fur- bearing amide functionality as anticancer agents (89, Fig. 59). All
ther explored as a potential lead compound for the development the synthesized compounds were evaluated for anticancer activi-
of novel therapeutic agents of gastric cancer [138]. ties against four different cancer cell lines including breast can-
Holota et al., described the synthesis, characterization and in cer (MCF-7, MDA MB-231), lung cancer (A549), and prostate can-
vitro evaluation of some novel thiazole clubbed 1,2,4-triazolones as cer (DU-145) using MTT reduction assay method. All compounds
possible anticancer agents (88, Fig. 58). All the synthesized com- showed good to moderate activity where compounds 89a-f dis-
pounds were evaluated in vitro for anticancer activity at the con- played excellent activity with IC50 ranging from 0.10 - 11.5 μM
centration of 10 μM against a panel of approximately sixty cancer when compared with the standard etoposide [140].
cell lines including leukemia, melanoma, lung, colon, CNS, ovarian,
renal, prostate and breast cancers. In vitro outcomes revealed that 3.10. Miscellaneous
compounds 88a and 88b were the most potent compounds of the
series having IC50 values 28.99 and 24.43 μM, respectively. Hence, Khan et al. described the synthesis and biological potential of
the findings suggested that derivatives 88a and 88b could effec- coumarin clubbed thiazolotriazoles as efficient inhibitors of ure-
tively act against cancer cell lines without causing toxicity to nor- ase enzyme (90, Fig. 60). All the synthesized compounds were
mal somatic cells [139]. evaluated for their anti-urease potential using thiourea as a stan-
Pragathi et al., reported the design, synthesis, and biological dard where results revealed that all the tested compounds showed
evaluation of library of 1,2,4-thiadiazole-1,2,4-triazole derivatives good to moderate activity with IC50 values ranging between 4.35
32
Fig. 58. Thiazole clubbed 1,2,4-triazole as potential anticancer agents.
Fig. 59. Thiadiazole appended 1,2,4-triazole derivatives as anticancer agents.
Fig. 60. Coumarin clubbed thiazolotriazoles as efficient inhibitors of urease enzyme.
– 193.7 μM. Among the assayed derivatives, compound 90a was pose suggested that the most active compound 90a interacted
found to be the most potent compound with IC50 value of 4.35 μM. with the nickel atom present in the active site through its thia-
Further, molecular docking was performed to predict the binding zole sulfur, the amino group substituted at the phenyl ring facili-
mode of compounds within the active site of the urease enzyme tated hydrogen bonding with the sulfhydryl group of Cys322. The
which suggested that all the compounds were highly active in- chromenone moiety of compound 90a was stabilized by the side
hibitors compared to the standard drug. Analysis of the docked chains of various amino acid residues including Ala279, Thr301,
33
Fig. 61. 1,2,4 Triazole derivatives as promising xanthine oxidase inhibitors.
Val283 and conventional interactions of triazole ring with Val283

and His244, respectively. All these findings concluded the poten-
tial of these compounds as potential lead for tyrosinase inhibition
activity [143].
Ozil et al. reported the synthesis of some novel 1,2,4-
triazole derivatives and evaluated for carbonic anhydrase and
cholinesterase (AChE, BuChE) inhibition activity (93, Fig. 63). All
the synthesized derivatives were evaluated for inhibition effect
against human CA I and CA II isoenzymes, AChE ad BChE enzymes.
Results revealed that all the synthesized compounds showed good
inhibitory activity with IC50 in the range of 0.0538–0.1401 μM for
hCA-I isoenzyme whereas compound 93a showed the best hCA-
II inhibition. Compound 93b showed best AChE inbition display-
ing IC50 value of 0.0465 μM and compound 93c showed strong in-
hibitory against BChE with IC50 = 0.0486 μM. All these newly syn-
thesized derivatives can be used as potential drug precursors or
building blocks in the preparation of more effective drug molecules
for cholinesterase and carbonic anhydrase inhibition [144].
Fig. 62. Potent compound and SAR of novel 2,4,5-trisubstituted-1,2,4-triazole-3-one Bera et al. discussed the synthesis, structure activity relation-
derivatives. ship study of 1,2,4-triazole clubbed triazinedione and its 5-thioxo
hybrids as anti-thymidine phosphorylase (TP) and associated anti-
angiogenic activities (94 and 95, Fig. 64). All the synthesized com-
Pro303, Thr304, His315 and Met367. Overall studies suggested pounds were evaluated for anti-thymidine phosphorylase (anti-TP)
these hybrid motifs as a new class of urease inhibitors allowing activity which demonstrated that compounds 94 and 95 showed
their further investigation to find potential scaffold to overcome the best inhibition with IC50 value of 10.84 and 2.95 μM, respec-
pathological conditions associated with ureolytic enzymes [141]. tively when compared with the reference drug 7-DX. Further, en-
Li et al. designed and synthesized a series of 5-benzyl-3- zyme inhibition kinetic studies were performed with most potent
pyridyl-1H-1,2,4 triazole derivatives as promising Xanthine oxidase compounds 94 and 95 identified from the in vitro studies which
inhibitors (91, Fig. 61). All the synthesized compounds were in- showed that the screened compounds exhibited mixed inhibitor
vestigated in vitro for bovine XO inhibitory potency by determin- whereas standard 7-DX behaved as a competitive inhibitor. More-
ing the uric acid formation. Results revealed that compound 91 over, outcomes of anti-angiogenic activity (inhibition of VEGF ex-
was found to be the most promising compound with IC50 value pression assay and inhibition of MMP-9) showed that the tested
of 0.16 μM. Moreover, molecular docking study was performed to compounds displayed good inhibitory effect at different concentra-
examine the possible interactions between the synthesized com- tions. All these results concluded these compounds to provide a
pounds and XO (PDB code: 1V97) which revealed that potent com- new direction for the design and synthesis of novel TP inhibitors
pound 91 showed good binding interactions with binding pockets with promising anti-angiogenic property [145].
of XO as compared to standard drug topiroxostat [142]. Wu et al. reported the synthesis, biological evaluation and
Akin et al. reported the synthesis of some novel 2,4,5- 3D-QSAR studies of 1,2,4-triazole-5 substituted carboxylic acid
trisubstituted-1,2,4-triazole-3-one derivatives as tyrosinase in- bioisosteres as uric acid transporter 1 (URAT1) inhibitors for the
hibitors (92, Fig. 62). All the synthesized compounds were eval- treatment of hyperuricemia associated with gout (96, Fig. 65). All
uated for the tyrosinase inhibition efficacy which revealed that the synthesized compounds were evaluated in vitro against human
compound 92a was the most potent tyrosine inhibitor having IC50 URAT1 which revealed that compound 96 was the most potent
value of 5 nM value and 56.5% maximum inhibition. Kinetic studies with IC50 value of 0.032 μM. Moreover, 3D-QSAR pharmacophore
also suggested that potent compound 92a showed uncompetitive models was performed based on the activity of the compounds by
inhibition with the target enzyme. Additionally, molecular dock- Accelrys Discovery Studio 2.5/HypoGen where the best hypothesis,
ing studies was performed in order to study the binding inter- Hypo 1, was validated by three methods (cost analysis, Fisher’s
action of these compounds within the binding pocket of the en- randomization and leave-one-out). Concluding the outcomes, com-
zyme wherein results indicated that 92a showed highest binding pound 96 was among the most potent URAT1 inhibitors currently
affinity and binds to the enzyme strongly in comparison to other. under development in clinical trials, the Hypo1 appears to be
The bromo phenyl ring of 92a showed π -alkyl interaction with favourable for future lead optimization [146].
34
Fig. 63. 1,2,4-triazole derivatives as carbonic anhydrase and cholinesterase (AChE, BuChE) inhibitors.
Fig. 64. 1,2,4-triazole clubbed triazinedione and its 5-thioxo hybrids as anti-thymidine phosphorylase.
Fig. 65. 1,2,4-triazole-5 substituted carboxylic acid compounds as uric acid transporter 1 inhibitors.
4. Conclusion this compilation will be highly informative reference in suggesting

the massive scope of this efficient nucleus due to its enormous
1,2,4-Triazole has emerged as a diverse scaffold possessing wide potential on different biological targets.
array of medicinal activities. This review summarizes the research
work carried out in the field of 1,2,4-triazoles in the last decade.
1,2,4-Triazole offers a high degree of structural diversity that Declaration of Competing Interest
has helped in identifying novel and effective therapeutic agents
by improving the pharmacokinetics and other physicochemical The authors declare that they have no known competing finan-
features. Sufficient research progress has been made towards the cial interests or personal relationships that could have appeared to
medicinal chemistry of 1,2,4-triazoles that has fabricated it as influence the work reported in this paper.
a privileged scaffold. This review covered the various synthetic
Data availability
pathways that has contributed substantially in the preparation
of 1,2,4-triazoles. An attempt to summarize the current trends in
No data was used for the research described in the article.
the biological activity of 1,2,4-triazoles including antimicrobial,
antiviral, anticonvulsant, anticancer, anti-inflammatory, antioxidant
and some other medicinal properties have been made. The SAR Acknowledgement
studies of the discussed molecules have also been included which
provide a greater understanding of the accountability of the key The authors extend their sincere thanks to Jamia Hamdard, New
pharmacophoric substituents attached to the ring. We hope that Delhi for providing the necessary support.
35
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Journal of Molecular Structure 1274 (2023) 134487

Contents lists available at ScienceDirect

Journal of Molecular Structure

An updated review on diverse range of biological activities of

1. Introduction diunsaturated ring system containing three nitrogen atoms. Tri-

Fig. 1. Structural isomers of triazoles.

scientiﬁc databases in the last decade. Also, an attempt has been

2. Synthetic approaches for 1,2,4-triazoles

S. No. Drug name Structure Uses References

1. Fluconazole Antifungal [40,41]

2. Itraconazole Antifungal [42]

3. Voriconazole Antifungal [43]

4. Posaconazole Antifungal [44–46]

(continued on next page)

S. No. Drug name Structure Uses References

5. Isavuconazole Antifungal [47]

6. Primaconazole# Antifungal [48]

8. Ribavirin Antiviral [49]

9. Maraviroc Anti-retroviral [50]

10. Rizatriptan Anti-inﬂammatory [51]

(continued on next page)

S. No. Drug name Structure Uses References

11. Rilmazafone Anxiolytic [52]

12. Estazolam Sedative-hypnotic [53]

13. Nefazodone Antidepressant [54]

14. Trazodone Antidepressant [55]

15. Etoperidone Antidepressant [56]

16. Trapidil Antihypertensive [57]

17. Alprazolam Tranquillizer [58]

(continued on next page)

S. No. Drug name Structure Uses References

18. Letrazole Antiestrogen [59]

19. Vorozole Anti-neoplastic [60]

20. Anastrozole Antineoplastic [61]

amidines and trialkylamines in presence of DMF (scheme 4, ﬁg. 3)

S.no Patent no. Date Inventor Description References

Fig. 5. Antibacterial activity of some pyridine fused 1,2,4-triazolopyrimidinone hybrids.

Fig. 6. Antifungal potential of some new 1,2,4-triazole based chromenols.

Fig. 7. Triazole-based compounds derived from voriconazole.

the biological activity suggesting the formation of key interactions

Fig. 9. Isoxazole incorporated triazole analogs as antifungal agents.

Fig. 10. SYN-2869 inspired triazole derivatives as promising antifungal agents.

9a 0.0625 0.0313 0.125 0.125 0.0313 2.0 0.0625 0.5

(GF) based on the method of mycelial growth rate. Results of the

Fig. 15. Structural activity of 1,2,4-triazole containing derivatives.

Fig. 16. 1,2,4-triazol-3-yl]-naphthyridinones as promising DNA-gyrase inhibitors.

Fig. 17. Antitubercular activity of 1,2,4-triazol-1-yl-pyrazoles.

density. All the compounds possessed good to moderate inhibitory

Fig. 19. 1,2,4-triazole and 1,3,4-oxadiazole bearing analogs as antimalarial agents.

Fig. 20. Ribavarin analogues of 1,2,4-triazole having antiviral activity.

Fig. 21. Series of phenylcarbamoylazinane-1,2,4-triazole amides conjugates as anti-inﬂammatory agents.

Fig. 22. Phenylcarbamoylazinane-1,2,4-triazole thioethers conjugates as anti-inﬂammatory agents.

Fig. 23. Hydrazone derivatives of 1,2,4-triazole as promising anti-inﬂammatory agents.

Fig. 24. 1,2,4-triazole-based benzothiazole-2-amines as anti-inﬂammatory agents.

Fig. 25. Anti-inﬂammatory potential of 1,2,4-triazole based pyrimidines.

Fig. 26. Quinoline incorporated 1,2,4-triazole/oxime hybrids as potential anti-inﬂammatory agents.

further validate the potency of the potent compound 38e, enzyme

Fig. 28. Thiazole clubbed 1,2,4-triazoles having analgesic/anti-inﬂammatory properties.

Fig. 30. 1,2,4-Triazole based anti-inﬂammatory agents.