Res Chem Intermed

DOI 10.1007/s11164-016-2794-2

Synthesis and therapeutic potential of quinoline

derivatives

Sangeeta Narwal1 • Sanjiv Kumar1 • Prabhakar Kumar Verma1

Received: 31 May 2016 / Accepted: 19 October 2016

Ó Springer Science+Business Media Dordrecht 2016

Abstract Quinolines are nitrogen-containing bicyclic compounds that are widely

found throughout Nature in various forms. Quinoline derivatives are utilized in the
areas of medicine, food, catalysts, dyes, materials, refineries, electronics, etc. The
quinoline nucleus is present in numerous biological compounds, e.g., antimalarial,
antimicrobial, antimycobacterial, antidepressant, anticonvulsant, antiviral, anti-
cancer, antihypertensive, platelet-derived growth factor (PDGF) receptor tyrosine
kinase (RTK) inhibitory, antiinflammatory, antioxidant, and anti-human immun-
odeficiency virus (HIV) agents. However, owing to the swift development of new
molecules containing this nucleus, many research reports have been generated in a
brief span of time. There therefore seems to be a requirement to collect recent
information in order to understand the current status of the quinoline nucleus in
medicinal chemistry research, focusing in particular on the numerous attempts to
synthesize and investigate new structural prototypes with more effective anti-
malarial, antimicrobial, and anticancer activity.

Keywords Quinoline derivatives  Synthesis  Antimicrobial  Antimalarial 

Anticancer

Abbreviations
Candida utilis C. utilis
Aspergillus flavus A. flavus
Beer yeast B. yeast
Candida albicans C. albicans
Micrococcus luteus M. luteus

& Prabhakar Kumar Verma

[email protected]
1
Faculty of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak 124001, India

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 S. Narwal et al.

Eberthella typhosa E. typhosa

Bacillus subtilis B. s.
Pseudomonas aeruginosa P. a.
Aspergillus clavatus A. c.
Methicillin-resistant Staphylococcus aureus MRSA
Staphylococcus aureus S. aureus
Pseudomonas aeruginosa P. aeruginosa
Escherichia coli E. coli
Shigella dysenteriae S. dysenteriae
Quinolone-resistant S. aureus QRSA
Clostridium tetani C. t.
Vibrio cholera V. c.

Introduction

The number of antimicrobial drugs available on the market is vast, but there remains
a need to discover novel antimicrobial agents with better pharmacodynamic and
pharmacokinetic properties but lesser or no side effects. Most quinoline derivatives
exhibit good antimicrobial activity against various Gram-positive and Gram-
negative microbial species. The antimicrobial activity of quinoline derivatives
depends on the substitution on the heterocyclic pyridine ring rather than the
aromatic moiety [1].
Quinoline (Fig. 1) is also known as 1-benzazine, benzopyridine, and 1-azanaph-
thalene. Chemical modification of quinoline is one of the commonest approaches
used in drug discovery, resulting in improved therapeutic effects and explaining the
wide occurrence of quinolones in bioactive natural products. Quinolines are also
known to inhibit DNA synthesis by promoting cleavage of bacterial DNA gyrase
and type IV topoisomerase, ultimately leading to rapid bacterial death [2].
Quinolines, containing nitrogen group, exhibit important biological activities,
e.g., antimalarial [3, 4], antimicrobial [5], antimycobacterial [6], antidepressant,
anticonvulsant, antiviral [7], anticancer [8], antihypertensive, and antiinflammatory
effects [9], being used extensively in treatment of urinary tract, respiratory, and
bone joint infections as well as sexually transmitted diseases, pneumonia, prostatitis,
and acute bronchitis [10, 11]. Quinine and quinidine, obtained from bark of
cinchona plant, were utilized to treat palpitation, fevers, and tertian fever and as
antiarrhythmic compounds, respectively [12]. Various quinoline derivatives are
used in synthesis of alkaloids, fungicides, biocides, virucides, and rubber chemicals,
and as flavoring agents [13].

Fig. 1 Synthesis of 3-((5- NH2 OH

chloro-2-phenyl-1H-indol-3- HO
ylimino)methyl)quinoline- OH
2(1H)-thione N
Aniline Quinoline

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Synthesis and therapeutic potential of quinoline derivatives

Some marketed preparations of quinoline derivatives with antimalarial properties

are shown below:

OH H
OH
H3CO
H
F3C
H N H
N N N
H
Mefloquine Quinine
O
N
HN N
O

N O
Cl N Et OH

Chloroquine Camptothecin

Biological activities of quinoline derivatives

Antimicrobial activity

During the past few decades, infectious diseases caused by multidrug-resistant

bacterial microorganisms have become a serious issue, representing a growing
threat to human health and being a major problem in many countries worldwide.
There has been a significant increase in clinical drug resistance over the past few
decades, owing to exploitation of antimicrobial agents, thus many infectious
diseases can no longer be treated successfully with general antiinfective agents.
Quinoline derivatives show high antimicrobial activity against various microbial
infections.
A novel class of quinoline derivatives was synthesized by Vivekanand et al. [5],
from 5-chloro-2-phenyl-1H-indole-3-amine (a) and 2-thioxo-1,2-dihydroquinoline-
3-carbaldehyde (b) as starting materials, as presented in Scheme 1. These
derivatives were characterized by ultraviolet–visible (UV–Vis), Fourier-transform
infrared (FTIR), and 1H and 13C nuclear magnetic resonance (NMR) spectroscopy,
electron spin resonance (ESR), thermogravimetric analysis (TGA), and mass
spectroscopy (MS) and their in vitro antimicrobial potential evaluated against
Aspergillus niger and Aspergillus flavus by cup–plate technique. Among the tested

H S
NH2 Cl C
OHC N NH
Cl
EtOH/AcOH
Ph + S N Ph
N H N
H H
(a) (b) (1)

Scheme 1 Synthesis of 5-chloro-2-phenyl-1H-indole-3-amine (a) and 2-thioxo-1,2-dihydroquinoline-3-

carbaldehyde (b)

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 S. Narwal et al.

Table 1 In vitro antimicrobial

Compound Zone of inhibition in mm against microbial strains
activity of compound 1
S. aureus P. aeruginosa A. flavus A. niger

1 42 40 36 36
Cu complex 40 38 36 35

S
S
KOH ClCH2COONa HCl
S C S NaOOC S NHR RHN COOH
+ + S
2HN R Methanedithione
NH2NH2.H2O

O X
X Cl N S
X N Cl N O NH2
N N S RHN N
S N H
Cl RHN N
RN H
O
N-(4-Acetyl-5-(2-chloro-substitutedquin-
olin-3-yl)-4,5-dihydro-1,3,4-thiadia-
zol-2-yl)-N-substitutedacetamide
(2,3,4,5)

Comp. X R Comp. X R
2 Cl 4 H
F F

3 H 5 H

Scheme 2 Synthesis of 3-(1,3,4-thiadiazole-2-yl)quinoline derivatives

compounds, 3-((5-chloro-2-phenyl-1H-indol-3-ylimino)methyl)quinoline-2(1H)-
thione (1) was found to be the most potent antimicrobial agent, and the resulting
synthesized Cu(II) metal complex showed excellent antimicrobial activity. The
results obtained are presented in Table 1.
Bhatt et al. [14] developed a new class of 3-(1,3,4-thiadiazol-2-yl)quinoline
derivatives (Scheme 2). Their chemical structure was confirmed by FTIR, 1H and
13
C NMR, and mass spectrophotometry studies. The antimicrobial potential of the
synthesized derivatives was evaluated using tube dilution technique against Gram-
negative (E. coli and Salmonella typhimurium) and Gram-positive (Staphylococcus
pyogenes and Staphylococcus aureus) microbial species. Among the synthesized
derivatives, compounds 2 and 4 exhibited good activity against S. aureus, and
compounds 3 and 5 were found to be most potent against S. pyogenes. The
antimicrobial activity results for these compounds were almost equal to the standard
drug amoxicillin (Table 2).
Desai et al. [15] synthesized a novel class of 3-chloro-1-(aryl)-4-(2-(2-chloro-6-
methylquinolin-3-yl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl)-4-ethyl-azetidin-2-
ones using 2-chloro-6-methylquinoline-3-carbaldehyde and isonicotinohydrazide as
starting materials (Scheme 3); their chemical structure was confirmed by 1H and 13C

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Synthesis and therapeutic potential of quinoline derivatives

Table 2 In vitro antimicrobial

Compound Bacterial strains
potential of compounds 2, 3, 4, 5
S. typhimurium E. coli S. aureus S. pyogenes

2 32 32 16 64
3 32 32 32 16
4 32 32 16 64
5 64 32 32 16
Amoxicillin 32 32 32 32

NMR, IR, and mass spectrophotometry studies, then they were screened for their
in vitro antimicrobial potential against E. coli, P. aeruginosa, S. aureus, S. pyoge-
nes, C. albicans, A. niger, and A. clavatus by broth dilution method. Among this
series, 3-chloro-1-(4-chlorophenyl)-4-(2-(2-chloro-6-methylquinolin-3-yl)-5-(pyri-
din-4-yl)-1,3,4-oxadiazol-3(2H)-yl)-4-methylazetidin-2-one (6) showed excellent
antibacterial activity and 3-chloro-4-(2-(2-chloro-6-methylquinolin-3-yl)-5-(pyri-
din-4-yl)-1,3,4-oxadiazol-3(2H)-yl)-4-methyl-1-p-tolylazetidin-2-one (7), due to
presence of electron withdrawing group (EWG) –Cl and methyl at p-position of
phenyl ring, exhibited good antifungal activity comparable with standard drugs
(ampicillin and griseofulvin, respectively). The antimicrobial activity results are
presented in Table 3.

Cl N
H3C
1,4-Dioxane N N
OHC CH3 + H2NHNOC N
HN
N Cl C
2-Chloro-6-methylquin- Isonicotinohydrazide
O
oline-3-carbaldehyde
(CH3CO)2O

R
CH3
CH3
O CN N
N CN N Ethanol,AcOH
H3C N
H3C N O
O H2N R
N Cl N Cl
TEA
ClCOCH2Cl
1,4-Dioxane

O O

Cl N Cl H3C N Cl

N N N N

N N O
O

Cl N Cl N
(6) (7)

Scheme 3 Synthesis of 3-chloro-1-(aryl)-4-(2-(2-chloro-6-methylquinolin-3-yl)-5-(pyridin-4-yl)-1,3,4-

oxadiazol-3(2H)-yl)-4-ethyl-azetidin-2-ones

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Table 3 Minimum inhibitory concentration (MIC)unit (lg/ml) and In vitro antimicrobial potential of the compounds (6 and 7)
Compound Bacterial species Fungal species

E. coli P. aeruginosa S. aureus S. pyogenes C. albicans A. niger A. clavatus

6 100 ± 3.78 50 ± 2.64 100 ± 4.55 25 ± 2.21 100 ± 4.04 100 ± 1.24 500 ± 2.35
7 – – – – 100 ± 2.30 100 ± 3.78 500 ± 4.04
Ampicillin 100 100 250 100 – – –
Griseofulvin – – – – 500 100 100
S. Narwal et al.
Synthesis and therapeutic potential of quinoline derivatives

Emami et al. [1] developed a novel class of 7-(4-((6-(chloromethyl)-3-hydroxy-

4-oxo-4H-pyran-2-yl)methyl)piperazin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-
oxoquinoline-3-carboxylic acid derivatives by taking 1-cyclopropyl-6-fluoro-4-oxo-
7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid as starting material, as
presented in Scheme 4; their chemical structures were elucidated by 1H and 13C
NMR and IR studies, then they were checked for their in vitro antimicrobial activity
against Gram-positive (S. aureus, S. epidermidis, B. subtilis) and Gram-negative
bacteria (E. coli, P. aeruginosa, Klebsiella pneumoniae) by agar dilution technique.
Among the tested compounds, 7-(4-((6-(chloromethyl)-3-hydroxy-4-oxo-4H-pyran-
2-yl)methyl)piperazin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-
carboxylic acid (8) demonstrated satisfactory antimicrobial activity due to the
presence of cyclopropyl group, compared with norfloxacin (Table 4).
Feng et al. [10] developed the novel class of quinoline derivatives presented in
Scheme 5, characterized them by IR, 1H NMR, and electrospray ionization (ESI)
mass spectrophotometry studies, and evaluated their in vitro antibacterial potential
against methicillin-resistant S. epidermidis (MRSE) and S. aureus (MRSA), E.
faecalis, E. faecium, and Streptococcus pneumoniae bacteria. Among the synthe-
sized compounds, 7-[3-aminomethyl-4-substituted pyrrolidin-1-yl]-1-cyclopropyl-
6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid dimesylate (9) was
found to be the most potent antimicrobial agent against Gram-negative bacterial
strains with minimum inhibitory concentration (MIC)\0.008–4 lg/ml, being 2–128
and 8–2048 times more effective than gemifloxacin (GMFX) and levofloxacin
(LVFX), respectively. The results obtained are presented in Table 5a, b.
A novel class of quinoline derivatives was synthesized by Cui et al. [16], taking
diethyl malonate and triethoxymethane as starting materials (Scheme 6), and
characterized by IR, 1H and 13C NMR, high-resolution mass spectrometry (HRMS)
spectral studies, and elemental analysis. The in vitro antibacterial potency of the
synthesized compounds was tested against Gram-positive (S. pneumoniae, M. lu-
teus, MRSA, S. aureus, and B. subtilis) and Gram-negative strains (P. aeruginosa,

O O
O
F COOH COOH
OH F
O
Cl OH
N N O
N N
HN O
Cl N
C O
H H
1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (8)
(piperazin-1-yl)quinoline-3-carboxylic acid

Scheme 4 Synthesis of (7-(4-((6-(chloromethyl)-3-hydroxy-4-oxo-4H-pyran-2-yl)methyl)piperazin-1-

yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid)

Table 4 Minimum inhibitory concentrations (lg/ml) of compound 8 against different bacterial species
Compound S. aureus S. epidermidis E. coli B. subtilis K. pneumonia P. aeruginosa

8 0.097 0.39 0.78 0.39 0.195 0.195

Norfloxacin 0.39 0.39 0.195 0.195 0.39 1.56

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 S. Narwal et al.

OCH3

O OCH3 NH2.MeSO3H H3CO

F COOH NO
ON NH
Cl N N OCH3 N N
N N CHC6H5
C6H5CHO, Et3N,
56-86% F
HOOC
7-Chloro-1-cyclopropyl-6- O
fluoro-1,4-dihydro-4-oxo-1,8- MeSO3H
naphthyridine-3-carboxylic acid
47-94%
O
F COOH
HO3SMe.H2N
N N N

N
O
H3CO
OCH3
(9)

Scheme 5 Synthesis of 7-[3-aminomethyl-4-substituted pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-1,4-

dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

Table 5 In vitro antibacterial potential of compound 9 against Gram-positive strains

Compound MIC (lg/ml)

S. a. MRSA1a MRSA2a MSSA1a MSSA2a MRSE1a MRSE2a MSSE2a

9 \0.008 1 0.125 0.03 0.03 0.25 0.25 0.03

LVFX 0.25 32 16 0.5 8 0.25 4 4
GMFX 0.06 4 1 0.25 0.06 2 0.5 1

Compound MIC (lg/ml)

E. fa.1 E. fa.2 E. fa.3 E. fm.1 E. fm.2 S. p.1a S. p.2a

9 0.25 4 0.25 4 4 0.06 0.015

LVFX 8 64 16 32 32 16 32
GMFX 1 8 2 8 8 2 2
a
gemifloxacin (GMFX) and levofloxacin (LVFX) used as standard

E. coli DH52, S. dysenteriae, and E. typhosa) and their in vitro antifungal activity
against A. flavus, b. yeast, C. albicans, and C. mycoderma strains by micro broth
dilution method. Among the synthesized derivatives, 1,4,4a,8a-tetrahydro-1-(2-
hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-6-methyl-4-oxoquinoline-3-carboxylic
acid (10) was found to be the most active, compared with chloromycin, norfloxacin,
and fluconazole. Their antimicrobial activity was affected by fluoro substituent on
benzene ring and nitroimidazole ring, as presented in Table 6a, b.

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Synthesis and therapeutic potential of quinoline derivatives

H
C2H5O OC2H5 N
(a) C2H5OOC HN CH3 (b)
O O
C2H5OOC H3C COOC2H5
Diethyl malonate
O

(c)

COOH COOC2H5 O
O O C2H5OOC CH3
N OH N OH
N (e) N (d)
N N N N
N
O
CH3 CH3
(10)

Scheme 6 Synthesis of 1,4,4a,8a-tetrahydro-1-(2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-6-methyl-4-

oxoquinoline-3-carboxylic

Table 6 In vitro (a) antibacterial and (b) antifungal potential (MIC in lg/ml) of compound 10
Compound Gram-positive bacteria Gram-negative bacteria

M. MRSA S. aureus P. aeruginosa E. coli S. E.

luteus DH52 dysenteriae typhosa

(a)
10 16 8 32 16 32 32 8
Chloromycin 8 16 16 32 32 32 32
Norfloxacin 2 8 0.5 1 16 4 4

Compound Fungal strains

A. flavus C. utilis B. yeast C. albicans

(b)
10 0.5 [512 4 2
Fluconazole 256 8 16 1

Dhanapal et al. [17] discovered a novel class of quinoline derivatives. In this

series, aniline, phenanthrene aldehydes, and vinyl pyrrolidone were taken as starting
materials, applying amino Diel–Alder reactions as presented in Scheme 7; their
in vitro antimicrobial potential was evaluated against V. cholera, B. subtilis,
K. pneumoniae, S. aureus, and E. coli bacterial strains by micro broth dilution
assay method. Among the tested compounds, 9-(4-(2-oxopyrrolidin-1-yl)-2-
(phenanthren-10-yl)quinoline-6-carbonitrile) (11) exhibited potent antimicrobial
activity comparable to standard ciprofloxacin. The results obtained are presented in
Table 7.
A novel series of quinoline-containing benzimidazole derivatives were synthe-
sized by Garudachari et al. [18], taking aniline and isatin as starting materials, as
presented in Scheme 8a, b. The synthesized derivatives were characterized using IR,
NMR, and MS studies and their antimicrobial potential evaluated by well plate
method against S. aureus, E. coli, Xanthomonas sp., and Salmonella sp. bacterial

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 S. Narwal et al.

CHO O
Sc(OTf)3 N
N Acetonitrile
NC NH2 + + O
6-8 h, RT
4-Aminobenzonitrile 1-Vinylpyrr- NC NH
olidin-2-one
Phenanthrene-
9-carbaldehyde DDQ reflux,
Toluene 1-2 h

O
N

NC N

4-(2-Oxopyrrolidin-1-yl)-2-(phenan-
thren-10-yl)quinoline-6-carbonitrile
(11)

Scheme 7 Synthesis of 9-(4-(2-oxopyrrolidin-1-yl)-2-(phenanthren-10-yl)quinoline-6-carbonitrile)

Table 7 In vitro antimicrobial results (MIC = 250 lg/ml) of compound 11

Compound Bacterial strains

B. subtilis V. cholera K. pneumonia S. aureus E. coli

11 ? ? ? ? ?
Ciprofloxacin ? ? ? ? ?

(?) active

strains and A. niger, A. flavus, Penicillium sp., and A. terreus fungal strains. Among
the tested compounds, compounds 12–15 exhibited excellent inhibition of bacterial
growth compared with standard drug ciprofloxacin and compound 16 was a more
active antifungal agent compared with fluconazole. The antimicrobial potential of
compounds 12–16 was improved due to presence of two –Cl groups on
benzimidazole nucleus as well as 4-fluorophenyl group at m-position of quinoline
nucleus. The results for the active derivatives are presented in Table 8a, b.
Ghodile et al. [19] developed a novel class of 1-(3-bromo-5-chloro-2-hydrox-
yphenyl)-3-(2-chloro-8-methylquinolon-3-yl)prop-2-en-1-one compounds by con-
densation of 1-(3-bromo-5-chloro-2-hydroxyphenyl)ethanone and 2-chloro-8-
methylquinoline-3-carbaldehyde (Scheme 9); their chemical structures were con-
firmed by FTIR and 1H NMR techniques, and their in vitro antimicrobial potential
evaluated against various fungal (A. niger, A. flavus) and bacterial strains (E. coli,
P. aeruginosa, S. aureus, and S. pyogenes) by disc diffusion method. (E)-1-(3-Bromo-
5-chloro-2-hydroxyphenyl)-3-(2-chloro-8-methylquinolon-3-yl)prop-2-en-1-one (17)
showed potent antifungal and antibacterial results compared with nystatin and
ciprofloxacin, respectively (Table 9).
A new series of quinoline derivatives were synthesized from 6-hydroxy-3,4-
dihydroquinolin-2(1H)-one and 1-(chloromethyl)-4-methylbenzene (Scheme 10),

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Synthesis and therapeutic potential of quinoline derivatives

(a) O
O HO
Pyruvic acid
H2N Cl + F
Ethanol,TFA F
4-Fluorobenzaldehyde Cl N
4-Chlorobenzenamine

Aromatic-1,
2-diamine
PPA

Cl Cl

N
N
N
N
N HN Cl
HN F
F
(13) Cl
(12)

(b)
Cl
O
O
O HO
33% KOH Aromatic-
O + F 1,2-diamine N
Ethanol F N
N PPA X
H N R2
1-(4-Fluoroph- HN
Indoline-2,3-dione enyl)ethanone
F R1

(14,15,16)

Compound R1 R2 X
14 H H N
15 Cl Cl CH2
16 Cl H CH2

Scheme 8 a Synthesis of 6-substituted-4-carboxyquinolines. b Synthesis of of 2-aryl-quinoline-4-

carboxylic acid derivatives

characterized by 1H and 13C NMR, FTIR, and mass spectrometry, and further
evaluated for their antimicrobial potential against S. aureus and E. coli bacterial
strains, including clinical isolates of different multidrug-resistant Gram-positive
bacterial strains, by 96-well microtiter plate method and broth micro dilution
technique. Among the tested compounds, compounds 18–20 exhibited potent
antibacterial activity comparable to standards (norfloxacin, oxacillin, gatifloxacin,
and moxifloxacin). The results obtained are presented in Table 10 [20].
Based on that study, Gupta et al. [21] designed a new class of 3,5-pyrazolidine-
dione-substituted 4-quinolone compounds from substituted aromatic hydrazides
(Scheme 11), confirmed their structure by FTIR, 1H NMR, and mass spectrometry
studies, and tested their antimicrobial potential against Gram-positive (S. aureus,
B. subtilis) and Gram-negative bacterial (E. coli, S. sp.) and fungal strains (A. niger
and C. albicans) by micro broth dilution technique. Compound 22 showed potent
antibacterial activity and compound 21 exhibited good antifungal activity due to
presence of nitro group on the benzene, compared with ciprofloxacin and
fluconazole as reference drug, respectively (Table 11).

123
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Table 8 In vitro activity of (a) compounds 12–15 against bacterial strains, and (b) compound 16 against fungal strains
Compound S. aureus E. coli Xanthomonas sp. Salmonella sp.

(a)
Zone of inhibition in mm (mean ± SD)
Conc. (lg/ml) 6.25 12.5 6.25 12.5 6.25 12.5 6.25 12.5
12 14 ± 0.50 18 ± 1.00 16 ± 0.50 16 ± 0.50 15 ± 1.00 16 ± 0.50 9 ± 0.50 20 ± 0.50
13 10 ± 0.50 12 ± 0.50 12 ± 0.50 17 ± 0.50 14 ± 0.50 16 ± 0.50 20 ± 0.50 28 ± 0.50
14 16 ± 1.00 16 ± 1.00 14 ± 0.50 14 ± 0.50 10 ± 0.50 14 ± 0.50 9 ± 0.50 12 ± 0.50
15 12 ± 0.50 16 ± 0.50 12 ± 0.50 16 ± 0.50 16 ± 0.50 22 ± 0.50 11 ± 0.50 11 ± 0.50
Ciprofloxacin 18 ± 0.87 20 ± 0.50 19 ± 1.00 21 ± 0.50 18 ± 0.50 22 ± 0.50 19 ± 0.50 31 ± 0.50

Compound A. niger A. flavus Penicillium sp. A. terreus

(b)
Zone of inhibition in mm (mean ± SD)
Conc. (lg/ml) 6.25 12.5 6.25 12.5 6.25 12.5 6.25 12.5
16 15 ± 0.50 18 ± 1.00 11 ± 0.50 16 ± 0.50 12 ± 1.00 12 ± 0.50 10 ± 0.50 16 ± 0.50
Fluconazole 14 ± 0.50 18 ± 1.00 15 ± 0.50 20 ± 0.50 19 ± 0.50 21 ± 0.50 16 ± 0.50 18 ± 0.50
S. Narwal et al.
Synthesis and therapeutic potential of quinoline derivatives

Br
Cl
OH N Cl
N Cl
+ H
EtOH/KOH
Cl
Br
O O
1-(3-Bromo-5-chl- 2-chloro-8-methyl O OH
oro-2-hydroxyp- quinoline-3-carbaldehyde (17)
henyl)ethanone

Scheme 9 Synthesis of 1-(3-bromo-5-chloro-2-hydroxyphenyl)-3-(2-chloro-8-methylquinolon-3-

yl)prop-2-en-1-one

Table 9 Zone of inhibition of compound 17 against microbial strains (in mm)

Compound Gram-negative bacteria Gram-positive bacteria Fungi

E. coli P. aeruginosa S. aureus S. pyogenes A. niger C. albicans

17 22 22 17 15 20 19
Nystatin 28 24 21 21 – –
Ciprofloxacin – – – – 24 24

HO
O
DMF/K2CO3
H3C O NH
Cl
+ N O H3C
H
1-(Chloromethyl)- 3,4-Dihydro-6-hydrox-
4-methylbenzene yquinolin-2(1H)-one DMF/POCl3

S H3C
Cl N
HOOC S EtOH/Piperidine
N Acetic acid O CHO
F O O
O F N Cl
(18,19,20) CH3 N
S COOH
S

Compound R
18 –CH2C6H5
19 –CH(CH3)CH2CH3
20 –CH2CH(CH3)2

Scheme 10 Synthesis of -[1,2,4]triazolo[3,2-b][1,3]thiazino[6,5-b]quinolin-9-yl)ethanones

A novel class of chloro-fluoro-quinoline compounds were synthesized by Jadhav

et al. [13], taking N-(3-chloro-4-fluorophenyl)acetamide as starting material, as
presented in Scheme 12. The molecular structures were confirmed by 1H NMR, IR,
and mass spectrometry studies, and their in vitro antimicrobial potential further
evaluated against Gram-positive (S. aureus) and Gram negative (P. aeruginosa)
bacterial strains by agar diffusion/paper disc technique. Among the tested
compounds, 3-(2,7-dichloro-6-fluoroquinolin-3-yl)-1-(4-hydroxyphenyl)prop-2-en-

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 S. Narwal et al.

Table 10 (a, b) Antibacterial activity (MIC, lg/ml) of compounds 18–20

Compound Gram-positive strains Gram-negative strains

S. aureus E. coli

4220 209 503 1356

(a)
18 2 8 8 [64
19 2 4 4 [64
20 1 8 8 [64
Norfloxacin 2 2 2 16
Oxacillin 1 1 1 [64
Gatifloxacin 0.25 2 4 16
Moxifloxacin 0.25 2 2 [64

Compound Multidrug-resistant Gram-positive strains

MRSA QRSA

3167 3506 3167 3506

(b)
18 1 1 1 1
19 2 2 2 2
20 1 2 1 1
Norfloxacin 8 4 [64 [64
Oxacillin [64 [64 1 1
Gatifloxacin 2 1 8 4
Moxifloxacin 1 1 4 4

1-one (23 ) and 3-(2,7-dichloro-6-fluoroquinolin-3-yl)-1-(4-chlorophenyl)prop-2-

en-1-one (24) showed potent antibacterial activity because of the presence of
electron-withdrawing group on benzene ring, comparable to ampicillin as reference
drug (Table 12).
Jardosh et al. [22] designed a novel class of quinoline-based aurone analogues as
presented in Scheme 13. The molecular structures of the synthesized compounds
were confirmed by 1H and 13C NMR, IR, and mass spectral studies, and their in vitro
antimicrobial potential evaluated against Gram-positive [S. aureus (MTCC 96),
B. subtilis (MTCC 441), Clostridium tetani (MTCC 449)] and Gram-negative
bacterial [E. coli (MTCC), P. aeruginosa (MTCC 1688), V. cholerae (MTCC 3906)]
and fungal strains [Candida albicans (MTCC 227), A. clavatus (MTCC 1323)] by
micro dilution technique. In this class, 1-allyl-3-((Z)-(4,6-dihydroxy-3-oxobenzofu-
ran-2(3H)-ylidene)methyl)-6-methylquinolin-2(1H)-one (26) demonstrated good
antibacterial activity compared with reference drugs (ampicillin, chloramphenicol,
ciprofloxacin, and norfloxacin) while 6-chloro-3-((Z)-(3-oxobenzofuran-2(3H)-yli-
dene)methyl)quinolin-2(1H)-one (25) demonstrated good antifungal activity

123
Synthesis and therapeutic potential of quinoline derivatives

O O
O CH3COCH2COOC2H5
C2H5OH
HOOC NH2 NH2 C2H5O
CON.H2SO4 C H O Reflux
4-Aminobenzoic acid 2 5
N CH3
H

O2N Reflux
NHNH2
O O O
O H
NO2
N N N
CH2(COOC2H5)2 N
HN H
H3C O Reflux
R2 R1 N CH3
H
O
1-(2-Methyl-4-oxo-1, 4-dihydro quinoline-6- CH2(COOC2H5)2
carbonyl)-2-(o-nitrophenyl)-pyrazolidine-3, 5-dione Reflux
(21)
O
O
N N
HN
H3C O
NO2
O
1-(2-Methyl-4-oxo-1, 4-dihydro quino-
line-6-carbonyl)-2-(p-nitrophenyl)
-pyrazolidine-3, 5-dione
(22)

Scheme 11 Synthesis of 3, 5-pyrazolidine-dione substituted-4-quinolone derivatives

Table 11 Antimicrobial activity (MIC in lg/ml) of compounds 21, 22

Compound Gram-positive species Gram-negative species Fungal species

S. aureus B. subtilis E. coli S. species C. albicans A. niger

21 – – – – 62 66
22 66 64 66 68 – –
Ciprofloxacin 8 10 12 6 – –
Fluconazole – – – – 6 10

F
F F
(CH3CO)2O O Microwave O
Cl NH2 G.A.A, POCl3,DMF
3-Chloro-4-fluoro- Reflux Cl N CH3 Cl N Cl
H
benzenamine
CH3OH, O
10% aq.NaOH R

F Cl F OH

Cl Cl

N N
Cl O Cl O

(23) (24)

Scheme 12 Synthesis of (3-(2,7-dichloro-6-fluoroquinolin-3-yl)-1-(4-hydroxyphenyl)prop-2-en-1-one)

and 24 (3-(2,7-dichloro-6-fluoroquinolin-3-yl)-1-(4-chlorophenyl)prop-2-en-1-one)

123
 S. Narwal et al.

compared with griseofulvin and nystatin. The results obtained for these compounds
are presented in Table 13.
Jayanna et al. [23] developed a novel class of quinoline derivatives, taking 5,7-
dichloro-2-hydrazino-1,3-benzoxazole and substituted-2-chloro-3-quinoline car-
baldehydes as starting materials (Scheme 14); their molecular structures were
characterized by IR, 1H and 13C NMR, and mass spectrometry studies, and their
in vitro antimicrobial potential further tested against various Gram-positive and
Gram-negative bacterial species (V. cholera, S. aureus, K. pneumonia, P. aerugi-
nosa, B. cereus, E. coli, and S. flexneri) by agar well diffusion method. Among this
series, 13-(1-(5,7-dichlorobenzo[d]oxazol-2-yl)-1H-pyrazolo[3,4-b]quinoline) (27)
showed potent antibacterial activity compared with ciprofloxacin; its MIC values
are presented in Table 14.
A novel set of quinoline analogues were synthesized by Joshi et al. [24], taking
2-chloroquinoline-3-carbaldehydes as staring material (Scheme 15); their structures
were elucidated by FTIR, 1H and 13C NMR, and mass spectrophotometry, and their
in vitro antimicrobial potential evaluated against S. aureus, B. subtilis, E. coli, and
V. cholera. Among them, N-(2-(6-bromo-2-methoxyquinolin-3-yl)-3-chloro-4-

Table 12 In vitro antibacterial potential of compounds 23, 24

Compound Zone of inhibition in mm (100 lg/ml)

Gram-negative bacterium (P. aeruginosa) Gram-positive bacterium (S. aureus)

23 2.2 2.1
24 2.1 2.4
Ampicillin 2.5 3.3

O R4 HO
R1 CHO
10 mol% NaOH O N
+ O
N O O R3 EtOH, MWI
R2 HO CH3
O
10 mol% NaOH
1-Allyl-3-((Z)-(4,6-dihydroxy-3-oxobenzofuran-2
EtOH, MWI (3H)-ylidene)methyl)-6-methylquinolin-2(1H)-one
H
O N (25)
O

Cl
O
6-Chloro-3-((Z)-(3-oxobenzofuran-2(3H
)-ylidene)methyl)quinolin-2(1H)-one
(26)

Scheme 13 Synthesis of 1-allyl-3(Z) (4,6-dihydroxy-3-oxobenzofuran 2 (3H)-yildiene) methyl 6 methyl

Quinolene 2 (H) one and 6 choloro 3(Z) 3- oxobenzofuran 2 (3H)-yildiene) methyl 6 methyl Quinolene 2
(H) one

123
 Table 13 Antimicrobial activity (MIC in lg/ml) of compounds 25, 26
Compound Gram-negative strains Gram-positive strains Fungi

E. coli P. aeruginosa V. cholerae S. aureus B. subtilis C. tetani C. albicans A. clavatus

25 – – – – – – 100 100
26 50 12.5 62.5 500 100 125 – –
Ampicillin 250 100 250 100 – 100 – –
Chloramphenicol 50 50 50 50 50 50 – –
Synthesis and therapeutic potential of quinoline derivatives

Ciprofloxacin 50 50 100 25 25 25 – –
Norfloxacin 10 100 50 10 10 10 – –
Nystatin – – – – – – 100 100
Griseofulvin – – – – – – 500 100

123
 S. Narwal et al.

Cl
Cl N
O Cl
H2O O Cl
HN + O Reflux NH
H2N N Cl
Cl N N
1-(5,7-Dichlorobenzo[d] 3-Chloronaphthalene-
oxazol-2-yl)hydrazine 2-carbaldehyde PTSA
Reflux,
3h

Cl
N
O
Cl N
N
N
1-(5,7-Dichlorobenzo[d]oxazol-
2-yl)-1H-pyrazolo[3,4-b]quinoline
(27)

Scheme 14 Synthesis of 13-(1-(5,7-dichlorobenzo[d]oxazol-2-yl)-1H-pyrazolo[3,4-b]quinoline)

Table 14 In vitro antimicrobial activity of compound 27

Compound Zone of inhibition in cm

V. cholera S. aureus K. pneumoniae P. aeruginosa B. cereus E. coli S. flexneri

27 2.5 2.6 2.8 2.6 2.8 2.8 2.5

Ciprofloxacin 2.8 2.7 3.1 2.8 2.9 3.0 2.8

H3CO N
DMF/POCl3, MeOH/KOH
Br NHCOCH3
100-1100C OHC Br
N-(4-Bromophenyl)acetamide

Reflux Ar-CO-NH-NH2,
EtOH
Cl O
O
CH N H3CO N
N C NEt3,ClCH2COCl, N
Br H H
OCH3 Benzene N CH Br
N N C N
N-(2-(6-Bromo-2-methoxyquinolin-3-yl)-3- O
chloro-4-oxoazetidin-1-yl)isonicotinamide
(28)

Scheme 15 Synthesis of N-(2-(6-bromo-2-methoxyquinolin-3-yl)-3-chloro-4-oxoazetidin-1-yl)

isonicotinamide

oxoazetidin-1-yl) isonicotinamide (28) demonstrated good antimicrobial activity

compared with ciprofloxacin and norfloxacin (Table 15).
Kathrotiya et al. [25] synthesized a novel set of b-aryloxyquinoline-based N-
arylquinoline analogues, taking 2-chloro-3-formylquinolines as starting material, as
presented in Scheme 16. Their chemical structures were elucidated by FTIR, 1H and

123
Synthesis and therapeutic potential of quinoline derivatives

Table 15 In vitro antimicrobial

Compound Gram-positive species Gram-negative species
activity (MIC in lg/ml) of
compound 28 S. aureus B. subtilis E. coli V. cholera

28 3.125 3.125 0.4 0.4

Ciprofloxacin 2 2 2 1
Norfloxacin 2 2 12 1

R1

R3 R2
H O
N O O N R4 Ethanol R2
Piperidine N
+ NC CN + Reflux R3
R1 CHO CN Malononitrile R5 O N R4
R2 R2 R6 N
Substituted -3-formylquinolin-2- NH2
R5
yloxy)benzonitrile N
R6

(29,30,31,32)

Where R1=Cl, CH3 : R2=H, CH3 ; R3=R5=R6=H, F ; R4=H, CF3

Scheme 16 Synthesis of b-aryloxyquinoline based N-aryl quinoline analogues

13
C NMR, and mass spectrophotometry, and their in vitro antimicrobial potential
evaluated against Gram-positive (B. subtilis, Clostridium tetani, S. pneumonia) and
Gram-negative bacterial (E. coli, S. typhi, V. cholerae) and fungal strains (C. al-
bicans, A. fumigates) by broth micro dilution method in comparison with ampicillin,
ciprofloxacin, norfloxacin, chloramphenicol, griseofulvin, and nystatin as reference
drugs. The enhanced antimicrobial activity of these derivatives is due to presence of
fluorine on N-arylquinoline ring. The results obtained are presented in Table 16.
A novel set of quinoline analogues were synthesized from 2-chloro-3-
formylquinoline, malononitrile, and thiophenol as starting materials as presented
in Scheme 17, their chemical structures confirmed by FTIR, 1H and 13C NMR, and
mass spectral studies, and their in vitro antimicrobial potential evaluated against
Gram-positive (B. subtilis, C. tetani, S. pneumonia) and Gram-negative bacterial
(E. coli, S. typhi, V. cholerae) and fungal strains (C. albicans, A. fumigatus) by
broth micro dilution technique. In this series, 2-(4-chlorophenylthio)-6-amino-4-(2-
chloro-6-methylquinolin-3-yl)pyridine-3,5-dicarbonitrile (33) was found to be a
more active antimicrobial agent when compared with ampicillin, norfloxacin, and
griseofulvin as standard drugs. The results obtained are presented in Table 17 [26].
Mandhane et al. [27] reported a novel series of quinoline derivatives synthesized
from 3-(bromomethyl)-2-chloroquinoline and quinazolin-4(3H)-one as starting
materials, as depicted in Scheme 18; they were characterized by IR, 1H NMR,
and mass spectrometry studies, and their in vitro antimicrobial potential evaluated
against Gram-positive (B. subtilis, S. aureus) and Gram-negative bacterial
(S. typhimurium, P. aeruginosa) and fungal strains (C. albicans, A. niger) by
well-diffusion method. Among the tested compounds, 3-((2-chloro-5-methylquino-
lin-3-yl)methyl)quinazolin-4(3H)-one (34) and 3-((2-(4-hydroxybenzyl)-5-

123
123
Table 16 Antimicrobial activity (MIC in lg/ml) of compounds 29–32
Compound Gram-positive species Gram-negative species Fungal species

B. subtilis C. tetani S. pneumonia E. coli S. typhi V. cholera A. fumigatus C. albicans

29 125 200 250 100 50 62.5 – 250

30 200 100 100 62.5 200 25 – –
31 200 100 100 100 62.5 100 1000 250
32 200 200 62.5 250 200 62.5 1000 1000
Ampicillin 250 250 100 100 100 100 – –
Chloramphenicol 50 50 50 50 50 50 – –
Ciprofloxacin 50 100 50 25 25 25 – –
Norfloxacin 100 50 10 10 10 10 – –
Griseofulvin – – – – – – 100 500
Nystatin – – – – – – 100 100
S. Narwal et al.
Synthesis and therapeutic potential of quinoline derivatives

NH2
Ethanol Cl CN
N Cl N
Piperidine
+ NC CN + HS Cl
Reflux S
CH3
H3C CHO Malononitrile
4-Chlorobenzenethiol CN
2-Chloro-6-methylquinoline- Cl N
3-carbaldehyde 2-(4-Chlorophenylthio)-6-amino-4-(2-chloro-6-
methylquinolin-3-yl)pyridine-3,5-dicarbonitrile
(33)

Scheme 17 Synthesis of 2-(4-chlorophenylthio)-6-amino-4-(2-chloro-6-methylquinolin-3-yl) pyridine-

3,5-dicarbonitrile

methylquinolin-3-yl)methyl)quinazolin-4(3H)-one (35) showed potent antibac-

terial and antifungal activity compared with streptomycin, ampicillin, and
fluconazole (Table 18).
Mistry et al. [28] developed a novel class of quinoline-based azetidinone and
thiazolidinone analogues, taking 2-chloroquinoline-3-carbaldehyde and substituted
amines as starting materials, as described in Scheme 19; their structures were
elucidated by IR, 1H and 13C NMR, and EMI mass spectrophotometry techniques,
and their antimicrobial potential evaluated against Gram-positive [B. subtilis
(MTCC 430), S. aureus (MTCC 96)] and Gram-negative bacterial [E. coli (MTCC
739), P. aeruginosa (MTCC 741)] and fungal species [C. albicans (MTCC 183),
A. niger (MTCC 282)] by paper disc diffusion method. Among the synthesized
derivatives, 3-chloro-4-(2-chloroquinolin-3-yl)-1-(substitutedphenyl)azetidin-2-one
and 3-(substitutedphenyl)-2-(2-chloroquinolin-3-yl)thiazolidin-4-one (36–39)
exhibited potent antimicrobial activity compared with ciprofloxacin and ketocona-
zole. The antimicrobial activity was enhanced due to presence of electron-
withdrawing groups (nitro/chloro substitution) on the synthesized compounds
(Table 19).

Antimalarial activity

Malaria is widespread throughout much of the tropics and subtropics, placing

approximately 40% of the world’s population at risk [29]. This situation is currently
worsening due to emergence and extension of drug-resistant Plasmodium
falciparum infection, which can lead to capillary obstruction and death if treatment
is not instituted properly, also exhibiting resistance to conventional antimalarials.
The quinoline nucleus is found in marketed preparations such as quinine,
chloroquine, amodiaquine, and mefloquine.
Barteselli et al. [3] designed a new class of indenoquinoline compounds, taking
2,6-dichloro-7H-indeno[2,1-c]quinolin-7-one (d) and 2-(piperidin-1-yl)ethanamine
(e) as starting materials, as presented in Scheme 20; Their chemical structures were
confirmed by 1H NMR and HRMS studies, and their in vitro antiplasmodial activity
evaluated against D-10 and/or 3D7 (CQ-S) and W-2 (CQ-R) strains of P. falci-
parum. Among the synthesized derivatives, 2-chloro-6-(2-(piperidin-1-yl)ethy-
lamino)-7H-indeno[2,1-c]quinolin-7-one oxime (40), having low micromolar
activity against P. falciparum, showed potent antimalarial activity compared with
chloroquine as standard (Table 20).

123
123
Table 17 In vitro antimicrobial activity (MIC in lg/ml) of compound 33
Compound Bacterial strains Fungal strains

Gram-positive Gram-negative

S. pneumonia C. tetani B. subtilis E. coli S. typhi V. cholera A. fumigatus C. albicans

33 200 250 200 62.5 100 200 500 500

Ampicillin 100 250 250 100 100 100 – –
Norfloxacin 10 50 100 10 10 10 – –
Griseofulvin – – – – – – 100 500
S. Narwal et al.
Synthesis and therapeutic potential of quinoline derivatives

O
R1 N N
NH NaH, DMF
Br
+ 15-20 min rt N O
N
3-(Bromomethyl)-substituted Quinazolin-4(3H)-one HO
-8-methylquinoline
N
NaH, DMF
15-20 min rt (35)

N Cl N
(34)

Scheme 18 Synthesis of 3-((2-Chloro-5-methylquinolin-3-yl)methyl)quinazolin-4(3H)-one and 3-((2-(4-

Hydroxybenzyl)-5-methylquinolin-3-yl)methyl)quinazolin-4(3H)-one

Table 18 In vitro antimicrobial results (MIC in lg/ml) of compounds 34, 35

Compound Zone of inhibition in mm

Bacterial strains Fungal strains

Gram-positive Gram-negative

B. subtilis S. aureus S. typhimurium P. aeruginosa C. albicans A. niger

34 14.8 (10) 13.4 (10) 16.7 (05) 16.4 (05) 16.2 (05) 16.6 (05)
35 15.4 (10) 15.7 (10) 16.3 (05) 16.3 (05) 16.8 (05) 16.5 (05)
Ampicillin 14.3 (10) 14.7 (10) 16.3 (05) 15.9 (05) – –
Streptomycin 15.1 (10) 14.9 (10) 16.4 (05) 16.1 (05) – –
Fluconazole – – – – 16.4 (05) 16.5 (05)

Vandekerckhove et al. [4] developed a novel class of halo-substituted 3-bromo-

1-(2,3-dibromo-2-methylpropyl)-4-quinolones, taking 7-chloroquinolin-4-ol as
starting material, as presented in Scheme 21. The molecular structures of the
synthesized compounds were confirmed by NMR and mass spectrophotometry
techniques, and their in vitro antiplasmodial potential evaluated. Among this series,
3-bromo-1-(2,3-dibromo-2-methylpropyl)-7-chloroquinolin-4(1H)-one (41), having
low micromolar activity against both CQS (NF54) and CQR (Dd2) strains of
malaria parasite P. falciparum, showed potent antimalarial activity compared with
artesunate as reference drug (Table 21).
Vandekerckhove et al. [30] reported synthesis of a novel class of (hydroxyalky-
lamino)quinoline derivatives via cyclization of diallylaminoquinolines and
4-chloro-N-quinolinylbutanamides as indicated in Scheme 22; their chemical
structures were characterized by IR, 1H and 13C NMR, and mass spectral studies,
and their in vitro antiplasmodial potential screened against a chloroquine-sensitive
strain (CQS) of P. falciparum (NF54) and chloroquine-resistant strain (CQR) of
P. falciparum(Dd2) by parasite lactate dehydrogenase assay. Among the prepared

123
 S. Narwal et al.

Cl S
N CH Cl O
CHO N
EtOH DMF/ZnCl2 N
+ H2N R Reflux N
N Cl SHCH2COOH
X1
2-Chloroquinoline-3- R
carbaldehyde X2
(38,39)
1,4-Dioxane
Et3N Reflux
ClCOCH2Cl
Cl O

N
R1
Cl
N
R2
(36,37)

Comp. R1 R2 X1 X2
36 NO2 H - -
37 H Cl - -
38 - - NO2 H
39 - - H Cl

Scheme 19 Synthesis of 3-chloro-4-(2-chloroquinolin-3-yl)-1-(substitutedphenyl)azetidin-2-one and

3-(substitutedphenyl)-2-(2-chloroquinolin-3-yl)thiazolidin-4-one

Table 19 Zone of inhibition in mm (MIC of lg/ml) of compounds 36–39

Compound (100 lg/disc) Microbial strains

Gram-positive strains Gram-negative strains Fungal strains

P. aeruginosa E. coli S. aureus B. subtilis A. niger C. albicans

36 23 (12.5) 20 (100) 25 (12.5) 23 (50) 24 (50) 19 (100)

37 22 (25) 21 (62.5) 25 (25) 23 (12.5) 25 (62.5) 20 (62.5)
38 25 (12.5) 21 (62.5) 23 (50) 23 (50) 24 (12.5) 24 (25)
39 23 (25) 22 (62.5) 26 (25) 24 (12.5) 24 (50) 20 (100)
Ciprofloxacin 33 (B1) 32 (B1) 30 (B1) 31 (B1) — —
Ketoconazole — — — — 30 (B3) 33 (B1)

derivatives, 4-(quinolin-5-ylamino)butanol (42) and 2-methyl-3-(2-methylpyrro-

lidin-1-yl)quinoline (43), having low micromolar activity against CQS (NF54) and
CQR (Dd2) strains of malaria parasite P. falciparum, were found to be the most
potent antimalarial agents compared with artunesate as standard. The results
obtained are presented in Table 22.
Wube et al. [29] developed a new class of 1,2-substituted 4-(1H)-quinolone
derivatives, taking a,x-dibromoalkane and phenyllithium as starting materials, via
Friedel–Crafts acetylation (Scheme 23), characterized their molecular structures by
IR, 1H and 13C NMR, and ESI mass spectral studies, and evaluated their
antimalarial potential against P. falciparum (NF54) by microculture radioisotope
technique. In this series, 1-methyl-2-[40 -(600 -bromohexyl)phenyl]-4(1H)-quinolone
(44) was the most active antimalarial agent at low micromolar concentrations due to

123
Synthesis and therapeutic potential of quinoline derivatives

Cl
N Cl
O

+ N Pyridine N
NH2 100oC N
Cl 2-(Piperidin-1-yl)ethanamine N
H
(d) (e) O
NaOH,
EtOH/H2O(2:1)
NH2OH*HCl Reflux
HO
N
H
N
N
N

Cl (40)

Scheme 20 Synthesis of 2-Chloro-6-(2-(piperidin-1-yl)ethylamino)-7H-indeno[2,1-c]quinolin-7-one

oxime

Table 20 In vitro antimalarial activity (IC50 in lM) of compound 40

Compound D-10 (CQ-S) 3D7 (CQ-S) W-2 (CQ-R) Ratio IC50 Ratio IC50
IC50 (lM) IC50 (lM) IC50 (lM) W-2/D-10 W-2/3D7

40 0.850 ± 0.181 0.843 ± 0.096 0.255 ± 0.119 0.3 0.3

Chloroquine 0.020 ± 0.005 0.012 ± 0.003 0.316 ± 0.051 16 26

N Br
Br
K2CO3,acetone N Cl CH2Cl2
Cl N
HO Br Br2, rt, 1h Br
7-Chloroquinolin-4-ol 24h Cl
O
O
3-Bromo-1-(2,3-dibromo-2-methyl
propyl)-7-chloroquinolin-4(1H)-one
(41)

Scheme 21 Synthesis of 3-bromo-1-(2,3-dibromo-2-methylpropyl)-7-chloroquinolin-4(1H)-one

Table 21 Antimalarial activity (IC50 in lM) results for compound 41

Compound NF54, IC50 (lM) Dd2, IC50 (lM) RI

41 3.18 4.02 1.27

CQ 0.016 0.378 23.73
Artesunate 0.005 0.046 8.75

RI (resistance index) = IC50 Dd2/IC50 NF54

123
 S. Narwal et al.

Cl

O O
O
Cl (1) HO N
Cl KOtBu N
NH2 NH CH CN,
K2CO3, CH2Cl2, 3 N (2) NH
N r.t., 2h N 4-(Quinolin-5-
,2h
ylamino)butanol
CH3Li,THF
(42)
0oC,2 h

H
N AcOH,NaCNBH3 N
O
MeOH,r.t., 3h
N N
2-Methyl-3-(2-methyl-
pyrrolidin-1-yl)quinoline
(43)

Reagents and conditions: (1) LiAlH4, THF, r.t., 2.5h; (2) NaBH4, THF/MeOH, r.t., 3h.

Scheme 22 Synthesis of (4-(quinolin-5-ylamino)butanol) and (2-methyl-3-(2-methylpyrrolidin-1-

yl)quinoline)

Table 22 Antimalarial activity (IC50 in lM) results of compounds 42, 43

Compound CQR P. falciparum strain CQS P. falciparum strain

NF54, IC50 (lM) Dd2, IC50 (lM) RI NF54, IC50 (lM)

42 19.9 ± 5.6 49.0 ± 10.2 2.5 19.9 ± 5.6

43 13.3 ± 3.5 38.0 ± 4.4 2.9 13.3 ± 3.5
CQ (n = 14) 0.021 0.274 13.0 0.021 ± 0.005
Artunesate (n = 8) 0.005 0.011 2.2 0.005

Br Li Br O
THF, 0oC
(CH2)6 + (H2C)6 + Cl
Br
Dibromohexane Phenyl
lithium AlCl3,
CH2Cl2,
O 0oC
O
O Br O O
LDA,THF, -78oC
N (H2C)6 +
CH3 N O
(CH2)6 1-(4-(6-Bromohexyl) CH3
Br phenyl)ethanone
(44)

Scheme 23 Synthesis of 1-methyl-2-[40 -(600 -bromohexyl)phenyl]-4(1H)-quinolone

phenylalkyl substitution at position 2 and addition of –Br at the end of the aliphatic
side chain, compared with chloroquine as reference drug. The antimalarial data are
presented in Table 23.

123
Synthesis and therapeutic potential of quinoline derivatives

Table 23 In vitro antimalarial

Compound NF54, IC50 (lM)
activity (IC50 in lM) of
compound 44
44 0.09
Chloroquine 0.0063

Anticancer activity

Cancer is among the most challenging health problems worldwide, exhibiting an

increasing mortality rate globally and being characterized by rapid formation of
abnormal cells and spreading through metastasis to different organs [31]. Currently
available treatments (chemotherapy and radiotherapy) for most types of cancer only
provide temporary therapeutic benefits as well as being limited by a narrow
therapeutic index, remarkable toxicity, and acquired resistance [32].
Arafa et al. [31] developed a novel class of N0 -(substituted)benzylidene-2-(5,7-
dibromoquinolin-8-yloxy) acetohydrazide derivatives, taking 5,7-dibromo-8-hy-
droxyquinoline as starting material, as presented in Scheme 24; their molecular
structures were confirmed by 1H NMR, IR, and mass spectral studies, and their
in vitro cytotoxicity screened against human colon HT29 and breast cancer MDA-
MB231 cell lines. Among this series, 2-(5,7-dibromoquinolin-8-yloxy)-N0 -(4-
hydroxy-3-methoxybenzylidene)acetohydrazide (45) was found to be a more potent
anticancer agent due to presence of hydrogen bond as donor group (Table 24).

Br Br Br
ClCH2CO2Et, NH2NH2.H2O,
DMF, K2CO3 gl.HOAc, EtOH

Br N 6h, Reflux 3h, reflux

Br N Br N
OH OCH2COOC2H5 OCH2CONHNH2
5,7-Dibromoquinolin-8-ol

RCHO,
gl.HOAc,
EtOH,
Br Br 5h, reflux
H
N O
O N
N O
OH
(45)

Scheme 24 Synthesis of 2-(5,7-dibromoquinolin-8-yloxy)-N0 -(4-hydroxy-3-methoxybenzylidene)

acetohydrazide

Table 24 Cytotoxicity of
Compound HT29, IC50 (lM) MDA-MB231, IC50 (lM)
compound 45
45 4.7 4.6

123
 S. Narwal et al.

OCH3 O O
O
NaH, toluene
H3CO + O O reflux O
O
1-(2,4-Dimethox- Diethyl carbonate H3CO OCH3
yphenyl)ethanone
3,4-methylene-
dioxyaniline,
toluene, reflux

O OCH3
O

HN PPA, 100o-110oC OCH3

O O
O

H3CO OCH3 O N O
H
(46)

Scheme 25 Synthesis of 6,7-methylenedioxy-4-(2,4-dimethoxyphenyl)quinolin-2(1H)-one

Chen et al. [33] synthesized a novel series of 6,7-methylenedioxy-4-substituted

phenylquinolin-2(1H)-one derivatives as shown in Scheme 25, confirmed their
structures by IR, 1H and 13C NMR, and HRMS studies, and assessed their in vitro
cytotoxicity against MCF-7 (breast adenocarcinoma), Hep3B (hepatoma), H460
(non-small-cell lung carcinoma), 2774 (ovarian carcinoma), SKOV-3 (ovarian
carcinoma), HL-60 (leukemia), COLO205 (colorectal adenocarcinoma), A498
(renal cell carcinoma), and Detroit 551 normal human cell lines by 3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. In this
series, 6,7-methylenedioxy-4-(2,4-dimethoxyphenyl)quinolin-2(1H)-one (46)
demonstrated significant antitumor activity with IC50 values of 0.4, 0.4, 0.4, and
0.9 lM against 2774, SKOV-3, HL-60, and H460 cancer cell lines, respectively,
because of presence of 2,4-dimethoxy group on 4-phenyl ring, when compared with
etoposide and 5-fluorouracil (5-FU) as standard drugs (Table 25).
A novel set of 4-oxoquinoline-3-carboxamide compounds were synthesized
(Scheme 26) by Forezi et al. [34], and their molecular structures confirmed by 1H
and 13C NMR, IR, and ESI HRMS studies; their in vitro anticancer activity was
evaluated against colon (HCT-116), breast (MDAMB-231), stomach (ACP03), and
normal fibroblast (MRC-5) cell lines by MTT assay. Among the tested compounds,
6-chloro-4-oxo-N0 -(p-tolyl)-1,4-dihydroquinoline-3-carboxamide (47) and 6-chloro-

Table 25 In vitro anticancer activity of compound 46

Compound IC50 (lM, concentration of 50% proliferation-inhibitory effect)

Hep3B HL-60 2774 MCF-7 COLO205 Detroit 551 SKOV-3 A498 H460

46 1.0 0.4 0.4 6.0 7.4 [25 0.4 48 0.9

Etoposide – 5.48 – – – – – – 1.0
5-FU – 22.3 – – – – – – 26.7

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Synthesis and therapeutic potential of quinoline derivatives

Cl
Diethyl ethoxymethylenemalonate, C2H5OOC HN Cl
ethanol, reflux
NH2 C2H5OOC
4-Chlorobenzenamine Diphenyl ether,
reflux

O Cl Cl
Cl COOC2H5
Diphenyl ether, Diphenyl ether, HN
O NH
amine, 210oC amine, 210oC O C O
C N
H3C NH H
O
Cl Cl NH
(47)
(48)

Scheme 26 Synthesis of (6-chloro-4-oxo-N0 -(p-tolyl)-1,4-dihydroquinoline-3-carboxamide) and (6-

chloro-4-oxo-N0 -(2,5-dichlorophenyl)-1,4-dihydroquinoline-3-carboxamide)

4-oxo-N0 -(2,5-dichlorophenyl)-1,4-dihydroquinoline-3-carboxamide (48) demon-

strated potent antiproliferative activity against cancer cells, with IC50 values of
1.92 and 5.18 lM, respectively, compared with doxorubicin as standard. The results
obtained are presented in Table 26.
Makawana et al. [35] synthesized a novel class of Schiff base derivatives bearing
nitroimidazole and quinoline nuclei, from 2-phenoxyquinoline-3-carbaldehydes and
2-(2-methyl-5-nitro-1H-imidazol-1-yl)acetohydrazide, as presented in Scheme 27;
their molecular structures were confirmed by FTIR, 1H and 13C NMR, mass
spectrophotometry, and elemental analysis. The in vitro anticancer activity of these
derivatives was evaluated against epidermal growth factor receptor (EGFR) and
human epidermal growth factor receptor (HER)-2 kinases and also against
mammalian cancer cell lines including A549 adenocarcinomic human alveolar
Table 26 Cytotoxicity of compounds 47, 48 against cancer cell lines
Compound IC50 (lM, concentration of 50% proliferation-inhibitory effect)

ACP-03 HCT-116 MDAMB231 MRC5

47 1.92 (1.39–2.66) [10 [10 [20

48 5.18 (3.61–7.45) [10 [10 [20
Doxorubicin 0.274 (0.22–0.33) 0.1 (0.047–0.28) 0.43 (0.36–0.52) 0.2 (0.16–0.25)

H3CO
H3C H CH3
H3C CHO OCH3 O N N
EtOH O N N
+ HN
N
reflux
N
O
N
N O O2N
NH2 NO2
2-(4-Methoxyphenoxy)-6-
methylquinoline-3-carbaldehyde 2-(2-Methyl-5-nitro-1H-
imidazol-1-yl)acetohydrazide

CH3
(49)

Scheme 27 Synthesis of (E)-N0 -((2-(4-methoxyphenoxy)-6-methylquinolin-3-yl)methylene)-2-(2-

methyl-5-nitro-1H-imidazol-1-yl)acetohydrazide

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 S. Narwal et al.

Table 27 Inhibition of EGFR and HER-2 kinases as well as antiproliferative activity of compound 49
Compound IC50 (lM ± SD)

EGFR HER-2 A549 HepG2

49 0.12 ± 0.05 2.18 ± 0.08 0.16 ± 0.03 3.15 ± 0.14

Erlotinib 0.032 ± 0.002 0.16 ± 0.02 0.13 ± 0.01 0.12

basal epithelial and HepG2 liver cancer cell lines. Among these compounds, (E)-N0 -
((2-(4-methoxyphenoxy)-6-methylquinolin-3-yl)methylene)-2-(2-methyl-5-nitro-
1H-imidazol-1-yl)acetohydrazide (49) was found to have excellent cytotoxicity
activity as compared with erlotinib (Table 27).
Matesic et al. [36] synthesized a new series of pyrrolo[3,2,1-hi]indole-1,2-
diones, pyrrolo[3,2,1-ij]quinoline-1,2-diones, and other polycyclic isatin com-
pounds by Stolle isatin method from acridine, as presented in Scheme 28. The
molecular structures of the synthesized compounds were confirmed by 1H and 13C
NMR, FTIR, mass spectrometry, and elemental analysis, and their cytotoxicity
evaluated against U937 human histiocytic lymphoma cell line using the CellTiter 96
AQueous One Solution Cell Proliferation (MTS) assay. Among the synthesized
derivatives, 4-bromo-6H-pyrrolo[3,2,1-de]acridine-1,2-dione (50) showed potent
anticancer activity (Table 28).
A novel set of 6H-1-benzopyrano[4,3-b]quinolin-6-ones were synthesized by
Mulakayala et al. [37], taking 4-chloro-2-oxo-2H-chromene-3-carbaldehyde (f) and
anilines as starting materials (Scheme 29). The synthesized derivatives were
characterized by 1H and 13C NMR, IR, and HRMS studies, and their antiprolif-
erative properties evaluated in vitro against human chronic myeloid leukemia

O O
H
N N
AcOH, EtOH, rt, 30 min THF, rt, 3.5 h N
NaCNBH3, rt, 1.5 h AlCl3, CHCl3, rt, 3.5 h
Acridine

Br2, AcOH,
O O 70o-75oC

Br
(50)

Scheme 28 Synthesis of 4-bromo-6H-pyrrolo[3,2,1-de]acridine-1,2-dione

Table 28 In vitro anticancer

Compound IC50 (lM)
activity of compound 50
50 3.01 (±1.1)
Vinblastine 6.88

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Synthesis and therapeutic potential of quinoline derivatives

O OH
O O
+ H2N Sonication O NaBH4, THF OH
rt, MeOH Room temp
CHO
Aniline
Cl N N
(f)
NaN3,PPh3,
CCl4-DMF,
90oC

HOOC COOH N3
NH2
OH
SO2NH2 OH
10% Pd/C,
O2N SO2NH2 EtOAc
O2N NH Cl
OH n-BuOH, 90oC N
N

(51)

Scheme 29 Synthesis of 6H-1-benzopyrano [4,3-b]quinolin-6-ones analogues

(K562), breast cancer (MDA-MB231), human colon carcinoma (Colo-205), and

human neuroblastoma (IMR32) cancer cell lines. Among this series, 4-((2-(2-
hydroxyphenyl)quinolin-3-yl)methylamino)-3-nitro-5-sulfamoylbenzoic acid (51)

Table 29 Anticancer activity

Compound IC50 (lM)
of compound 51
K562 Colo-205 MDA-MB231 IMR32

51 10 19 08 18
Harmine 45 46 54 68

O CN
Cl
NC N H
Cl Ethanol N O
H DMF
+ N Piperidine N O
t-KOBu
Cl N
H
2-Chloroben- 2-(1H-Benzo[d]imid- N CN
H
zoyl chloride azol-2-yl)acetonitrile

POCl3/
PCl5
CN
H
N N Cl
NHR2 or NH2R
N N N
NC CH3CN
N MW, 800W
(52) 170oC
NHR2 or
NH2R
CH3CN
MW

HN N N

NC N
(53)

Scheme 30 Synthesis of 5-[N-(N,N-dimethylaminopropyl-1-amino)]benzimidazo[1,2-a]quinoline-6-

carbonitrile) and (5-N-piperazinylbenzimidazo[1,2-a]quinoline-6-carbonitrile)

123
 S. Narwal et al.

exhibited potent antitumor activity compared with harmine as reference drug

(Table 29).
Perin et al. [38] developed a novel class of 5-aminobenzimidazo[1,2-
a]quinoline-6-carbonitrile derivatives (Scheme 30) and confirmed their molec-
ular structures by 1H and 13C NMR, FTIR, and mass spectrometry studies. The
cytotoxicity of the synthesized derivatives was evaluated by MTT assay method
against colon (HTC 116), breast (MCF-7), and lung (H 460) carcinoma cell
lines in vitro. In this series, 5-[N-(N,N-dimethylaminopropyl-1-amino)]benzim-
idazo[1,2-a]quinoline-6-carbonitrile (52) and 5-N-piperazinylbenzimidazo[1,2-
a]quinoline-6-carbonitrile (53) exhibited excellent anticancer activity compared
with doxorubicin and etoposide as standards. The results obtained are presented
in Table 30.
Sun et al. [39] developed a new class of 2-aminomethyl-5-(quinolin-2-yl)-1,3,4-
oxadiazole-2(3H)-thione quinolone compounds as presented in Scheme 31 and
confirmed their structure by IR, 13C and 1H NMR, and ESI mass spectrometry
studies. The synthesized derivatives were evaluated for their anticancer activity
against HepG2 (human hepatoma), SGC-7901 (human gastric cancer), and MCF-7
(human breast cancer) cell lines by MTT assay. Among this series, 3-(((2-
fluorophenyl)amino)methyl)-5-(quinolin-2-yl)-1,3,4-oxadiazole-2(3H)-thione (54)
and 3-(((4-chlorophenyl)amino)methyl)-5-(quinolin-2-yl)-1,3,4-oxadiazole-2(3H)-
thione (55) displayed the most potent anticancer activity compared with

Table 30 Cytotoxicity of
Compound IC50 (lM ± SD)
compounds 52, 53 against
cancer cell lines HTC 116 MCF-7 H 460

52 1.5 ± 0.3 2 ± 0.4 4 ± 0.6

53 2 ± 0.2 2 ± 0.4 4 ± 0.6
Doxorubicin 0.07 ± 0.02 0.02 ± 0.01 0.03 ± 0.01
Etoposide 5±2 1 ± 0.7 0.1 ± 0.04

N OC2H5 NH2NH2.H2O N NHNH2 CS2/KOH,ethanol N N NH

O EtOH, Reflux, 8h reflux, 24h, HCl
O O S
Ethyl quinoline-2-
carboxylate HCHO 40%,
S different amines
O HN
N Cl
N
N
(55)

N N N N
H F
O S
(54)

Scheme 31 Synthesis of (3-(((2-fluorophenyl)amino)methyl)-5-(quinolin-2-yl)-1,3,4-oxadiazole-2(3H)-

thione) and (3-(((4-chlorophenyl)amino)methyl)-5-(quinolin-2-yl)-1,3,4-oxadiazole-2(3H)-thione)

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Synthesis and therapeutic potential of quinoline derivatives

Table 31 In vitro anticancer activity (IC50, lM) of compounds 54, 55 against human tumor cell lines
Compound HepG2 SGC-7901 MCF-7

54 1.2 ± 0.2 8.3 ± 1.6 6.8 ± 0.5

55 0.8 ± 0.2 7.6 ± 1.0 7.1 ± 0.8
5-Fluorouracil 21.9 ± 1.4 28.5 ± 2.0 17.2 ± 1.5

5-fluorouracil as positive control due to presence of fluoro and chloro substitution at

o- and p-position of aniline, respectively (Table 31).

Conclusions

Appraisal of literature reports reveals that quinoline and its derivatives represent an
important class of compounds in the medicinal field with various therapeutic
potentials, i.e., antimalarial, antimicrobial, antimycobacterial, antidepressant, anti-
convulsant, antiviral, anticancer, antihypertensive, PDGF-RTK inhibitory, antiin-
flammatory, antioxidant, and anti-HIV activity. This review focuses especially on
synthesized active compounds of quinoline having antimicrobial, anticancer, and
antimalarial activities, playing an important role in the medicinal field. These most
active quinoline derivatives may be taken as leads to discover novel agents with
therapeutic potential in the future.

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