Design, development of new synthetic methodology, and biological evaluation of substituted quinolines as new anti-tubercular leads

Article abstract of DOI:10.1016/j.bmcl.2016.10.082

Two series of quinoline-based compounds were designed, synthesised and evaluated for anti-tubercular activity against Mycobacterium tuberculosis H₃₇Rv (ATCC 27294 strain). A new method for Friedl?nder quinoline synthesis has been developed in w

Full text of DOI:10.1016/j.bmcl.2016.10.082

Accepted Manuscript
Design, Development of New Synthetic Methodology, and Biological Evalua-
tion of Substituted Quinolines as New Anti-tubercular Leads
Babita Tanwar, Asim Kumar, Perumal Yogeeswari, Dharmarajan Sriram, Asit
K. Chakraborti
PII:
S0960-894X(16)31130-1
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.10.082
BMCL 24385
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Bioorganic & Medicinal Chemistry Letters
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27 September 2016
25 October 2016
27 October 2016
Please cite this article as: Tanwar, B., Kumar, A., Yogeeswari, P., Sriram, D., Chakraborti, A.K., Design,
Development of New Synthetic Methodology, and Biological Evaluation of Substituted Quinolines as New Anti-
tubercular Leads, Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.
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Bioorganic & Medicinal Chemistry Letters
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Design, Development of New Synthetic Methodology, and Biological Evaluation of
Substituted Quinolines as New Anti-tubercular Leads
a
a
b
b
a*
Babita Tanwar , Asim Kumar , Perumal Yogeeswari , Dharmarajan Sriram , and Asit K. Chakraborti
a
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar 160 062, Punjab, India.
Department of Pharmacy, Birla Institute of Technology & Science – Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500 078, India.
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Two series of quinoline-based compounds were designed, synthesized and evaluated for anti-
tubercular activity against Mycobacterium tuberculosis H37Rv (ATCC 27294 strain). A new
method for Friedländer quinoline synthesis has been developed in water under the catalytic
influence of the Brønsted acid surfactant DBSA. Among the forty two compounds tested for
anti-TB activity, twenty three compounds exhibited significant activity against the growth of M.
tuberculosis (MIC 0.02 - 6.25 µg/mL). In particular, the compounds 3b and 3c displayed
excellent anti-TB activity with MIC values of 0.2 and 0.39 μg/mL, respectively, and are more
potent than the standard drugs E, Cfx and Z that are clinically used to treat TB. The cytotoxicity
of the compounds with MIC ≤ 6.25 µg/mL was evaluated against Human Embryonic Kidney
293T cell lines and all of the active compounds were found to be nontoxic (< 50% inhibition).
The results suggest that the synthesised substituted quinolines are promising leads for
development of new drug to treat TB.
Available online
Keywords:
Anti-mycobacterial agents; Substituted quinolines;
New synthetic methodology; Water; DBSA; Catalyst;
Structural activity relationship
Tuberculosis (TB) is a disease of antiquity caused by infection
with members of the Mycobacterium tuberculosis complex,
which includes M. tuberculosis (Mtb), M. africanum, M. bovis,
M. caprae, M. microti, M. pinnipedii and M. canetti but the Mtb
organism is the main pathogen infecting more than one-third of
the world’s human population. [1] It is an airborne disease
affecting millions of people each year being the second leading
cause of death worldwide, after the human immunodeficiency
virus (HIV). In 1993, World Health Organisation (WHO)
declared TB ‘a global health emergency’. [2] According to
WHO, 9.0 million people developed TB worldwide in the year
the duration of tuberculosis chemotherapy or overcome drug-
resistant strains of the causative organism M. tuberculosis. [7]
NH2
O
NH
OH
O
H
N
N
N
NH2
N
H
N
HO
Ethambutol (E)
Isoniazide (INH)
Pyrazinamide (Z)
OH
2013 out of which India and China accounted for 24% and 11%
HO
O
H
of the total cases, respectively, and approximately 1.5 million
people died from the disease, 3,60,000 of whom were HIV-
positive. [3]
O
O
OH OH
O
NH
N
The recommended DOTS (Directly Observed Treatment,
Short Course) therapy for TB is a regimen that consists of four
drugs (Fig. 1) i.e., isoniazid (INH), rifampicin (R), pyrazinamide
N
O
O
OH
N
O
(
‘
Z), and ethambutol (E) taken daily for two months during the
intensive’ treatment phase, followed by two drugs - INH and R -
Rifampicin (R)
taken daily for four months in the ‘continuation’ or ‘sterilising’
phase. [4] The lengthy treatment, lack of drug supply,
underdeveloped health care and inappropriate drug prescription
or dose leads to increasing the risk of resistance development. [5]
All the existing drugs have acquired resistance and cross
resistance. [6] The recalcitrant nature of persistence infection and
increase in multi- and extensively-drug-resistant strains (MDR-
TB and XDR-TB) are the main challenges for effective treatment
of TB with the currently available anti-TB drugs. Thus, there is
an urgent need for new anti-mycobacterial drugs that will shorten
Figure 1. First-line anti-tubercular drugs.
Quinoline derivatives have drawn considerable attention for the
discovery of new anti-mycobacterial agents (Fig. 2). [8-16] The
well-known antimalarial drug mefloquine and its derivatives
have been found to possess substantial activity against
mycobacterium species. [17-24] Fluoroquinolones (FQs), such as
gatifloxacin and moxifloxacin are in phase III clinical trial and
ciprofloxacin (Cfx), ofloxacin, lomefloxacin, and norfloxacin are

used as second line anti-TB drugs for treatment of MDR-TB.
25-27] Quinoline moiety is the essential pharmacophoric feature
[
of the recently approved anti-TB drug bedaquiline developed by
Johnson & Johnson pharmaceutical company. [28] Bedaquiline
acts by a novel mechanism by targeting proton pump of
adenosine triphosphate (ATP) synthesis, leading to inadequate
synthesis of ATP. [29] The WHO and the US Centers for Disease
Control and Prevention suggested the use of bedaquiline for
treatment of adult MDR-TB patients when an effective treatment
regimen cannot otherwise be provided. [30]
Figure 4. Outline of the design of new quinoline-based scaffolds for potential
anti-TB activity.
The target compounds 3 can be obtained by Friedländer
quinoline annulation through cyclo-condensation of 2-amino-
substituted aromatic aldehydes/ketones with active-methylene
group containing carbonyl derivatives (Scheme 1). [41] However,
the development of newer methodologies that would be useful
addition to medicinal chemist’s toolbox [42] and address the
deficiency of ecofriendly need is in demand and subject of
current interest due to the adverse effect of the manufacturing
processes of drugs and pharmaceuticals on the environment. [43]
R1
R1
R2
R3
Figure. 2. Various quinoline-based compounds possessing anti-tubercular
R
R
2
3
O
activity.
R
R
NH2
O
N
On the other hand, many potential anti-TB compounds [31-38]
and anti-TB drugs such as INH, PZA, PAS etc. has amide or
carboxylic acid (Fig. 3) functionality as the essential structural
feature.
Scheme 1. Synthesis of functionalized quinolines via Friedländer annulation.
The use of water as a reaction medium addresses adequately
the aspect of maintaining greenness. Due to the unique physical
and chemical properties, particularly hydrogen bond formation
ability, water offers distinct advantages to increase the reaction
rate unattainable in organic solvents that extend its role beyond
the capacity of the reaction medium. [44-51] Although, the
solubility of organic compounds in water is often a detrimental
factor for using water as a reaction medium, the use of
surfactants can overcome the issue [52-54]. However, the role of
the surfactant may not be limited to solubility enhancer as
surfactant exhibits new chemistry [55] and accelerates the
reaction by generation of microreactor assemblies at the
interface. [56] The reported methodologies of Friedländer
O
O
R1
O
N
N
N
N
NH
2
NH
N
N
R
2
X
NC
NC
N
H
R
X = O, NH
MIC = 25->200
μg/mL
MIC = 6.25->100 μg/mL
MIC = 10->800 μg/mL
R2
R3
R2
O
O
N
N
R
R1
1
N
N
H
N
N
N
R2
N
H
NH
R1
X
N
O
MIC = 50->100 μg/mL MIC = 50->100 μg/mL
MIC = 6.25->50 μg/mL
quinoline synthesis utilize surfactant such as Zr(DS)
4
, [57]
Figure. 3. Various compounds bearing amide functionality with anti-
tubercular activity.
dodecylphosphonic acid (DPA) [58] and Sc(DS) [59] in water.
3
These methodologies are associated with one or more drawback
such as the requirement of higher reaction temperature, additional
cost because of synthesis of catalyst, and long reaction time.
Therefore, in order to develop a greener and more efficient
methodology we started our systematic investigation by
screening various cationic, anionic, and non-ionic surfactants
As a part of investigation of new chemotherapeutic agents for
tuberculosis, [39] our research efforts have been focused towards
the development of new scaffolds with potent anti-mycobacterial
activity. Herein, we describe the synthesis and in vitro screening
of substituted quinoline derivatives as potential anti-tubercular
agents.
(data provided in the supporting information).
Herein, we describe the scope and limitations of surfactant
In the present study, we adopted scaffold hopping strategy
catalysis with particular emphasis on DBSA as a catalyst for
Friedländer annulation of 1 with 2 to form 3 in good to excellent
yield in water (Scheme 2).
This method was found to be more advantageous as compared
to other reported methodologies. The product was isolated by
diluting the reaction mixture with cold water followed by
filtration of the precipitated solid to furnish the final product,
which did not require any further purification.
[36-40] and incorporate amide group in the quinoline moiety for
designing new anti-TB scaffold (Fig. 4). Two series of
substituted quinolines have been designed by modifications on
the quinoline core. In the first series various substitutions were
made at C2, C3, C4, and C6 position of the quinoline nucleus in
the Scaffold I (3a-3u) and in second series variations were made
on quinoline-3-carboxamide (5a-5u) in Scaffold II.

R1
R1
R2
DBSA
X
X
R2
R3
(
15 mol%)
O
R3
Water (2 mL),
O
NH2
N
3a-3u
o
5
0
C
1
2
Scheme 3. Synthesis of quinoline-3-carboxamide derivatives.
Scheme 2. Synthesis of functionalized quinolines (3a-3u).
In total forty-two target compounds have been synthesised and
evaluated for their anti-mycobacterial activity (Table 1) against
M. tuberculosis H37Rv (ATCC 27294 strain) in a micro plate
using Alamar blue assay (MABA). [61] The MIC (minimum
inhibitory concentration required to inhibit the complete growth
of Mtb) values were measured in µg/mL. The synthesised
compounds were found to be effective to inhibit the growth of
the Mtb with MIC ranging from 0.2->25 µg/mL.
The quinoline-3-carboxamides (5a-5u) were synthesised via
amidation reaction of methyl 2-methyl-4-phenylquinoline-3-
carboxylate (3a) with differently substituted arylamines (4a-4u)
t
in the presence of KO Bu (2 equiv) in THF at rt (Scheme 3, Table
1). [60]
The structures of all the synthesized compounds were
1
13
characterized by NMR ( H, C), IR, LC-MS and HRMS.
Table 1. Synthesis and biological evaluation of substituted quinolines 3a-3u, 5a-5u and a few standard ant-TB drugs.
a
b
b
d
Time
Yield
MIC
MIC
HEK
293T%
inhibition
CLogP
Compd
No.
Entry
Structure
c
(h)
(%)
(µg/mL)
(µM)
1
2
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
X = H, R = Ph, R = OMe
2
2
2
90
92
88
83
80
82
85
87
81
84
12.5
0.2
45.07
0.69
25.6
25.6
13.6
ND
4.54
5.00
5.78
4.25
5.85
5.80
3.68
5.27
6.59
4.99
1
2
X = H, R = Ph, R = OEt
1
2
t-
X = H, R = Ph, R = O Bu
0.39
12.5
6.25
25
1.22
1
2
X = H, R = Ph, R = Me
2.5
2.5
2.5
3
47.83
19.33
76.74
109.04
80.19
8.73
1
2
X = H, R = R = Ph
22.1
ND
1
2
X = Cl, R = Ph, R = OEt
1
2
3g
3h
3i
X = H, R = Me, R = OEt
25
ND
1
2
X = Cl, R = Ph, R = OMe
2
25
ND
1
2
X = Cl, R = R = Ph
2.5
2
3.125
3.125
26.1
19.9
1
2
10
3j
X = Cl, R = Ph, R = Me
10.57
Ph
n
N
11
12
13
14
3k
3l
n = 1
n = 2
n = 3
n = 4
2.5
2.5
2.5
2.5
83
85
80
76
6.25
12.5
12.5
3.125
25.48
48.20
45.73
10.87
30.0
ND
4.93
5.49
6.05
6.61
3m
3n
ND
31.1
1
2
15
16
17
18
3o
3p
3q
3r
R = R = H
3
3
3
3
82
81
85
78
12.5
6.25
6.25
12.5
45.73
21.75
20.74
35.77
ND
4.30
4.82
5.33
5.85
1
2
R = Me, R = H
28.0
22.0
ND
1
2
R = R = Me
1
2
R = Ph, R = H
19
20
21
3s
3t
Ar = Ph
3.5
3.5
4
76
75
76
3.125
1.56
6.25
11.11
5.75
18.1
34.0
25.5
6.02
5.40
5.91
Ar = furan-2-yl
Ar = thiophen-2-yl
3u
21.75

1
2
3
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
5a
5b
5c
5d
5e
5f
n = 0, R = R = R = H
5
7
6
7
6
7
5
7
5
7
6
6
6
6
6
6
5
5
65
41
45
27
34
29
52
32
44
54
28
43
44
51
61
49
39
52
3.125
3.125
6.25
6.25
12.5
25
9.23
25.6
35.2
16.3
12.5
ND
4.87
4.84
5.67
5.10
5.82
4.25
4.82
4.50
5.36
5.02
4.94
5.05
5.50
5.76
4.97
5.76
5.19
6.87
1
2
3
n = 0, R = R = H, R = OMe
8.48
1
2
3
n = 0, R = R = H, R = Cl
17.54
16.76
30.92
67.86
33.53
35.07
29.59
3.36
1
2
3
n = 0, R = R = H, R = F
1
2
3
n = 0, R = R = H, R = Br
1
2
3
n = 0, R = OMe, R = R = H
ND
1
2
3
5g
5h
5i
n = 0, R = Cl, R = R = H
12.5
12.5
12.5
1.56
6.25
25
ND
1
2
3
n = 0, R = F, R = R = H
ND
1
2
3
n = 0, R = OCF
3
, R = R = H
ND
1
2
3
5j
n = 0, R = I, R = R = H
17.9
15.6
ND
1
2
3
5k
5l
n = 0, R = Br, R = R = H
14.98
70.94
8.53
1
2
3
n = 1, R = R = R = H
1
2
3
5m
5n
5o
5p
5q
5r
n = 1, R =Me, R = R = H
3.125
1.56
>25
25
20.6
13.6
ND
1
2
3
n = 1, R = Cl, R = R = H
4.03
1
2
3
n = 1, R =OMe, R = R = H
>65.37
64.62
33.75
3.82
1
3
2
n = 1, R = R = H, R = Cl
ND
1
3
2
n = 1, R = R = H, R = F
12.5
1.56
ND
1
2
3
t
n = 1, R = R = H, R = butyl
35.6
40
41
42
43
45
46
47
48
5s
Het Ar = pyridine-2-yl
Het Ar = pyridine-4-yl
Het Ar = 2-chloro-pyridin-yl
5 h
5 h
5 h
51
52
34
25
73.66
18.42
16.72
ND
3.78
3.78
3.70
-0.67
5t
6.25
6.25
0.098
0.197
1.56
6.25
1.56
12.6
11.3
5u
INH
R
c
ND
E
0.12
Z
-0.68
-0.73
Cfx
a
b
c
d
Isolated yield.
99% inhibition of growth of M. tuberculosis H37Rv ATCC 27294 strain.
%
inhibition at 50 µg/mL concentration determined against HEK 293T cells lines. ND: Not determined.
ClogP (hydrophobicity) calculated using the ChemDraw Ultra, version 12.0.
Structural activity relationship of compounds (3a-3u): A
complete structure activity relationship (SAR) can be drawn by
correlating the MIC values (µg/mL) of the synthesized
compounds with their structures (Table 1). Among the 2,3,4,6-
tetrasubstituted quinolines (Scaffold I), replacement of the
methyl ester at C3 position of 3a (MIC 12.5 μg/mL) with tert-
butyl ester led to thirty-two fold increase in activity (3c, MIC of
ring at C4 position of 3b (MIC 0.2 μg/mL) with methyl resulted
in completely loss in activity of compound 3g (MIC 25 μg/mL).
Next we envisioned the effect of aliphatic cyclic fused ring at
C2 and C3 position of 4-phenylquinoline to explore the SAR. All
the tested compounds 3k-3r, yielded anti-mycobacterial potency
with MICs ranging from 3.125-12.5 μg/mL. Among these
substitutions, the better potency was observed with cyclopentyl
quinoline 3k (MIC 6.25 μg/mL) and cyclooctyl quinoline 3n
(MIC 3.125 μg/mL). The cyclic ring with four and five carbons
(3l and 3m) led to two-fold reduced activity as compared to 3k.
Next, we investigated the effect of the keto and alkyl substitution
in 3l on anti-TB activity. Substitution of 3l with keto at C1
position resulted into similar activity (3o: MIC 12.5 μg/mL) and
methyl substitution at C3 position resulted two-fold increase in
activity (3p and 3q). Among the investigated 2-aryl/heteroaryl-4-
phenylquinoline, the better potency was obtained with 2-(furan-
2-yl)-4-phenylquinoline (3t: MIC 1.56 μg/mL). In general, from
the above SAR it can be concluded that the C3 ester and C4
0.39 μg/mL). The replacement of the methyl ester of 3a with
ethyl ester resulted in excellent MIC up to 0.2 μg/mL of the
compound 3b. The activity remained same when C3 methyl ester
(3a) was replaced with methyl ketone of 3d (MIC 12.5 μg/mL).
This indicates that ester substitution plays essential role in the
anti-tuberculosis activity of substituted quinolines. Among the
C3 ketone substituents, incorporating chlorine at C6 position of
the quinoline nucleus resulted in two and four fold increase in
activity, respectively (3e vs. 3i and 3d vs. 3j). However, chloro
substitution at C6 position in the ester derivatives (3a and 3b)
resulted in loss of activity of 3h and 3f. Replacement of phenyl

7
6
5
4
3
2
1
0
50
45
40
phenyl ring favours the activity and chloro substitution at C6
position disfavours the activity.
MIC
Cytotoxicity
Structural activity relationship of quinoline 3-
carboxamide derivatives (5a-5u): Finally, we investigated the
effect of C3 amide substitution in 2-methyl-4-phenylquinoline
nucleus on anti-TB activity (Table 1). With the expectation to get
more potent compound, various N-aryl/arylalkyl and heteroaryl
substitutions have been tried on 2-methyl-4-phenylquinoline-3-
carboxamide. By replacing methoxy substituent of 3a with N-
phenyl, the lipophilicity (cLogP) increased from 4.5 to 4.9 and
MIC also increased from 12.5 to 3.125 μg/mL. The lipophilicity
plays an important role in the passage of compounds through the
high lipid containing mycobacterium cell wall. [62] Comparison
of the cLogP data of compounds with those of the standard drugs
reveal that the synthetic analogues are more lipophilic in nature
compared to the first line drugs i.e., INH (-0.668), E (0.118), and
Z (-0.676).
35
30
25
20
1
1
5
5
0
Compound Number
7
6
5
4
3
2
1
0
50
MIC
Cytotoxicity
4
5
40
However, N-benzyl substitution led to drastically loss in
activity of 5l (MIC 25 μg/mL). At para position of N-phenyl
ring, various substitutions were investigated. The methoxy
substitution in 5b led to similar activity and all tested
halogenated compounds led to slightly decrease in activity of 5c-
3
5
0
3
25
2
1
1
5
0
5
0
5
e (MIC 3.125-6.25 μg/mL). The electronic character of the
substituent apparently contributes to the anti-TB activity as can
be seen when comparing para-methoxy (5b: MIC 3.125 μg/mL)
vs para-halo substitutents in 5c-5e. Introduction of electron
withdrawing and electron donating substitutents at ortho position
decrease the potency by two- to eight-fold (5c vs. 5h, 5d vs. 5g
and 5b vs. 5f). The iodo substitutent at ortho position 5j (MIC
Compound Number
Figure 5. Graphical representation of anti-tubercular activity and
cytotoxicity profile of compounds with MIC ≤ 6.25 µg/mL in comparison
with standard drugs.
1
.56 μg/mL) exhibited better anti-mycobacterial activity than that
of the parent compound 5a. In general, this indicates that para
substitution on N-phenyl increases the anti-TB activity. Various
substitutions were investigated at ortho, meta, and para positions
of the N-benzyl ring. Chloro and fluoro substitution at meta
position of the N-benzyl ring led to similar and two-fold
improved activity (5p and 5q, respectively) compare to the
compound without any substitution on the N-benzyl ring (5l).
The activity has been further improved by eight- to sixteen-fold
when methyl and chloro substitutions was introduced at ortho
position (5m: MIC 3.125 μg/mL; 5n: MIC 1.56 μg/mL) as
In conclusion, quinoline based compounds with good anti-TB
activity against M. tuberculosis H37Rv (ATCC 27294 strain)
have been reported. A new and greener method of Friedländer
quinoline synthesis have been developed to synthesize the
designed compounds in aqueous medium under the catalytic
influence of the acidic surfactant DBSA. Several compounds
showed MICs with low μg/mL. The most potent compounds 3b
and 3c exhibited MICs of 0.2 and 0.39 μg/mL, respectively. The
inferior anti-TB activity of the methyl ester compared to that of
the ethyl ester could be related to the lesser lipophilic character
suggesting scope for enhancement of the anti-TB activity in
introducing more lipophilic long chain alkyl group in the ester
moiety. Compounds (3t, 5j, 5n and 5r) also exhibited good
activity (MIC 1.56 μg/mL) with potency equal to that of the
standard drugs E and Cfx and are better than Z. Seven
compounds (3i, 3j, 3n, 3s, 5a, 5b and 5m: MIC 3.125 μg/mL)
showed better potency than that of Z. Ten compounds (3e, 3k,
t
compare to 5l. The introduction of Bu group at para position led
to sixteen-fold increase (5r: MIC 1.56 μg/mL) in anti-TB activity
in comparison with its unsubstituted counterpart 5l. Hence,
substitution at ortho and para positions of the N-benzyl ring
favours the activity. We introduced the pharmacophoric feature
of INH, the first-line anti-TB drug, in the 2-methyl-4-
phenylquinoline-3-carboxamide nucleus by replacement of the N-
phenyl ring with N-pyridine but this led to decrease in potency of
5t as compared to 5a. The distance of the pyridine N atom from
3p, 3q, 3u, 5c, 5d, 5k, 5t and 5u: MIC 6.25 μg/mL) showed
the NH of the amide also influenced the potency. The potency
was increased when the pyridine ring is substituted in the 4-
position with amide group (5t) compare to that of 5s.
potency similar to that of Z. Plausible SARs could be derived
from the substitution pattern of the quinoline core, suggesting
that C3 ester and C4 phenyl ring favours the activity and chloro
substitution at C6 position disfavours the activity in Scaffold I. In
To eliminate the possibility that the anti-TB activity arises
from general toxicity, HEK 293T (Human Embryonic Kidney)
were used for in vitro cytotoxicity evaluation. The in vitro cell
viability of the compounds with MIC ≤ 6.25 µ g/mL have been
evaluated against HEK 293T cell lines at 50 μg/mL concentration
by using MTT [(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl
tetrazolium bromide)] assay. The % inhibitory cytotoxicity data
are summarized in Table 1 and graphically represented in figure
2-methyl-4-phenylquinoline-3-carboxamide nucleus (Scaffold
II), substitution at ortho and para positions of N-benzyl ring
improves the activity. In general, these compounds did not show
toxicity on HEK 293T cell lines at 50 μg/mL concentration and
therefore have excellent selectivity. These results provide
impetus for further structural modification in the designed
substituted quinoline compounds by introducing (i) more
lipophilic long chain alkyl group in the ester moiety, (ii)
substitution with varying electron in the benzenoid part of the
quinoline nucleous, and (iii) substituted phenyl/aryl at C4
position of the quinolone ring in Scaffold I to develop more
potent compounds for anti-TB drug development.
5
along with the MIC values of the respective compounds. In
general, all the twenty-three compounds with MIC ≤ 6.25 µ g/mL
were found to be non-toxic (< 50% inhibition) and the most
active compound 3b had a therapeutic index > 250.

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Graphical Abstract
Design, Development of New Synthetic Methodology, and
Biological Evaluation of Substituted Quinolines as New
Anti-tubercular Leads
Leave this area blank for abstract info.
a
a
b
Babita Tanwar , Asim Kumar , Perumal Yogeeswari ,
b
a*
Dharmarajan Sriram , and Asit K. Chakraborti
a
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER),
Sector 67, S. A. S. Nagar 160 062, Punjab, India.
Department of Pharmacy, Birla Institute of Technology & Science -Pilani, Hyderabad Campus, Jawahar
b
Nagar, Hyderabad 500 078, India.
*
2
Corresponding Author. E-mail: akchakraborti@niper.ac.in; akchakraborti@rediffmail.com. Tel: 91-(0)-172
214683. Fax: 91-(0)-172 2214692.