Synthesis, antituberculosis studies and biological evaluation of new quinoline derivatives carrying 1,2,4-oxadiazole moiety

Article abstract of DOI:10.1016/j.bmcl.2018.11.002

Tuberculosis is the infectious disease caused by mycobacterium tuberculosis (Mtb), responsible for the utmost number of deaths annually across the world. Herein, twenty-one new substituted 1,2,4-oxadiazol-3-ylmethyl-piperazin-1-yl-quinoline derivatives were designed and synthesized through multistep synthesis followed by in vitro evaluation of their antitubercular potential against Mtb WT H37Rv. The compound QD-18 was found to be promising with MIC value of 0.5 μg/ml and QD-19 to QD-21 were also remarkable with MIC value of 0.25 μg/ml. Additionally, we have carried out experiments to confirm the metabolic stability, cytotoxicity and pharmacokinetics of these compounds along with kill kinetics of QD-18. These compounds were found to be orally bioavailable and highly effective. Altogether, these results indicate that QD-18, QD-19, QD-20 and QD-21 are promising lead compounds for the development of a novel chemical class of antitubercular drugs.

Full text of DOI:10.1016/j.bmcl.2018.11.002

Accepted Manuscript
Synthesis, antituberculosis studies and biological evaluation of new quinoline
derivatives carrying 1,2,4-oxadiazole moiety
T.G. Shruthi, Sumesh Eswaran, Prasad Shivarudraiah, Shridhar Narayanan,
Sangeetha Subramanian
PII:
S0960-894X(18)30856-4
https://doi.org/10.1016/j.bmcl.2018.11.002
BMCL 26113
DOI:
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
30 August 2018
22 October 2018
2 November 2018
Please cite this article as: Shruthi, T.G., Eswaran, S., Shivarudraiah, P., Narayanan, S., Subramanian, S., Synthesis,
antituberculosis studies and biological evaluation of new quinoline derivatives carrying 1,2,4-oxadiazole moiety,
Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.11.002
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Synthesis, antituberculosis studies and biological evaluation of new quinoline derivatives
carrying 1,2,4-oxadiazole moiety
a
a
a
b
Shruthi T G , Sumesh Eswaran , Prasad Shivarudraiah , Shridhar Narayanan , Sangeetha
Subramanianc*
aAnthem Biosciences Pvt. Ltd, 49 Bommasandra Industrial Area, Bommasandra,
Bangaluru - 560099, Karnataka, India
bFoundation for Neglected Disease Research, Bengaluru - 562157, Karnataka, India
cSBST, Vellore Institute of Technology, Vellore – 632014, Tamil Nadu, India
ABSTRACT:
Tuberculosis is the infectious disease caused by mycobacterium tuberculosis (Mtb), responsible
for the utmost number of deaths annually across the world. Herein, twenty-one new substituted
1
,2,4-oxadiazol-3-ylmethyl-piperazin-1-yl-quinoline derivatives were designed and synthesized
through multistep synthesis followed by in vitro evaluation of their antitubercular potential against
Mtb WT H37Rv. The compound QD-18 was found to be promising with MIC value of 0.5 µg/ml
and QD-19 to QD-21 were also remarkable with MIC value of 0.25 µg/ml. Additionally, we have
carried out experiments to confirm the metabolic stability, cytotoxicity and pharmacokinetics of
these compounds along with kill kinetics of QD-18. These compounds were found to be orally
bioavailable and highly effective. Altogether, these results indicate that QD-18, QD-19, QD-20
and QD-21 are promising lead compounds for the development of a novel chemical class of
antitubercular drugs.
Keywords: Quinoline; Oxadiazole; Antitubercular activity; Cytotoxicity; Bioavailability.
*
Corresponding author, Tel: +91-9443800939
E-mail address: sangeethasubramanian@vit.ac.in
1

1
. Introduction:
Tuberculosis (TB) continues to be a serious and potentially fatal infection with a worldwide
distribution. The World Health Organization (WHO) reported TB is the ninth foremost cause of
1
death worldwide and leading cause from a single infectious agent . The high mortality rate of TB
1
has even beaten the number of deaths caused by human immunodeficiency virus . Worldwide, the
mortality rate due to TB has dropped by 3% per year and new TB cases have decreased only about
2
2
% per year . Furthermore, according to an estimate one-third of the world’s population is infected
3
with a latent form of TB . The appearance of multidrug-resistant TB (MDR–TB) has given a huge
3
challenge throughout the world in the fight against TB . All the above facts reveal that there is a
serious need for the development of new drugs with divergent unique structure and with a
mechanism of action possibly different from that of existing drugs.
Quinoline compounds are important privileged structures in medicinal chemistry due to wide
5
6
7
medical benefits, such as anti-inflammatory , anticancer , antihypertensive , tyrokinase PDGF-
RTK inhibiting agents , anti-HIV9,10, anti-malarial11,12 and anti-bacterial13,14 activities. They are
also known to exhibit excellent anti-TB15 properties. For example, the USFDA approved
8
1
6
Bedaquiline is a clinically important anti-TB drug for the treatment of MDR-TB . On the other
hand, it has been well recognized that 1,2,4-oxadiazole nucleus is an active pharmacophore and
1
7
shows diverse biological potential . It attracted researchers for development of new therapeutic
agents and it also revealed the prominence of the nucleus. An idea to keep piperazine as a spacer
between quinoline and 1,2,4-oxadiazole nucleus was supported from a literature survey. A variety
of piperazine incorporated benzothiazinone-piperazine derivatives, nitrofuranyl methyl
piperazines are anti-TB agents18,19 and well-known antiparasitic drug piperaquine contain
2
0
piperazine as a spacer is also used in combination with dihydroartemisinin to treat malaria .
We have designed new quinoline derivatives containing substituted 4-Piperazin-1-yl-quinoline
carrying 1,2,4-oxadiazole moiety. In the present work, all the new structures have been designed
on the basis of combinatorial synthesis along with keeping structural activity relationship studies
in the mind which is the current trend being practiced in most of the drug discoveries. In a
2

continuing effort to develop new drug candidates for the treatment of TB, we herein describe the
synthesis and biological activities of a series of quinoline derivatives carrying 1,2,4-oxadiazole
moiety.
2
. Results and Discussion
2
.1. Chemical synthesis
Twenty-one new compounds containing a hybrid of substituted quinoline and 1,2,4-oxadiazole
were synthesized according to the synthetic methodologies presented in the scheme (figure-1). The
-Chloro-phenylamine was converted to 2-[(3-Chloro-phenylamino)-methylene]-malonic acid
3
diethyl ester (2) by reacting with diethyl ethoxymethylenemalonate at 110 °C and subsequent
cyclisation in dowtherm medium at 240 °C afforded 7-chloro-4-hydroxyquinoline (3). The
chlorination of intermediate using POCl at reflux temperature result in 4,7-Dichloro-quinoline (4)
3
and condensation of 4,7-Dichloro-quinoline and piperazine in IPA at 95 °C result in 7-Chloro-4-
piperazin-1-yl-quinoline (5) with excellent yield. The common intermediate, [4-(7-Chloro-
quinolin-4-yl)-piperazin-1-yl]-acetonitrile (6) was synthesized by coupling of chloroacetonitrile
with 7-Chloro-4-piperazin-1-yl-quinoline. Intermediates 7(a-c) were prepared via suzuki coupling
of respective boronic acids with intermediate 6 using Pd
2
(dba)
3
catalyst and s-Phos The
.
intermediate 6 and 7(a-c) were readily converted into corresponding hydroxy-acetamidine 8(a-d)
by treating with hydroxylamine in presence of suitable base. The quinoline amide derivatives 9(a-
f), 10(a-f), 11(a-f) and 12(d-f) were obtained by acid amine coupling of 8(a-d) with carboxylic
acids in presence EDCI and HOBt with good yield. The target compounds, viz. quinoline
derivatives carrying 1,2,4-oxadiazole moiety i.e., QD-1 to QD-21 were synthesized in good yield
from their precursors by heating them with DBU at 90 °C. All the newly synthesized compounds
1
13
were characterized by FTIR, H and C NMR and LC-MS studies.
3

N
N
H
N
N
N
N
N
OH
N
Cl
N
Cl
NH
O
O
b
c
d
N
f
e
O
Cl
Cl
1
Cl
N
Cl
N
R
N
O
2
3
4
5
6
7(a-c)
a
OH
NH
OH
N
O
N
N
HN
2
O
R
2
R
2
Cl
NH
N
g
2
N
N
N
N
N
1
i
h
N
N
1
1
1
R
N
R
N
R
QD-1 to QD-21
8(a-d)
9(a-f), 10(a-f), 11(a-f), 12(d-f)
Figure 1. scheme for synthesis of quinoline derivatives carrying 1,2,4-oxadiazole.
Reagents and conditions: (a) 3-Chloro-phenylamine, diethyl ethoxymethylenemalonate, 110 °C;
b) dowtherm medium, 240 °C; (c) 7-chloro-4-hydroxyquinoline, POCl , reflux; (d) 4,7-Dichloro-
quinoline, piperazine, IPA, 95 °C; (e) 7-Chloro-4-piperazin-1-yl-quinoline, chloroacetonitrile,
Et N, ACN, DMF, RT; (f) [4-(7-Chloro-quinolin-4-yl)-piperazin-1-yl]-acetonitrile, aromatic
boronic acids, Pd (dba) , s-Phos, K PO , 1,4-dioxane, water, 100 °C; (g) quinoline intermediate
6, 7a-c) hydroxylamine hydrochloride, NaHCO / Et N, methanol, 70 °C; (h) hydroxy-acetamidine
derivatives, aromatic/aliphatic acid, EDCI, HOBT, DIPEA, RT (i) amide derivatives, DBU, DMF,
(
3
3
2
3
3
4
(
3
3
9
0 °C.
2
.2 Biology
2
.2.1. Antituberculosis studies
Antitubercular activity of compounds (QD-1 to QD-21) was evaluated against Mtb WT H37Rv
2
1
using broth micro dilution method . A turbidometric assay was employed and the results were
counted. Isoniazid (INH) and rifampicin (RIF) were used as standard drugs. The first dilution that
shows growth inhibition is recorded as MIC (Minimum Inhibitory Concentration). The MIC
(
µg/ml) values of all compounds against Mtb strain H37Rv are tabulated in table-1.
Antituberculosis screening data revealed that compound QD-4, QD-5 and QD-6 possess a
promising inhibitory activity of MIC 2 µg/ml. The activity is attributed to the presence of
4

substituted 4-pyridine ring at position-7 of quinoline ring and occurrence of 2,3-dimethyl phenyl,
cyclopentyl and 4-isopropyl phenyl at position-3 of 1,2,4-oxadiazole ring in the compounds QD-
4
, QD-5 and QD-6 respectively. Compound QD-18 containing chloro group at position-7 of
quinoline ring and 4-isopropyl phenyl at position-3 of 1,2,4-oxadiazole ring was found to be more
potent with excellent inhibition of MIC 0.5 µg/ml. Replacing 4-pyridine ring with 3-pyridine at
position-7 of quinoline has tremendously increased the activity of compounds QD-19, 20 and 21
to MIC 0.25 µg/ml. The compounds which have shown MIC <1 µg/ml were considered to be
promising for further studies.
Table 1. Antitubercular activity of quinoline derivatives carrying 1,2,4-oxadiazole ring against
Mtb strain H37Rv
N O
2
R
N
N
N
1
N
R
1
F
R →
S.No
Cl
N
N
F
R2
Compound ID (QD-XX)
MIC_Mtb (µg/ml)
↓
Cytotoxicity IC50 (µM)
1
2
3
O
QD-01
QD-07
256
-
QD-13
-
-
-
>
128
-
32
-
O
F
QD-02
QD-08
QD-14
16
64
>128
F
-
-
QD-09
>256
-
-
QD-15
64
QD-03
32
CN
-
-
5

4
5
6
QD-04
QD-10
QD-16
64
QD-19
0.25
2
32
-
-
QD-11
128
-
-
>100
QD-20
0.25
QD-05
QD-17
32
2
-
-
>50
QD-06
QD-12
32
QD-18
0.5
QD-21
0.25
2
-
-
>100
>100
INHa
7
8
0.015
RIFa
0.03
(aIsoniazid (INH) and Rifampicin (RIF) were used as a control against Mtb strain H37Rv)
The lead compound QD-18, which recorded MIC value of 0.5 µg/mL against Mtb WT H37Rv
was also tested on well characterised mono-resistant (SDR) strains of Mtb, viz. Rif-r, InH-r, SM-
r, Mox-r, Kan-r and CS-r. During the assay rifampivin, isoniazid, moxifloxacin and linezolid were
used as a control. The MIC (µg/ml) values are tabulated in table-2. This assay was read by
colorimetric assay on day-7 using resazurin dye. QD-18 showed encouraging MIC against mono-
resistant strains of Mtb which are tabulated in table-2.
Table 2. Antitubercular Activity of QD-18 against mono-resistant (SDR) strains of Mtb
MIC (µg/mL)
Compound
b
ID
RMPr
3.81
INHr
4.17
SMr
28.58
0.05
KMr
3.24
MOXre
4.01
CSr
3.68
QD-18
>
4
<0.02
<0.02
0.23
<0.02
Rifampicin
Isoniazid
0
0
.49
.42
>8
1.00
0.94
0.49
0.21
0.49
>16
3.78
0.46
0.49
Moxifloxacin
6

1.68
2.33
14.08
1.91
3.65
10.34
Linezolid
(bRMPr, rifampicin resistant; INHr, isoniazid resistant; SMr, streptomycin resistant; KMr, Kanamycin resistant;
MOXr, moxifloxacin resistant; CSr, d-Cycloserine resistant)
Treatment of tuberculosis preferably requires a drug with a narrow spectrum such as isoniazid.
All the four compounds (QD-18, 19, 20 and 21) were found to be inactive against Gram +ve and
Gram -ve bacterial strains. It shows these compounds exhibit only specific activity towards
mycobacterium tuberculosis. Vancomycin and ciprofloxacin were used as a control. The MIC
(
µg/ml) values against Gram +ve and Gram -ve bacteria are tabulated in table-3.
Table 3. Antimicrobial Activity of QD-18 against ESKAPE panel of bacterial stains
MIC (µg/mL)
Escherichia
coli
ATCC25922 ATCC 19606
Acinetobacter
baumanii
Staphylococcus
aureus
ATCC 33591
Enterococcus
faecium
ATCC 51559
Pseudomonas Klebsiella
aeruginosa pneumoniae
ATCC 15442 ATCC 700603
Compound ID
QD-18
QD-19
QD-20
QD-21
Vancomycin
ciprofloxacin
>32
>32
256
>32
>512
0.007
>32
>32
512
>32
256
<1
>32
>32
512
>32
2
>32
>32
64
>32
<1
>32
>32
512
>32
512
<1
>32
>32
256
>32
512
<1
<1
8
2
.2.2. Cytotoxicity studies of QD-18, QD-19, QD-20 & QD-21
We evaluated the cytotoxicity of the QD-18, QD-19, QD-20 and QD-21 against the HepG2
2
2
cell line by MTT Cytotoxicity assay . After 48 hours of plating, HepG2 cells were treated with
test/ control items ranging concentration from 100-1.56 µM. The data obtained in the cytotoxicity
studies of quinoline derivatives indicated a high selectivity of these compounds against Mtb. when
treated for 24 h, the IC50 value of QD-18, QD-19 and QD-21 were found to be > 100 µM and QD-
2
0 was found to > 50 µM (IC50 values are tabulated in table-1). Astemizole was used as a control
and IC50 value of astemizole was found to be 7.97 µM. These four compounds were selected for
further experiments as these possessed the highest potency against Mtb and the lowest cytotoxicity.
QD-1 to QD-17 compounds did not display promising antitubercular activity and consequently
were excluded from the cytotoxicity studies.
7

2
.2.3. Metabolic stability of QD-18, QD-19, QD-20 & QD-21 in Human liver microsomes
The major site of drug metabolism in the body is liver. Hence, measurement of the rate of
clearance and identity of the metabolites of a drug is important. Metabolic stability of QD-18 to
QD-21 was estimated in human liver microsomes with cofactor and without cofactor23,24. The
comparative data of compound concentration at five time points (0, 15, 30, 60 and 120 min) were
examined for all the four test compounds and for control samples those are dichofenac and
imipramine. Retention of QD-19, QD-20 and QD-21 in percentage ranges between 18 to 23 %
and QD-18 has comparatively slite higher retention of 39.7 % at 120 min with cofactors. It is
agreed from the comparative data tabulated in table-4 and figure-2 with cofactors also in table-5
and figure-3 without cofactors that these test compounds are metabolically stable enough to
proceed further as a lead compounds.
Table 4. Metabolic stability of QD-18, QD-19, QD-20 and QD-21 in human liver microsomes
with cofactors at different time intervals.
Comparative data: Metabolic stability in Human Liver microsomes - With Cofactors
%
remaining compared to 0.0 min
0.0 min 15 min 30 min 60 min
Test/ control compounds
QD-18
120 min
39.71
18.08
21.91
22.98
30.64
86.89
100.00
100.00
100.00
100.00
100.00
100.00
82.04
65.06
60.77
74.11
85.90
98.48
67.24
47.32
54.77
56.82
75.20
88.43
55.31
31.71
37.95
40.08
59.77
92.72
QD-19
QD-20
QD-21
Diclofenac
Imipramine
8

Figure 2. Graphical presentation of metabolic stability of QD-18, QD-19, QD-20 and QD-21 in
human liver microsomes with cofactors at different time intervals.
Table 5. Metabolic stability of QD-18, QD-19, QD-20 and QD-21 in human liver microsomes
without cofactors at different time intervals.
Comparative data: Metabolic stability in Human Liver microsomes - Without Cofactors
%
remaining compared to 0.0 min
Test/ control compounds
0.0 min
120 min
QD-18
QD-19
100.00
100.00
100.00
100.00
100.00
100.00
89.19
77.99
97.83
76.54
100.79
97.18
QD-20
QD-21
Diclofenac
Imipramine
9

Figure 3. Graphical presentation of metabolic stability of QD-18, QD-19, QD-20 and QD-21 in
human liver microsomes without cofactors at different time intervals.
2
.2.4. Single Dose Oral Pharmacokinetics Study of QD-18, QD-19, QD-20 and QD-21 in Male
BALB/c Mice
Bioavailability or oral absorption of the drug is one of the essential requirement for a compound
intended to be developed into an orally administered drug, it is a basic requirement that must be
met by a candidate compound25,26. Herein, adult healthy male BALB/c mice aged 8-10 weeks were
used for experimentation after a minimum three days of acclimation. Fasted animals were
administered with QD-18, QD-19, QD-20 and QD-21 respectively in recommended vehicle by
oral route with a dose of 30 mg/kg body weight and at a dose volume of 10 ml/kg body weight.
These compounds showed good T1/2, Cmax and AUC (h*ng/ml) which is tabulated in table-6. The
data was analyzed and graphs were plotted as a plasma concentration V/S time (figure 4 and 5).
Compound QD-20 has a high Cmax of 9599.59 ng/ml and AUClast of 20015.13 h*ng/ml but
comparatively short elimination time T1/2 of 0.75 h. Compound QD-18 has a high elimination time
T
1/2 of 1.63 h but comparatively short Cmax of 2503.25 ng/ml and AUClast of 5268.26 h*ng/ml.
Compound QD-19 and QD-21 possess moderately high Cmax of 6407.59, 7442.73 ng/ml, AUClast
of 8289.39, 11860.96 h*ng/ml and T1/2 of 0.94, 1.05 h respectively. It is evident from the
pharmacokinetics studies, these compounds are encouraging molecules for the development of a
novel chemical class of antitubercular drugs.
10

Table 6. Single Dose Oral Pharmacokinetics Studies of QD-18, QD-19, QD-20 and QD-21 in Male
BALB/c Mice (30 mg/kg b.w.)
Single Dose Oral Pharmacokinetics Studies of QD-18, QD-19, QD-20 and QD-21
Mean PK Parameters
Parameters
QD-18
QD-19
QD-20
QD-21
Route of administration
Oral
Oral
Oral
Oral
Dose (mg/kg b.w.)
30
30
30
30
C
max (ng/ml)
2503.25
1.00
6407.59
0.50
9599.59
0.50
7442.73
0.50
T
max (h)
AUClast (h*ng/ml)
AUCinf (h*ng/ml)
AUCextrap (%)
5268.26
5330.73
1.17
8289.39
8307.67
0.22
20015.13
20157.60
0.71
11860.96
11932.67
0.60
T
1/2 (h)
1.63
1.50
0.94
1.34
0.75
1.31
1.05
1.38
MRTlast (h)
Figure 4. Plot of plasma concentration (ng/mL) v/s time curve
11

Figure 5. Plot of plasma concentration (ng/mL) v/s time in log scale
2
.2.5. Kill kinetics of QD-18 on the WT strain of Mtb (Mycobacterium tuberculosis WT H37Rv)
The killing kinetics pattern of QD-18 was evaluated27,28 on different days (Day-0, 3, 7, 14, 21)
7
post exposure to the compound. The assay was started at an inoculum of 3-8 X 10 cfu/ml. Since
the MIC of the compound was found to be low (0.5 µg/ml), a 2-fold 13-conc. DR (64 µg/mL -2-
0
.002 µg/mL) was set up for the compound exposure to Mtb culture. The survivors were
-1
-8
enumerated by plating multiple dilutions (10 to 10 dil.s) of culture to get countable colony
forming units (cfu) on different days: Day-0, Day-3, Day-7, Day-14, and Day-21. The QC drug
used was Rifampicin (with similar procedure). The maximum effect (Emax) obtained on any of
the enumeration days were tabulated in table-7. The compound QD-18 demonstrated an Emax of
1
.1 log10cfu/ml. As per the bactericidal definition (>2 log10cfu/ml kill), it was found to be a
bacteriostatic compound. The data was analyzed and time-kill curve of QD-18 were plotted
figure-6 and 7).
(
Table-7. The maximum effect (Emax) of QD-18 obtained on Day-0, Day-3, Day-7, Day-14 and
Day-21
Killing kinetics on Day-0, Day-3, Day-7, Day-14, Day-21
Emax achieved (log 10 cfu/ mL)
KK E max Day-0
Day-3
0.2
Day-7
1.1
Day-14
0.9
Day-21
0.9
QD-18
RIF
0.0
0.0
4.2
6.2
6.2
6.3
12

Kill Kinetics of QD-18
1
1
0
9
8
7
6
5
0.002
0.004
0
0
0
0
0
0
0
1
2
4
8
1
.008
.0156
.031
.0625
.125
.25
.5
1
.0
.0
.0
.0
6.0
32.0
64.0
0
Control
0
3
7
14
21
Days
Figure 6. Time-kill curve of QD-18
Kill Kinetics of QD-18
dose response
11
Day 3
Day 7
Day 14
Day 21
1
0
9
8
7
6
5
0.001
0.01
0.1
1
10
100
1000
Conc. (g/ml)
Day 0 Day 3
Day 7 Day 14 Day 21
R square
1.000 0.7491 0.9335 0.9777 0.9659
Figure 7. Dose-response curve of QD-18
13

3
. Conclusion:
The present research study reports the successful synthesis, characterization of a new series of
quinoline derivatives carrying 1,2,4-oxadiazole moiety. Compound QD-18, QD-19, QD-20 and
QD-21 are a novel class of TB-specific compounds with excellent MIC values. The QD-18
exibited MIC value of 0.5 µg/ml and QD-19 to QD-21 exhibited significant MIC value of 0.25
µg/ml against Mtb WT H37Rv. These compounds are metabolically stable, bioavailable and
nontoxic with good T1/2 and AUC (h*ng/ml) to take for further studies in an animal model of TB-
infection. QD-18 exhibited encouraging MIC against mono-resistant strains of Mtb. It is
bacteriostatic in nature and the PK revealed it to be orally bioavailable with blood levels above
MIC 2.5 µg/mL. Our efforts to perform PK study of QD-20 and QD-21 will be continued in
forthcoming days. Nevertheless, being a novel class of compounds, these represent good candidate
lead molecules.
Acknowledgment
Authors are thankful to Dr. Ganesh Sambhasivam, CSO, Anthem biosciences, Bangalore, India,
for his invaluable support and allocation of resources for this work. They are thankful to FNDR,
Bangalore, India, for valuable support and allocation of resources for this work.
References and notes:
[
[
[
[
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16

Highlights:


Compound QD-18, QD-19, QD-20 and QD-21 are potent against Mtb WT H37Rv with
encouraging MIC values.
Four identified compounds are tuberculosis specific, orally bioavailable, non-cytotoxic and
metabolically stable.


Compound QD-20 and QD-21 exhibited an excellent pharmacokinetic profile.
A series of quinoline hybrids synthesized are a new class of anti-tubercular molecules.
17

Graphical abstract
A new series of quinoline carrying 1,2,4-oxadiazole moiety have been synthesized and evaluated
for their antituberculosis studies. Majority of them showed moderate to good antituberculosis
activity.
18