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Chander et al.
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luminometry method. The minimum inhibitory concentra-
tion (MIC) values (in terms of μg/mL and μm) of tested
compounds and standard drug rifampicin are shown in
Table 2. Among the tested compounds, four compounds
(6h, 6j, 6l, and 6m) displayed significant anti-Mtb activity
with MIC <20 μg/mL (highlighted by bold font in Table 2).
In further study, we investigated the effect of different
substitution pattern of phenyl ring on anti-tubercular
potency of compounds. Prototype compound 6a containing
un-substituted phenyl ring exhibited weak anti-Mtb activity.
Further, substitution of phenyl ring with electron-donating
groups like methyl and methoxy at ortho and meta posi-
tion respectively, further decreased their anti-tubercular
potency. Whereas, substitution by methoxy group at the
para position (6d) slightly enhanced the potency (38.51 μg/
mL). Further, substitution with strong electron withdrawing
fluoro group at ortho and para position (compound 6e
and 6f) also resulted decrease in anti-tubercular potency
(84.75 and 60.74 μg/mL respectively). Interestingly, chloro
substitution at ortho position of phenyl ring (6g) markedly
decreased the potency (>180.78 μg/mL), while at the para
position (6h), potency against Mtb was significantly
increased (11.58 μg/mL). Substitution with bromo at meta
position (6i) not significantly changed the anti-tubercular
potency, while para substituted compound 6j exhibited
seven times more potency (7.70 μg/mL) as compared to
the unsubstituted one. Among the nitro substituted com-
pounds (6k, 6l and 6m), compound 6k exhibited moderate
while compounds 6l and 6m showed significant anti-
tubercular potency. Over all anti-Mtb potency of com-
pounds 6k, 6l and 6m changed in the order
ortho < meta < para (MIC 38.33, 14.27 and 7.13 μg/
mL), respectively. Further, 4-cyano substituted compound
6n exhibited moderate potency while di-chorlo and tri-
methoxy substituted compounds (6o and 6p) exhibited
very weak anti-Mtb potency. Compounds constitute iso-
propyl group instead of phenyl (6q), also exhibited weak
anti-Mtb activity. So, overall SAR study of the tested
compounds revealed that, their anti-tubercular potency
changed significantly with the position and nature of the
substituent on phenyl ring. Compounds substituted with
electron withdrawing group of moderate to large size at
the para position of phenyl ring (especially 6j and 6m)
exhibited significant inhibitory potency against Mtb with
good safety index.
2.3.2 | Cytotoxicity evaluation
All the synthesized compounds were evaluated for their
cytotoxic effect on the MRC-5, human lung fibroblast cell
at concentration of 512 μm. Interestingly, none of the
compound showed toxicity at the tested concentration.
3
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CONCLUSION
In summary, we designed and synthesized seventeen (6a–q)
novel quinoline-based carboxylic hydrazides with anti-Mtb
properties based on molecular hybridization as well as
in-silico evaluated for drug likeness. Based upon the pre-
dicted in-silico physicochemical and pharmacokinetic
parameters, all the compounds possessed drug-likeness
behavior. Subsequently, compounds (6a–q) were tested to
evaluate their cytotoxicity and whole cell activity against
Mtb. Four compounds (6h, 6j, 6l, and 6m) exhibited sig-
nificant anti-Mtb activity (MIC <20 μg/mL), in which
two most potent compounds (6j and 6m) exhibited MIC
values 7.70 and 7.13 μg/mL, respectively against Mtb.
None of the compound exhibited cytotoxicity against lung
fibroblast cells at tested concentration (512 μm). SAR study
of the tested compounds revealed that, electron withdraw-
ing group of moderate to large size especially at para
position of phenyl ring (like 6h, 6j, and 6m) significantly
increased the potency against M. tuberculosis while retain-
ing a good safety index. The tested compounds exhibited
moderate potency against Mtb as compared to the refer-
ence drug rifampicin. We consider this study as a helpful
starting point for further lead optimization efforts aiming
to find more potent anti-tubercular agents with an improved
physicochemical profile.
ACKNOWLEDGMENTS
Authors gratefully acknowledge BITS-Pilani for providing
the necessary facilities to do this work. This work was car-
ried out under a grant from Science and Engineering Research
Board of Department of Science and Technology, New Delhi
(Ref. No: SR/FT/LS-58/2011). The work of DC and PC is
funded by the FWO under grant agreement 12N5915N.
CONFLICT OF INTEREST
In the recent studies, several carbohydrazide of heterocy-
clic moieties containing N′-benzylidene at terminal part, are
reported as potent inhibitor of pantothenate synthetase enzyme
of M. tuberculosis.[26,27] Moreover, our reported compounds
also exhibit the similar pharmacophoric features, so probably
they may share the similar mechanism of action, but further
studies are required to know the exact mechanism of action.
The authors declared that there is no conflict of interest.
REFERENCES