New indole and indazole derivatives as potential antimycobacterial agents
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The study reports on the synthesis and in vitro assessment of the antimycobacterial activity of a series of new indole- and indazole-based aroylhydrazones evaluated against Mycobacterium tuberculosis H37Rv. Isoniazide and ethambutol were used as reference drugs. The most active compounds 3a (MIC 0.4412 μM) and 3e (MIC 0.3969 μM) demonstrated excellent antimycobacterial activity, a very low toxicity against the human embryonic kidney cell line HEK-293T and high selectivity index values (SI = 633.49 and SI > 1978.83, respectively). Importantly, the oral administration of compound 3e at the highest dose of 2000 mg/kg b.w. resulted in no mortalities or evidence of adverse effects, implying that compound 3e is nontoxic. The other derivatives with an indole and indazole scaffold also exhibited high antimycobacterial activity with exception of indole derivatives with Br substituents at the 5th position which exhibited activity weaker than that of ethambutol. The molecular docking investigations performed in an enoyl-ACP reductase (InhA) displayed good docking scores and promising insights on possible interactions with the InhA receptor.
KeywordsAntimycobacterial activity Cytotoxicity Indazole Indole InhA LD50 Molecular docking
This work was supported by grant contract no. 77./03.05.2018 at Medical Science Council, MU-Sofia, Bulgaria. The authors are grateful to Dr. PT Nedialkov for taking the mass spectra and to Dr. Marin Rogozerov and Dr. Javor Mitkov for the IR spectra. Acknowledgements are due to Stefka Ivanova and our student Nadezda Janakieva for their technical assistance. We would like to thank Rositsa Mihaylova for determining IC50 of the compounds.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were calculated.
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