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New indole and indazole derivatives as potential antimycobacterial agents

  • Violina T. AngelovaEmail author
  • Tania Pencheva
  • Nikolay Vassilev
  • Rumyana Simeonova
  • Georgi Momekov
  • Violeta Valcheva
Original Research
  • 17 Downloads

Abstract

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.

Keywords

Antimycobacterial activity Cytotoxicity Indazole Indole InhA LD50 Molecular docking 

Notes

Acknowledgements

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.

Ethical approval

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.

Supplementary material

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Supplementary Information
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Supplementary Table S1

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Chemistry, Faculty of PharmacyMedical University of SofiaSofiaBulgaria
  2. 2.Institute of Biophysics and Biomedical EngineeringBulgarian Academy of SciencesSofiaBulgaria
  3. 3.Laboratory of Nuclear Magnetic Resonance, Institute of Organic Chemistry with Centre of PhytochemistryBulgarian Academy of SciencesSofiaBulgaria
  4. 4.Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of PharmacyMedical University-SofiaSofiaBulgaria
  5. 5.Institute of MicrobiologyBulgarian Academy of SciencesSofiaBulgaria
  6. 6.In Vitro Laboratory for Evaluation of Biological Activity and ToxicitySofiaBulgaria

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