Antimycobacterial activity of nitrogen heterocycles derivatives: 7-(pyridine-4-yl)-indolizine derivatives. Part VII^8–12

Abstract

A series of 13 compounds having a monoindolizine mono-salt skeleton was designed and synthesised in order to evaluate their antimycobacterial activity. The synthesis is efficient, involving only three steps: two alkylations and one 3 + 2 dipolar cycloaddition. The antimicrobial activity against Mycobacterium tuberculosis H37Rv grown under aerobic conditions was evaluated, eight compounds showing a very good antimycobacterial activity. SAR correlation reveals a certain influence of the R substituent from the para position of benzoyl moiety at position 3 of indolizine. The most active five compounds passed the second stage of anti-TB testing, the assay demonstrating that they are potent against both replicating and non-replicating Mtb, have a bactericidal mechanism of action, are active against drug-resistant Mtb strains, present a moderate to good activity against nontuberculous mycobacteria, a good intracellular activity, and a moderate to high cytotoxicity. For one compound showing a promising anti-TB profile, a complete ADMET study has been performed.

Keywords:

• Antimycobacterial
• indolizine
• pyridinium salts
• ADMET

Acknowledgements

Part of this work (biological tests) was supported by National Institutes of Health and the National Institute of Allergy and Infectious Diseases, Contract no. HHSN27220110009I. Special thanks for Jim P. Boyce, senior officer to Division of Microbiology and Infectious Diseases, NIAID. The authors also thank the POSCCE-O 2.2.1, SMIS-CSNR 13984-901, Project no. 257/28.09.2010, CERNESIM, for the NMR experiments.

Disclosure statement

No potential conflict of interest was reported by the authors.