Journal
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
Volume 32, Issue 1, Pages 1291-1298Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2017.1375483
Keywords
Antimycobacterial; indolizine; pyridinium salts; ADMET
Funding
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases [HHSN27220110009I]
- [257/28.09.2010]
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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.
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