In Vitro Evaluation of Novel Nitazoxanide Derivatives against Mycobacterium tuberculosis

ACS Omega
Joshua OdingoTanya Parish

Abstract

Nitazoxanide has antiparasitic and antibiotic activities including activity against Mycobacterium tuberculosis. We prepared and evaluated a set of its analogues to determine the structure-activity relationship, and identified several amide- and urea-based analogues with low micromolar activity against M. tuberculosis in vitro. Pharmacokinetics in the rat suggested a path forward to obtain bioavailable compounds. The series had a good microbiological profile with bactericidal activity in vitro against replicating and nonreplicating M. tuberculosis. Analogues had limited activity against other Gram-positive bacteria but no activity against Gram-negative bacteria. Our studies identified the key liability in this series as cytotoxicity. Future work concentrating on identifying the target(s) could assist in removing activity against eukaryotic cells.

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Citations

Sep 3, 2020·Antibiotics·Álvaro MourenzaMichal Letek
Jan 29, 2021·Frontiers in Cellular and Infection Microbiology·Erik J HasenoehrlMichael Berney
May 1, 2021·Pharmaceutics·Filia StephanieUsman Sumo Friend Tambunan
Dec 23, 2020·ACS Infectious Diseases·Andrew V StachulskiPaul M O'Neill
Jan 19, 2022·Drug Development Research·Cauê Benito Scarim, Fernando Rogério Pavan

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Methods Mentioned

BETA
NMR
column chromatography

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