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Published on: February 26, 2018
In Vitro Evaluation of Novel Nitazoxanide Derivatives against Mycobacterium tuberculosis
Joshua Odingo1, Mai A Bailey1, Megan Files1
1Infectious Disease Research Institute, TB Discovery Research, 1616 Eastlake Avenue East, Seattle, Washington 98102, United States.
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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