In Vitro Evaluation of Novel Nitazoxanide Derivatives against Mycobacterium tuberculosis.
ACS Omega. 2017 Sep 30;2(9):5873-5890
Authors: Odingo J, Bailey MA, Files M, Early JV, Alling T, Dennison D, Bowman J, Dalai S, Kumar N, Cramer J, Masquelin T, Hipskind PA, Parish T
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.
PMID: 30023755 [PubMed]