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. 2017 Sep 30;2(9):5873-5890.
doi: 10.1021/acsomega.7b00892. Epub 2017 Sep 18.

In Vitro Evaluation of Novel Nitazoxanide Derivatives against Mycobacterium tuberculosis

Joshua Odingo  1 , Mai A Bailey  1 , Megan Files  1 , Julie V Early  1 , Torey Alling  1 , Devon Dennison  1 , Julie Bowman  1 , Suryakanta Dalai  2 , Naresh Kumar  2 , Jeffrey Cramer  3 , Thierry Masquelin  3 , Philip A Hipskind  3 , Tanya Parish  1
Affiliations

In Vitro Evaluation of Novel Nitazoxanide Derivatives against Mycobacterium tuberculosis

Joshua Odingo et al. ACS Omega. .

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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Conflict of interest statement

The authors declare the following competing financial interest(s): This work was funded by the Lilly TB Drug Discovery Initiative (http://www.tbdrugdiscovery.org/), and funding was provided by Eli Lilly and Company. The following authors are employed by Eli Lilly & Company: Jeffrey Cramer, Thierry Masquelin, and Philip A. Hipskind, and each were involved in data collection, analysis, and preparation of the manuscript as detailed in the authors’ contribution as part of their normal work.

Figures

Figure 1
Figure 1
General synthesis of analogues. Reagents and conditions: (a) RCOCl, Et3N, THF or RCO2H, T3P, Et3N, MeCN, rt, 16 h; (b) RNCO, Et3N, THF; (c) RSO2Cl, Et3N, DCM, rt,16 h; (d) RCHO, Et3SiH, trifluoroacetyl (TFA), MeCN, 80°C, 4 h.
Figure 2
Figure 2
Analogues of 1 have bactericidal activity under aerobic conditions.
Figure 3
Figure 3
Analogues of 1 have bactericidal activity under nonreplicating conditions.
See this image and copyright information in PMC

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