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Title:

Optimization of N-benzyl-5-nitrofuran-2-carboxamide as an antitubercular agent

Authors:
Ricardo Gallardo-Macias, Pradeep Kumar, Mark Jaskowski, Todd Richmann, Riju Shrestha, Riccardo Russo, Eric Singleton, Matthew D Zimmerman, Hsin Pin Ho, Véronique Dartois, Nancy Connell, David Alland, Joel S Freundlich
Date posted:
December 24, 2018
Publication type:
Article
Publication:
Bioorg Med Chem Lett. 2019;29(4):601-606
Publisher:
Elsevier
DOI:
doi:10.1016/j.bmcl.2018.12.053
Introduction:
The optimization campaign for a nitrofuran antitubercular hit (N-benzyl-5-nitrofuran-2-carboxamide; JSF-3449) led to the design, synthesis, and biological profiling of a family of analogs. These compounds exhibited potent in vitro antitubercular activity (MIC = 0.019-0.20 μM) against the Mycobacterium tuberculosis H37Rv strain and low in vitro cytotoxicity (CC50 = 40->120 μM) towards Vero cells. Significant improvements in mouse liver microsomal stability and mouse pharmacokinetic profile were realized by introduction of an α, α-dimethylbenzyl moiety. Among these compounds, JSF-4088 is highlighted due to its in vitro antitubercular potency (MIC = 0.019 μM) and Vero cell cytotoxicity (CC50 > 120 μM). The findings suggest a rationale for the continued evolution of this promising series of antitubercular small molecules.

 

 

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