| Literature DB >> 30600207 |
Ricardo Gallardo-Macias1, Pradeep Kumar2, Mark Jaskowski1, Todd Richmann2, Riju Shrestha2, Riccardo Russo2, Eric Singleton2, Matthew D Zimmerman3, Hsin Pin Ho3, Véronique Dartois3, Nancy Connell2, David Alland2, Joel S Freundlich4.
Abstract
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.Entities:
Keywords: Benzamide; Mycobacterium tuberculosis; Nitrofuran; α, α-Dimethyl
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Year: 2018 PMID： 30600207 PMCID： PMC6368976 DOI： 10.1016/j.bmcl.2018.12.053
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823