Optimization of N-benzyl-5-nitrofuran-2-carboxamide as an antitubercular agent. Issue 4 (15th February 2019)

• Record Type: Journal Article
• Authors: Gallardo-Macias, Ricardo; Kumar, Pradeep; Jaskowski, Mark; Richmann, Todd; Shrestha, Riju; Russo, Riccardo; Singleton, Eric; Zimmerman, Matthew D.; Ho, Hsin Pin; Dartois, Véronique; Connell, Nancy; Alland, David; Freundlich, Joel S.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 4(2019)
• Page Start: 601
• Page End: 606
• Publication Date: 2019-02-15
• Subjects: Mycobacterium tuberculosis -- Nitrofuran -- Benzamide -- α, α-Dimethyl; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.12.053
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.