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

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

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)601-606
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume29
Issue number4
DOIs
StatePublished - Feb 15 2019
Externally publishedYes

Bibliographical note

Funding Information:
The authors gratefully acknowledge support from NIH grants R33AI11167 , R21AI111647 , and U19AI109713 .

Keywords

  • Benzamide
  • Mycobacterium tuberculosis
  • Nitrofuran
  • α α-Dimethyl

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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