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 journalArticle

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

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Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Gallardo-Macias, R., Kumar, P., Jaskowski, M., Richmann, T., Shrestha, R., Russo, R., Singleton, E., Zimmerman, M. D., Ho, H. P., Dartois, V., Connell, N., Alland, D., & Freundlich, J. S. (2019). Optimization of N-benzyl-5-nitrofuran-2-carboxamide as an antitubercular agent. Bioorganic and Medicinal Chemistry Letters, 29(4), 601-606. https://doi.org/10.1016/j.bmcl.2018.12.053