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

Fingerprint

Nitrofurans
Antitubercular Agents
Cytotoxicity
Vero Cells
Pharmacokinetics
Liver
Mycobacterium tuberculosis
Molecules
In Vitro Techniques

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., ... 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

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

In: Bioorganic and Medicinal Chemistry Letters, Vol. 29, No. 4, 15.02.2019, p. 601-606.

Research output: Contribution to journalArticle

Gallardo-Macias, R, Kumar, P, Jaskowski, M, Richmann, T, Shrestha, R, Russo, R, Singleton, E, Zimmerman, MD, Ho, HP, Dartois, V, Connell, N, Alland, D & Freundlich, JS 2019, 'Optimization of N-benzyl-5-nitrofuran-2-carboxamide as an antitubercular agent', Bioorganic and Medicinal Chemistry Letters, vol. 29, no. 4, pp. 601-606. https://doi.org/10.1016/j.bmcl.2018.12.053
Gallardo-Macias R, Kumar P, Jaskowski M, Richmann T, Shrestha R, Russo R et al. Optimization of N-benzyl-5-nitrofuran-2-carboxamide as an antitubercular agent. Bioorganic and Medicinal Chemistry Letters. 2019 Feb 15;29(4):601-606. https://doi.org/10.1016/j.bmcl.2018.12.053
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. / Optimization of N-benzyl-5-nitrofuran-2-carboxamide as an antitubercular agent. In: Bioorganic and Medicinal Chemistry Letters. 2019 ; Vol. 29, No. 4. pp. 601-606.
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