2. Academic Validation
  3. Optimization of N-benzyl-5-nitrofuran-2-carboxamide as an antitubercular agent

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

  • Bioorg Med Chem Lett. 2019 Feb 15;29(4):601-606. doi: 10.1016/j.bmcl.2018.12.053.
Ricardo Gallardo-Macias 1,  Pradeep Kumar 2,  Mark Jaskowski 1,  Todd Richmann 2,  Riju Shrestha 2,  Riccardo Russo 2,  Eric Singleton 2,  Matthew D Zimmerman 3,  Hsin Pin Ho 3,  Véronique Dartois 3,  Nancy Connell 2,  David Alland 2,  Joel S Freundlich 4
Affiliations

Affiliations

  • 1 Department of Pharmacology, Physiology, and Neuroscience, Rutgers University - New Jersey Medical School, Newark, NJ, USA.
  • 2 Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenço Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University - New Jersey Medical School, Newark, NJ, USA.
  • 3 Public Health Research Institute, Rutgers University - New Jersey Medical School, Newark, NJ, USA.
  • 4 Department of Pharmacology, Physiology, and Neuroscience, Rutgers University - New Jersey Medical School, Newark, NJ, USA; Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenço Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University - New Jersey Medical School, Newark, NJ, USA. Electronic address: freundjs@rutgers.edu.
PMID: 30600207 DOI: 10.1016/j.bmcl.2018.12.053
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.

Keywords

Benzamide; Mycobacterium tuberculosis; Nitrofuran; α, α-Dimethyl.

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