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
  • 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: [email protected].
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.