Synthesis and activity of BNF15 against drug-resistant Mycobacterium tuberculosis

Future Med Chem. 2021 Feb;13(3):251-267. doi: 10.4155/fmc-2019-0154. Epub 2020 Dec 9.

Abstract

Aim: Tuberculosis is the leading cause of mortality among infectious diseases worldwide. Finding a new competent anti tubercular therapy is essential. Materials & methods: We screened thousands of compounds and evaluated their efficacy against Mycobacterium tuberculosis. Results: Initially, 2-nitronaphtho[2,3-b]benzofuran-6,11-dione was active against M. tuberculosis. Next, among 15 newly synthesized derivatives, BNF15 showed promising effect against all drug-sensitive and drug-resistant M. tuberculosis (MIC: 0.02-0.78 μg/ml). BNF15 effectively killed intracellular M. tuberculosis and nontuberculous mycobacteria. BNF15 exhibited a prolonged post antibiotic effect superior to isoniazid, streptomycin, and ethambutol and synergistic interaction with rifampicin. In acute oral toxicity test, BNF15 did not show toxic effect at a concentration up to 2000 mg/kg. Conclusion: These results highlight the perspective of BNF15 to treat drug-resistant M. tuberculosis.

Keywords: BNF15; PAE; acute oral toxicity; drug combination; drug-resistant M. tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitubercular Agents / chemical synthesis*
  • Antitubercular Agents / pharmacology
  • Benzofurans / chemical synthesis
  • Benzofurans / chemistry*
  • Benzofurans / pharmacology
  • DNA Replication / drug effects
  • Drug Resistance, Bacterial / drug effects
  • Drug Synergism
  • Female
  • Fungi / drug effects
  • Gram-Negative Bacteria / drug effects
  • Gram-Positive Bacteria / drug effects
  • Humans
  • Isoniazid / pharmacology
  • Mice
  • Mice, Inbred ICR
  • Microbial Sensitivity Tests
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / genetics
  • RAW 264.7 Cells
  • Structure-Activity Relationship

Substances

  • Antitubercular Agents
  • Benzofurans
  • Isoniazid