Facile synthesis and antimycobacterial activity of isoniazid, pyrazinamide and ciprofloxacin derivatives

Chem Biol Drug Des. 2021 Jun;97(6):1137-1150. doi: 10.1111/cbdd.13836. Epub 2021 Mar 16.

Abstract

Several rationally designed isoniazid (INH), pyrazinamide (PZA) and ciprofloxacin (CPF) derivatives were conveniently synthesized and evaluated in vitro against H37Rv Mycobacterium tuberculosis (M. tb) strain. CPF derivative 16 displayed a modest activity (MIC = 16 µg/ml) and was docked into the M. tb DNA gyrase. Isoniazid-pyrazinoic acid (INH-POA) hybrid 21a showed the highest potency in our study (MIC = 2 µg/ml). It also retained its high activity against the other tested M. tb drug-sensitive strain (DS) V4207 (MIC = 4 µg/ml) and demonstrated negligible cytotoxicity against Vero cells (IC50 ≥ 64 µg/ml). Four tested drug-resistant (DR) M. tb strains were refractory to 21a, similar to INH, whilst being sensitive to CPF. Compound 21a was also inactive against two non-tuberculous mycobacterial (NTM) strains, suggesting its selective activity against M. tb. The noteworthy activity of 21a against DS strains and its low cytotoxicity highlight its potential to treat DS M. tb.

Keywords: ciprofloxacin; hybrid molecules; indoleamides; isoniazid; pyrazinamide; tuberculosis.

Publication types

  • Letter
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitubercular Agents / chemical synthesis*
  • Antitubercular Agents / metabolism
  • Antitubercular Agents / pharmacology
  • Binding Sites
  • Catalytic Domain
  • Cell Survival / drug effects
  • Chlorocebus aethiops
  • Ciprofloxacin / analogs & derivatives*
  • Ciprofloxacin / chemistry
  • Ciprofloxacin / metabolism
  • Ciprofloxacin / pharmacology
  • DNA Gyrase / chemistry
  • DNA Gyrase / metabolism
  • Drug Design
  • Drug Resistance, Bacterial / drug effects
  • Isoniazid / analogs & derivatives*
  • Isoniazid / metabolism
  • Isoniazid / pharmacology
  • Microbial Sensitivity Tests
  • Molecular Conformation
  • Molecular Docking Simulation
  • Mycobacterium tuberculosis / drug effects
  • Nontuberculous Mycobacteria / drug effects
  • Pyrazinamide / analogs & derivatives*
  • Pyrazinamide / metabolism
  • Pyrazinamide / pharmacology
  • Structure-Activity Relationship
  • Vero Cells

Substances

  • Antitubercular Agents
  • Pyrazinamide
  • Ciprofloxacin
  • DNA Gyrase
  • Isoniazid