Design, synthesis and biological evaluation of 4,5-dibromo-N-(thiazol-2-yl)-1H-pyrrole-2-carboxamide derivatives as novel DNA gyrase inhibitors

Bioorg Med Chem. 2017 Jan 1;25(1):338-349. doi: 10.1016/j.bmc.2016.10.038. Epub 2016 Nov 1.

Abstract

Development of novel DNA gyrase B inhibitors is an important field of antibacterial drug discovery whose aim is to introduce a more effective representative of this mechanistic class into the clinic. In the present study, two new series of Escherichia coli DNA gyrase inhibitors bearing the 4,5-dibromopyrrolamide moiety have been designed and synthesized. 4,5,6,7-Tetrahydrobenzo[1,2-d]thiazole-2,6-diamine derivatives inhibited E. coli DNA gyrase in the submicromolar to low micromolar range (IC50 values between 0.891 and 10.4μM). Their "ring-opened" analogues, based on the 2-(2-aminothiazol-4-yl)acetic acid scaffold, displayed weaker DNA gyrase inhibition with IC50 values between 15.9 and 169μM. Molecular docking experiments were conducted to study the binding modes of inhibitors.

Keywords: Antibacterial; DNA gyrase; Docking; Inhibitor; Thiazole.

MeSH terms

  • Acetanilides / chemical synthesis
  • Acetanilides / pharmacology*
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / pharmacology*
  • Benzothiazoles / chemical synthesis
  • Benzothiazoles / pharmacology*
  • Drug Design
  • Enterococcus faecalis / drug effects
  • Escherichia coli / drug effects
  • Hydrogen Bonding
  • Ligands
  • Molecular Docking Simulation
  • Pseudomonas aeruginosa / drug effects
  • Pyrroles / chemical synthesis
  • Pyrroles / pharmacology*
  • Staphylococcus aureus / drug effects
  • Structure-Activity Relationship
  • Topoisomerase II Inhibitors / chemical synthesis
  • Topoisomerase II Inhibitors / pharmacology*

Substances

  • Acetanilides
  • Anti-Bacterial Agents
  • Benzothiazoles
  • Ligands
  • Pyrroles
  • Topoisomerase II Inhibitors