Design, synthesis and anti-tubercular evaluation of new 2-acylated and 2-alkylated amino-5-(4-(benzyloxy)phenyl)thiophene-3-carboxylic acid derivatives. Part 1

Eur J Med Chem. 2011 Sep;46(9):3551-63. doi: 10.1016/j.ejmech.2011.05.018. Epub 2011 May 19.

Abstract

A series of 2-acylated and 2-alkylated amino-5-(4-(benzyloxy)phenyl)thiophene-3-carboxylic acid derivatives were synthesized and evaluated for anti-tubercular activity. Among these compounds, 10d, 15, 12h and 12k inhibited Mycobacterium tuberculosis (Mtb) growth with MIC values between 1.9 and 7.7 μM and low toxicity against VERO cells. The four compounds were also tested against multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) clinical strains, which were found to show moderate activity. In addition, molecular docking simulation was performed to position compounds 10d, 15, 12h and 12k into mtFabH active site to predict the probable binding mode. These studies thus suggest that the designed 2-amino-5-phenylthiophene-3-carboxylic acid scaffold may serve as new promising template for further elaboration as anti-TB drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitubercular Agents / chemical synthesis*
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacology*
  • Carboxylic Acids / chemistry*
  • Chlorocebus aethiops
  • Drug Design
  • Magnetic Resonance Spectroscopy
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Mycobacterium tuberculosis / drug effects*
  • Spectrometry, Mass, Electrospray Ionization
  • Thiophenes / chemical synthesis*
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*
  • Vero Cells

Substances

  • Antitubercular Agents
  • Carboxylic Acids
  • Thiophenes