Synthesis and HIV-1 RT inhibitory action of novel (4/6-substituted benzo[d]thiazol -2-yl)thiazolidin-4-ones. Divergence from the non-competitive inhibition mechanism

J Enzyme Inhib Med Chem. 2013 Feb;28(1):113-22. doi: 10.3109/14756366.2011.636362. Epub 2012 Mar 1.

Abstract

Reverse transcriptase (RT) inhibitors play a major role in the therapy of human immunodeficiency virus type 1 (HIV-1) infection. Although, many compounds are already used as anti-HIV drugs, research on development of novel inhibitors continues, since drug resistant strains appear because of prolonged therapy. In this paper, we present the synthesis and evaluation of HIV-1 RT inhibitory action of eighteen novel (4/6-halogen/MeO/EtO-substituted benzo[d]thiazol-2-yl)thiazolidin-4-ones. The two more active compounds (IC50 : 0.04 µM and 0.25 µM) exhibited better inhibitory action than the reference compound, nevirapine. Docking analysis supports a stable binding of the most active derivative to the allosteric centre of RT. Kinetic analysis of two of the most active compounds indicate an uncompetitive inhibition mode. This is a desired characteristic, since mutations that affect activity of traditional non-competitive NNRTIs may not affect activity of compounds of this series. Interestingly, the less active derivatives (IC50 > 40 µM) exhibit a competitive mode of action.

MeSH terms

  • Chemistry Techniques, Synthetic
  • Drug Evaluation, Preclinical / methods
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / chemistry
  • HIV Reverse Transcriptase / metabolism
  • Inhibitory Concentration 50
  • Kinetics
  • Molecular Docking Simulation
  • Nevirapine / pharmacology
  • Nitriles
  • Pyridazines / chemistry
  • Pyridazines / metabolism
  • Pyrimidines
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Thiazolidines / chemistry
  • Toxicity Tests

Substances

  • Nitriles
  • Pyridazines
  • Pyrimidines
  • Reverse Transcriptase Inhibitors
  • Thiazolidines
  • etravirine
  • Nevirapine
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase