Synthesis of 5-enamine-4-thiazolidinone derivatives with trypanocidal and anticancer activity

Bioorg Chem. 2019 May;86:126-136. doi: 10.1016/j.bioorg.2019.01.045. Epub 2019 Jan 22.

Abstract

A series of novel 2-(5-aminomethylene-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropionic acid ethyl esters has been synthesized. Target compounds were evaluated for their trypanocidal activity towards Trypanosoma brucei brucei and Trypanosoma brucei gambiense. Several hit-compounds (8, 10, 12) inhibited growth of the parasites at sub-micromolar concentrations (IC50 0.027-1.936 µM) and showed significant selectivity indices (SI = 108-1396.2) being non-toxic towards the human primary fibroblasts. The screening of anticancer activity in vitro within NCI DTP protocol allowed to identify active 2-(5-{[5-(2,4-dichlorobenzyl)-thiazol-2-ylamino]-methylene}-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropionic acid ethyl ester 14 that demonstrated inhibition against all 59 human tumor cell lines with the average GI50 value of 2.57 μM. It was established that the activity type (antitrypanosomal or anticancer) as well as its level depends on the character of enamine fragment in the C5 position of thiazolidinone core.

Keywords: 5-ene-4-thiazolidinones; Anticancer activity; Antitrypanosomal activity; X-ray.

MeSH terms

  • Animals
  • Antiprotozoal Agents / chemical synthesis
  • Antiprotozoal Agents / chemistry
  • Antiprotozoal Agents / pharmacology*
  • Cell Line
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Parasitic Sensitivity Tests
  • Rats
  • Structure-Activity Relationship
  • Thiazolidines / chemical synthesis
  • Thiazolidines / chemistry
  • Thiazolidines / pharmacology*
  • Trypanocidal Agents / chemical synthesis
  • Trypanocidal Agents / chemistry
  • Trypanocidal Agents / pharmacology*
  • Trypanosoma brucei brucei / drug effects*

Substances

  • Antiprotozoal Agents
  • Thiazolidines
  • Trypanocidal Agents