Stereoselective synthesis and QSAR study of cytotoxic 2-(4-oxo-thiazolidin-2-ylidene)-2-cyano-N-arylacetamides

(2Z,5Z) 2-[(5-Arylidene-4-oxo-3-phenyl)-thiazolidin-2-ylidine]-2-cyano-N-arylacetamides 4a–l were stereoselectively prepared via condensation of aromatic aldehydes with 4-thiazolidinones 3a–c. The latters were obtained via electrophilic attack of phenylisothiocyanate on 2-cyano-N-arylacetamides 1a–c followed by reaction with chloroacetyl chloride under basic condition. Single crystal X-ray study of 3a allows good confirmation for the assigned structure. Additionally, 5-arylhydrazono analogs 5a–e were prepared via condensation of the appropriate diazonium salts with 4-thiazolidinones 3a,b. Many of the synthesized compounds exhibited promising antitumor properties against colon HCT116, breast MCF7 and liver HEPG2 cell lines. 3D-Pharmacophore modeling and QSAR analysis were combined to explain the observed antitumor properties.

Graphical abstract4-Thiazolidinones were prepared in a high stereoselective manner and tested for their antitumor activity. Compound 4b was the most effective agent against colon HCT116 and breast MCF7 cancer cell lines. Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► 5-Arylidene-4-thiazolidinones and their hydrazono derivatives were prepared. ► X-ray crystallography of compound 3a supported the formation of Z-isomer. ► The synthesized compounds were tested against HCT116, MCF7 and HEPG2 cell lines. ► Most of the tested compounds showed promising activity against HCT116 cell line. ► QSAR study was undertaken to validate and understand the antitumor properties.