(2 Z,5 Z) 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.