A series of N-substituted (Z)-2-imino-(5Z)-ylidene thiazolidines/thiazolidin-4-ones were synthesized and their antiproliferative activities against colon (HCT-116) and breast (MCF7) cancer cell lines were evaluated utilizing an MTT growth assay. A 2D-QSAR investigation was conducted to probe and validate the obtained antiproliferative properties for the thiazolidine derivatives. The majority of the thiazolidines exhibit higher potency against a colon cancer cell line relative to the standard reference. The p-halophenylimino p-anisylidene derivatives exhibited the highest anti-proliferative activity against HCT116 relative to control (IC<sub>50</sub> = 8.9-10.0 μM compared to 20.4 μM observed for 5-fluorouracil as positive control). An X-ray study confirmed the Z, Z'-configurations for two examples of the synthesized compounds.