Design, Synthesis, Biological and Computational Assessment of New Thiazolidin-4-one Derivatives as Potential Anticancer Agents Through the Apoptosis Pathway

A variety of novel thiazolidin-4-one himachalene derivatives were designed and synthesized through hetero-cyclization of thiosemicarbazone analogs that have previously exhibited strong anticancer activity. The synthesized products 2 a-4 f were completely characterized by H-1 NMR, C-13 NMR, IR, and HRMS and were later submitted for in vitro evaluation of their anticancer activity and cytotoxicity on a panel of four human cancer cell lines ( i.eHT-1080, MCF-7, A-549, and MDA-MB-231). Most of the evaluated compounds showed potent antiproliferative activities against the four human cancer cell lines with tested IC50 values ranging from 5.25 +/- 0.32 to 9.26 +/- 0.73 mu M. The mechanism of action revealed that compounds 2 b and 4 b induced caspase-3/7-activated apoptosis and cell cycle arrest in the G0/G1 stage in HT-1080 and A-549 cells. Furthermore, molecular docking studies were conducted to evaluate the binding affinities and the possible binding modes of the top-performing compounds 2 b and 4 b. This was later supported by Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis predicting their prospective pharmacological profiles. The outcome of this study supports the validity of our strategy and presents 2 b and 4 b as a pattern for the discovery of novel cancer therapeutics.