Design, synthesis, in silico studies, and biological evaluation of tosyl-substituted thiazoles, thiazolidin-4-ones, and chromenes as potential anticancer agents

Abstract

A novel series of thiazole, thiazolidin-4-one, and chromene derivatives incorporating a 4-methylbenzenesulfonate (tosylate) moiety were designed, synthesized, and evaluated for their anticancer potential. All structures were elucidated using IR, 1H NMR, 13C NMR, and MS spectroscopy. Anticancer potential was assessed by MTT assay against HepG-2 (hepatocellular carcinoma) and MCF-7 (breast cancer) cell lines, with doxorubicin as a reference. Against MCF-7, compounds 3d (IC50 = 28.2 ± 2.08 µM), 6a (30.0 ± 0.82 µM), and 8a (25.9 ± 1.35 µM) exhibited relatively enhanced cytotoxicity. For HepG-2, derivatives 3a (46.5 ± 1.23 µM), 3e (49.1 ± 0.95 µM), and 3d (54.6 ± 1.34 µM) showed moderate cytotoxic activity relative to doxorubicin. Also, all the synthesized compounds were subjected to molecular docking against the receptor (PDB ID: 1X7B) when compared with the standard drug doxorubicin. However, 3b had the best binding energy (6.4543 kcal mol−1), resulting in a π–cation interaction with phenyl and Lys471, and was closely followed by 3c (6.3568 kcal mol−1), 8c (6.3141 kcal mol−1), and 8b (6.3020 kcal mol−1). From DFT analysis on the most active molecules 3d, 6a, and 8a, it is clear that molecule 8a exhibits the lowest energy difference between its HOMO and LUMO orbitals (Egap = 3.39 eV) as well as highest molecular softness value (δ = 0.59), which may contribute to its enhanced chemical reactivity and observed biological activity compared to other molecules. Moreover, the pharmacokinetic characteristics of the thirteen synthesized analogues using SwissADME exhibited poor solubility, possessed low GI absorption, and unveiled no BBB permeability. The newly developed analogs possessed a high lipophilicity, larger polar surface area and poor predicted gastrointestinal absorption, mainly due to the presence of the sulfonamide/sulfonate-functionalized core structure. In addition to this, some of the compounds exhibited an inhibitory effect on some of the important CYP450 enzymes (CYP2C19, CYP2C9 and/or CYP3A4). The pharmacokinetic challenges pose a great need to optimize the structures before preclinical evaluation. Overall, this study provides integrated experimental and computational insights into the anticancer potential of tosylate-bearing heterocyclic scaffolds, addressing gaps in understanding their structure–activity relationships. The identified promising compounds may serve as useful starting points for further structural optimization and mechanistic studies toward the development of improved anticancer candidates.