Design, Synthesis, and Mechanistic Understanding of Thioxothiazole Scaffolds as Possible Apoptotic Inducers and CDK2 Inhibitors in Melanoma

ABSTRACT

This study aimed to develop novel CDK2 inhibitors with potent antimelanoma activity. Accordingly, a series of 2‐thioxothiazolyl pyrazoles (2–11) was rationally designed through molecular hybridization and synthesized using efficient and straightforward synthetic procedures. The structures of the synthesized compounds were confirmed by IR, NMR, mass spectrometry, and elemental analyses. All compounds were evaluated by the NCI, USA, against the 60‐human cancer cell line panel at a single dose (10 µM). The preliminary screening revealed promising antiproliferative activity, particularly against melanoma cell lines, with compound 11 exhibiting the highest growth inhibition against LOX‐IMVI and MALME‐3 M cells (21.60% and 49.41%, respectively). Based on these results, compounds 2, 4, and 11 were further evaluated by the MTT assay. Compound 11 exhibited the greatest cytotoxicity, with IC ₅₀ values of 3.82 and 2.52 µM against LOX‐IMVI and MALME‐3 M cells, respectively, superior to doxorubicin and 5‐fluorouracil, together with excellent selectivity (SI = 12.14 and 18.40). Moreover, compound 11 potently inhibited CDK2 (IC ₅₀ = 1.07 µM), approaching the activity of roscovitine (IC ₅₀ = 0.84 µM), and induced cell cycle arrest at G1‐phase, besides promoting intrinsic apoptosis (23‐ to 40‐fold) in MALME‐3 M cells. These findings identify compound 11 as a promising selective CDK2‐targeted lead for melanoma therapy.