Biological and in Silico Studies of a Novel Pyrazolo[3,4‐d] Thiazole Derivatives: Anticancer, Anti‐inflammatory, Molecular Docking and SAR

This study synthesized and evaluated a series of novel 1,3,5‐trisubstituted‐1H‐pyrazolo[3,4‐d]thiazole derivatives (5a, 5b, 6a, 6b, and 7) for their cytotoxic, anti‐inflammatory, and anticancer properties. The cytotoxic activity of these derivatives was evaluated against MCF‐7  and HepG2 cell lines. Compound 6b demonstrated the most potent anticancer activity, with IC50 values of 15.57 ± 2.93 µg/mL for MCF‐7 cells and 43.72 ± 1.90 µg/mL for HepG2 cells, demonstrating greater efficacy than doxorubicin. Mechanistic studies revealed that compound 6b induced S‐phase arrest in MCF‐7 cells and G1/S‐phase arrest in HepG2 cells, along with a significant increase in apoptosis rates in the treated cancer cells. Moreover, compound 6b demonstrated significant VEGFR‐2 inhibition, surpassing the efficacy of sorafenib. Compounds 5b and 6b demonstrated significant anti‐inflammatory activity in RAW264.7 macrophage cells, as indicated by the decrease in nitric oxide (NO) production and the downregulation of proinflammatory cytokines, such as IL‐1β, IL‐6, and TNF‐α. The derivatives exhibited no cytotoxicity towards normal cell lines (MCF‐10A, THLE‐2, and Vero cells), as validated by MTT assays. Docking studies elucidated the interaction mechanism between the compounds and the enzyme receptors. These findings demonstrate compound 6b as a promising candidate for the development of dual‐function anticancer and anti‐inflammatory agents.