Abstract
AIM: To design and synthesize novel dihydropyrimidinone-pyrazole hybrid compounds as potent and selective antitumor agents, exploring their potential mechanism of action. MATERIALS & METHODS: A series of target compounds were synthesized and evaluated for their in vitro antiproliferative activity against three human cancer cell lines: A549 (lung adenocarcinoma), MIA PaCa-2 (pancreatic carcinoma), and HepG2 (hepatoblastoma). Cytotoxicity was also assessed in non-cancerous Vero cells, along with an in vivo acute toxicity evaluation in mice. The metabolic stability of the lead compounds was investigated using human liver microsomes. Potential molecular targets were identified through in silico prediction, and the proposed mechanism was further validated via molecular docking, molecular dynamics (MD) simulations, and enzymatic inhibition assays. RESULTS: Compounds 14 and 27 demonstrated potent, broad-spectrum antiproliferative activity in the submicromolar range, exhibiting high selectivity indices against cancer cells and favorable metabolic stability. Integrated computational and enzymatic studies identified Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) as a potential molecular target, suggesting that the antitumor activity may be mediated through its inhibition. CONCLUSION: Compounds 14 and 27 are established as promising anticancer candidates worthy of further development. Future work will focus on comprehensive in vivo efficacy studies and deeper mechanistic investigation to advance this novel chemical series.