Novel Fused Pyrimidines as Potent Cyclin‐Dependent Kinases Inhibitor for Gastric Adenocarcinoma: Combined In Vitro, In Silico Anticancer Studies

Abstract

Our research aims to design novel pyrimidine derivatives inspired by the common pyrimidine core found in many FDA‐approved drugs. However, extensive prior research on the pyrimidine scaffold has made discovering new molecules more challenging. To overcome this obstacle, we employed a molecular hybridisation strategy, opting to hybridise tetralin and pyrimidine, recognising their potential in cancer therapeutics. The fused pyrimidine was synthesised through a base‐mediated condensation of chalcone with amidine. The reaction conditions were further optimised for base, solvent, temperature and time to produce a series of 21 novel derivatives. These compounds were subsequently screened for anticancer activity against gastric adenocarcinoma cell lines using the MTT assay. Among the synthesised compounds, 2‐(pyridin‐3‐yl)‐4‐(pyridin‐3‐yl)‐5,6‐dihydrobenzo[h]quinazoline 8b and 4‐(2‐(pyridin‐3‐yl)‐5,6 dihydrobenzo[h]quinazolin‐4‐yl) phenol 5g exhibited potent anticancer activity compared to (R)‐Roscovitine. Additionally, a molecular docking study was conducted to assess the reactivity of compound 5g, revealing that the presence of a phenolic hydroxyl group enables hydrogen bonding with CDKs and enhances anticancer activity. Furthermore, the efficacy of compound 5g was validated through an in vitro CDK2/cyclin A2 enzyme inhibition assay. Interestingly, the observed CDK2 inhibitory activity showed a good correlation with the corresponding value for the antiproliferative activity of the tested compounds.