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

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.