Synthesis of Novel 3,4‐Dihydropyrimidine Derivatives, Cytotoxic Activity Evaluation, Apoptosis, Molecular Docking Studies, and MD Simulations

In this study, twelve 3,4-dihydropyrimidines derivatives were synthesized through Biginelli multi-component reaction. The efficacy of these compounds against MCF-7, A549, and HeLa cells was evaluated using the MTT method. The results showed that designed derivatives were more effective against A549 cancer cells than MCF-7 and HeLa cells. Compound 5l (bearing 4-Cl-phenyl at C4 of 3, 4-dihydropyrimidin-2(1H)-one ring) was the most potent analogue (A549: 18.65±1.87 μM, HeLa: 26.59±2.71 μM, MCF-7: 31.82±2.64 μM). The presence of an electron-withdrawing group with optimum lipophilicity at the C4 position of the phenyl ring increased the cytotoxic effect. The flow cytometry findings indicated that compound 5l induced apoptosis in A549 cancer cells in a dose-dependent manner. Eg5 and AKT1 were selected as molecular modeling target by applying pharmacology network analyses. The molecular docking results indicated that both enantiomers of compound 5l had significant interactions with key residues in both Eg5 (Gly117 and Glu116) and AKT1 (Ala123 and Glu121) active sites. However, MD simulation revealed that the R enantiomer had a more stable complex and a higher binding affinity to the Eg5 enzyme active site than the S-enantiomer. The affinity of 5l (R enantiomer) to Eg5 was predicted more than AKT1.