Green synthesis of new adamantane-containing dihydropyrimidine derivatives as potential anticancer agents

Abstract

Despite significant progress in cancer treatment, cancer remains a major focus of research due to medication resistance and side effects. In this study, bioactive adamantane-containing dihydropyrimidine (DHPM) derivatives were synthesized through the multi-component Biginelli reaction of N-(adamant-1-yl)acetoacetamide, benzaldehyde derivatives, and thiourea in the presence of trifluoroacetic acid (TFA, 2 mol%) as catalyst under solvent free conditions. This method provides an effective and significantly improved modification of the original Biginelli reaction in terms of yield and reaction time. The synthesized DHPM derivatives were subjected to cytotoxicity screening against the A-549 human non-small cell lung cancer (NSCLC) cell line to evaluate their effects on cell growth inhibition. MTT cytotoxicity assay was used to determine IC₅₀ values. Among the target analogs, IIb, IIj, IId, and IIg demonstrated the best activity with IC₅₀ values of 1.03, 8.36, 10.38, and 16.04 μg mL⁻¹, respectively. Additionally, we assessed the possible mechanisms for cell growth inhibition and induction of apoptotic cell death using the DAPI and Annexin V-FITC staining. The average percentages of apoptotic cells were 21.35%, 28.35%, 32.73, and 43.33% for IIg, IId, IIj, and IIb treatment groups, respectively. These results suggest that the synthesized adamantane-containing dihydropyrimidines can be considered as encouraging molecules for further drug development as anticancer agents.