Dihydropyrimidinone-Triazole Hybrids: Synthesis, Characterization, and In Silico Evaluation of ABCB1 Binding Affinity

Inhibition of P-glycoprotein (P-gp/ABCB1), an ATP-dependent efflux pump responsible for multidrug resistance (MDR) in cancer chemotherapy, remains a key strategy for restoring drug sensitivity^1,2. This work aimed to synthesize and characterize novel dihydropyrimidinone-triazole (DHPM-triazole) hybrids and evaluate their binding affinity toward P-gp/ABCB1 through computational approaches. The synthetic strategy comprised a Biginelli multicomponent reaction³ to obtain O-propargyl-DHPM intermediates, followed by copper-catalyzed 1,3-dipolar cycloaddition (CuAAC)⁴ with aryl azides, affording 10 unprecedented hybrids in yields exceeding 70%. Structures were confirmed by IR, NMR, and mass spectrometry. Molecular docking and molecular dynamics simulations, together with evaluation of physicochemical properties, were performed to assess binding affinity and drug-like behavior. Results showed that the hybrids are located and oriented within the active site occupied by the co-crystallized tariquidar reference drug, supporting their potential as promising MDR-reversing agents in cancer treatment.