Synthesis, single crystal analysis, hirshfeld surface analysis, computational insights of thiophene-linked triazole derivatives and evaluation of their BACE-1 inhibition

Abstract

A new series of triazole-based derivatives was synthesized and comprehensively characterized by FTIR, NMR, Mass Spectrometry, and single-crystal X-ray diffraction. Detailed crystallographic investigations of compound 6f , bearing a 4-methoxy substituent, revealed significant insights into its molecular packing and intermolecular interactions. Biological evaluation demonstrated that 6f achieved approximately 54.56 ± 3.09% inhibition of BACE-1 at 10 μM, underscoring its potential as a lead candidate among the synthesized triazoles. Structure–activity relationship analysis indicated that electron-donating substituents may enhance inhibitory activity. Complementary in silico analyses substantiated these findings, where molecular docking predicted a favorable binding orientation within the BACE-1 active site, involving π–π stacking interactions with PHE 108 ( 6a-g and 7c , 7f ), and molecular dynamics simulations confirmed the stability of the 6f -BACE-1 (2VA7) complex over a 100 ns trajectory. Drug-likeness profiling confirmed compliance with Lipinski’s rule, while density functional theory (DFT) calculations of frontier molecular orbitals and molecular electrostatic potential mapping, performed using the B3LYP functional with the 6-31G** basis set, provided valuable insights into electronic properties and reactive regions. These findings suggest that thiophene-triazole hybrids, particularly compound 6f , are promising scaffolds for future exploration as BACE-1 inhibitors.