Heteroaryl-Substituted Secondary Amines as Multifunctional Antimicrobial, Antibiofilm, Acetylcholinesterase, and α-Glucosidase Inhibitors

Abstract

A series of heteroaryl-substituted secondary amine derivatives (6a–g and 7a–g) were synthesized by reduction of Schiff bases obtained in our previous study with sodium borohydride (NaBH4). The molecules were characterized by spectroscopic techniques including 1H NMR, 13C NMR, FTIR, and GC-MS. Following synthesis, all compounds underwent extensive biological investigation, including studies of their antimicrobial, antifungal, antibiofilm, acetylcholinesterase (AChE), and α-glucosidase inhibitory activities, as well as their effects on membrane integrity and molecular docking capabilities. Some molecules exhibited measurable antimicrobial activity against Escherichia coli, Staphylococcus aureus, and Candida tropicalis. Among the tested derivatives, compound 6a exhibited the lowest MIC90 values against E. coli (749.1 μg/mL) and C. tropicalis (840.2 μg/mL), whereas compound 7d showed the lowest MIC90 value against S. aureus (789.1 μg/mL). In antibiofilm tests, compound 7e maintained high inhibitory activity even at low concentrations, while compound 7b showed the highest single-point biofilm inhibition. Membrane integrity studies revealed significant DNA and protein leakage effects, particularly for compounds 7c and 7g. Reactive oxygen species (ROS) analysis revealed compound-dependent differences in oxidative stress generation, suggesting that ROS production may contribute to the observed antimicrobial effects. In enzyme inhibition studies, compounds 6d and 6f emerged as the strongest AChE inhibitors with IC50 values of 89.17 and 73.35 μM, respectively, while compound 7a showed the strongest α-glucosidase inhibitory activity (IC50 = 173.92 μM). Molecular docking studies provided plausible binding modes and predicted interactions of the selected active compounds within the investigated target proteins.