Skoric_2026_SSRN__

A series of novel resveratrol-inspired benzimidazole and oxazole derivatives of morpholine and pyrrolidine carbamates bearing a diarylethene motif was designed, synthesized, and comprehensively evaluated for their biological and pharmacological properties. Twelve carbamates (112) were prepared and structurally characterized by spectroscopic methods. All compounds selectively inhibited butyrylcholinesterase (BChE), with no measurable inhibition of acetylcholinesterase. Pyrrolidine derivatives were consistently more potent than their morpholine counterparts, while benzimidazole incorporation markedly enhanced activity compared with the corresponding oxazole analogs. The most active compounds, 4 and 7, inhibited BChE with IC50 values of 44.3 and 45.5 nM, respectively, representing approximately 50-fold greater potency than the standard rivastigmine. Kinetic analysis of compound 9, as a representative, demonstrated time-dependent inhibition consistent with the classical two-step mechanism of carbamate-mediated BChE inhibition. Molecular docking and molecular dynamics simulations further supported prereactive binding modes in which the carbamate carbonyl is positioned near catalytic Ser198, with compound 4 maintaining this arrangement more persistently than compound 9. Several derivatives also exhibited antioxidant activity; compounds 6 and 8 showed pronounced DPPH radical-scavenging activity, whereas compound 2 displayed the highest CUPRAC reducing capacity, reaching 81% of Trolox activity. In silico genotoxicity assessment identified compounds 1, 2, 6, and 11 as negative in the combined Derek/Sarah Nexus evaluation, with compound 6 showing the most favorable activity-genotoxicity profile among the potent BChE inhibitors. ADMET predictions indicated high intestinal absorption and potential CNS exposure, while also revealing P-glycoprotein, CYP, cardiac, and hepatic liabilities requiring further optimization. Most compounds showed no cytotoxic effects in HepG2 cells. Overall, the findings identify pyrrolidine-containing benzimidazole carbamates as promising BChE-directed scaffolds and provide complementary activity, mechanistic, and developability profiles to guide further optimization toward multifunctional candidates for neurodegenerative disease research.