A dual- enzyme targeted approach: Flurbiprofen-linked 1,2,4-triazole-3-- thione schiff bases against acetylcholinesterase and α-glucosidase

Abstract

In this investigation, 1,2,4-triazole-3-thione Schiff bases containing a flurbiprofen moiety were designed and synthesized. The structures of these compounds were confirmed with moderate to good yields using NMR and IR spectroscopic analyses. To demonstrate their biological potential, the compounds were evaluated for their in vitro inhibitory activities against acetylcholinesterase (AChE) and alpha-glucosidase. Most of the synthesized products demonstrated notable inhibitory efficacy against the enzymes AChE and alpha-glucosidase when compared to the standard medications tacrine (IC50 = 265.78 nM for AChE) and acarbose (IC50 = 78.51 nM for alpha-glucosidase). Among the substances that were examined, 2t ((E)-5-(1-(2-fluoro-[1,1 '-biphenyl]-4-yl) ethyl)-4-((4hydroxybenzylidene) amino)-2,4-dihydro-3H-1,2,4-triazole-3-thione) demonstrated inhibitory action with IC50 values of 78.95 nM for AChE, and 2r ((E)-5-(1-(2-fluoro-[1,1 '-biphenyl]-4-yl) ethyl)-4-((2-hydroxybenzylidene) amino)-2,4-dihydro-3H-1,2,4-triazole-3-thione) demonstrated inhibitory activity with IC50 values of 80.08 nM for AChE, and 2j ((E)-5-(1-(2-fluoro-[1,1 '-biphenyl]-4-yl) ethyl)-4-((4-fluorobenzylidene) amino)-2,4-dihydro3H-1,2,4-triazole-3-thione) demonstrated inhibitory activity against alpha-glucosidase with an IC50 values of 9. 05 nM. The docking and kinetic tests confirmed the predicted drug-like properties and experimental outcomes from in vitro experiments. The discovery of such potent dual inhibitors is highly significant. These findings open new avenues for designing drugs that could simultaneously target mechanisms involved in complex diseases like Alzheimer's, where AChE inhibition is a key therapeutic strategy, and diabetes, managed by alpha-glucosidase inhibitors. Our research offers a promising foundation for the development of potentially highly effective therapeutic agents.