In Vitro Inhibitory Activity and Molecular Docking Study of Selected Natural Phenolic Compounds as AR and SDH Inhibitors**

Polyol pathway enzymes, aldose reductase (EC 1.1.1.21; AR, ALR2), and sorbitol dehydrogenase (EC 1.1.1.14; SDH, SORD) have been widely investigated as the enzymes crucially involved in the pathogenesis of several chronic complications, including nephropathy, neuropathy, retinopathy, and cataracts associated with diabetes mellitus. Although phenolic compounds have been reported to possess many other biological activities, in continuation of our interest in designing and discovering potent inhibitors of AR and SDH, herein, we have evaluated these agents’ inhibitory potential against polyol pathway enzymes. Our in vitro studies revealed that all the derivatives show activity against recombinant human AR (rhAR) and SDH (rhSDH), with KI constants ranging from 9.37±0.16 μM to 77.22±2.49 μM and 2.51±0.10 μM to 42.16±1.03 μM, respectively. Among these agents, Prunetin and Phloridzin showed prominent inhibitory activity versus rhAR and rhSDH, while some were also determined to possess perfect dual activity. Moreover, in silico studies were also performed to rationalize binding site interactions of these agents with the target enzyme AR and SDH. According to ADME-Tox was also determined that these derivatives be agents exhibiting suitable drug-like properties. The compounds identified therapeutic potentials in this study may be promising for developing lead therapeutic agents to prevent polyol pathway complications. © 2022 Wiley-VCH GmbH.