Synthesis, antidiabetic assessment, metal chelating impacts, and computational modeling of 4-fluorophenyl sulfonyl-indole based hydrazones

Abstract

The escalating global epidemic of diabetes mellitus (DM) has driven researchers and healthcare professionals to prioritize the synthesis of novel treatment strategies. We have synthesized novel N-substituted indole-based hydrazone derivatives 5(a-o) and evaluated their potential as alpha-amylase, alpha-glucosidase, and aldose reductase inhibitors with metal chelating properties. These compounds revealed remarkable inhibitory potency with IC50 values ranging from 1.67 to 179.51 nM. Additionally, the IC50 values of metal chelation for novel compounds ranged from 54.98 +/- 0.97 to 231.43 mu g/mL. Notably, these derivatives demonstrated superior efficacy to the reference inhibitors ACR and Clorgyline, highlighting their potential as groundbreaking candidates in antidiabetic drug development. Among the series, compounds 5a, 5o, and 5n emerged as the most promising. To explore the molecular basis of enzyme inhibition, a comprehensive computational strategy was employed. Molecular docking studies revealed favorable binding affinities and key interactions within the active sites of the chosen target enzymes. The reliability of docking poses was validated via redocking of co-crystallized ligands and root-mean-square deviation (RMSD) analysis. Furthermore, density functional theory (DFT) calculations provide insights into electronic properties relevant to biological activity. Molecular dynamics simulations further validated the stability and strong binding interactions of the most promising compounds. Overall, this study combines synthetic, biological, and multi-tiered computational approaches to propose structurally optimized indolebased hydrazones as potential next-generation antidiabetic agents. Their superior pharmacological profile ranks them as potential frontrunners in the quest for next-generation antidiabetic therapeutics.