Design, synthesis, antidiabetic evaluation and computational modeling of phenylnaphthalene-2-sulfonate derived hydrazones

Abstract

The inhibition of key enzymes such as alpha-amylase, aldose reductase and alpha-glucosidase plays a pivotal role in managing hypoglycaemia and associated complications in diabetes mellitus. A series of fourteen novel hydrazones have been synthesized and evaluated for their inhibitory activities against these enzymes. Out of those fourteen compounds, compound 5c, 5g and 5h showed maximum potency against alpha-amylase, aldose reductase and alpha-glucosidase with IC50 value of 0.66+0.02nM, 11.02+2.47 nM and 8.20+1.27nM, respectively and compared with reference compounds such as acarbose (IC50= 21.82+3.26nM) and quercetin (IC50= 60.71+ 7.98nM). The investigated compounds encompassing diverse structural frameworks, exhibiting promising activity profiles with potent and selective inhibition of alpha-amylase, aldose reductase and alpha-glucosidase. Density Function Theory (DFT), molecular docking and structure-activity relationship (SAR) analysis further elucidate the interactions between these inhibitors and the active sites of the target enzymes, offering insights into the design of more effective derivatives. In-silico ADMET studies were accomplished to explore drug-likeness properties, toxicity, and metabolism of the synthesized hydrazones.