Synthesis, antidiabetic evaluation, and computational modeling of 3-acetyl-8-ethoxy coumarin derived hydrazones and thiosemicarbazones

Abstract

Inhibiting important enzymes like alpha-amylase and alpha-glucosidase is essential for controlling hypoglycemia and its related complications in diabetes mellitus. A series of novel hydrazones and thiosemicarbazones have been synthesized and evaluated for their ability to inhibit enzymes, causing hypoglycemia and diabetes mellitus in the human body. From synthesized compounds, compound 3b from the carbohydrazide series, demonstrated the strongest potency against alpha-amylase and alpha-glucosidase, with respective IC50 values of 252.45 +/- 12.81 nM and 159.10 +/- 8.15 nM and in the case of the carbothioamide series, thiosemicarbazone 5e, exhibited the highest inhibitory potency, with IC50 values of 73.68 +/- 2.84 nM for alpha-glucosidase and 146.18 +/- 7.35 nM for alpha-amylase. These compounds were compared to the standard drug acarbose with IC50 values of 315.74 +/- 15.06 nM and 437.93 +/- 13.96 nM for alpha-glucosidase and alpha-amylase. Novel compounds having a variety of structural configurations, showed encouraging activity profiles with potent inhibition of alpha-amylase and alpha-glucosidase. The interactions between these inhibitors and the target enzyme's active sites were further examined by doing Density Function Theory (DFT), molecular docking, and structure-activity relationship (SAR) studies, which provides information about the derivatives that are more potent. Toxicity, metabolism, and drug-likeness characteristics of newly synthesized hydrazones and thiosemicarbazones were investigated by in silico ADMET tests.