Integrated In Silico and In Vitro Investigation of Chromene Derivatives as Potential Antidiabetic Agents in 3T3-L1 Cells.

Abstract

Type 2 diabetes mellitus is characterized by a progressive decline in insulin sensitivity and represents an important therapeutic target for improving glucose homeostasis. Chromen-derived compounds have attracted interest as potential antidiabetic agents because of their diverse pharmacological activities. Drug-likeness and pharmacokinetic properties were evaluated using ADME profiling. In silico docking and simulation analyses were performed to characterize ligand-protein interactions and evaluate the stability complex with carbohydrate-hydrolyzing enzymes. In vitro studies included MTT assay for cell viability/tolerability, α-glucosidase and α-amylase inhibition assays and 2-deoxyglucose (2-DG) uptake in 3T3-L1 cells. Conventional RT-PCR was further performed to assess PI3K and GLUT-4 mRNA expression. The 2-DG assay provided a functional measure of cellular glucose uptake under the experimental conditions and was not designed to directly establish insulin sensitization. Both compounds showed favorable predicted drug-like and pharmacokinetic properties. Docking and MD analyses predicted favorable ligand-enzyme interactions and complex stability. Experimentally, 7-methoxy-3-Phenyl-4H-Chromen-4-one showed stronger α-glucosidase inhibition, higher 2-DG uptake and marked upregulation of PI3K and GLUT-4 expression, whereas 7,8-Dihydroxy-3-(4-hydroxyphenyl)-4H-chromen downregulated PI3K, modestly increased GLUT-4 and showed lower 2-DG uptake. The findings indicate potential antidiabetic activity through complementary effects on carbohydrate digestion and cellular glucose handling. 7-methoxy-3-Phenyl-4H-Chromen-4-one showed the most consistent response among the chromen derivatives evaluated and emerged as a candidate for further investigation. The present findings do not establish direct activation of insulin-signaling pathway or reversal of insulin resistance. Comprehensive mechanistic investigations, together with in vivo validation, are needed to further substantiate the therapeutic potential of the compound.