Synthesis, In-vitro and In-silico studies of ether linked polyhydroquinoline derivatives for the management of diabetes mellitus

Abstract

Through an integrated approach combining synthetic chemistry, in vitro enzymatic assays, and advanced computational methods including molecular docking, and DFT calculations, we identified several compounds with superior inhibitory activity compared to the clinical standard acarbose. Compound 17 emerged as the most promising candidate, exhibiting exceptional potency (IC₅₀ = 4.89 ± 1.25 µM for α-amylase and 5.98 ± 1.67 µM for α-glucosidase) alongside favorable drug-like properties. DFT analyses revealed optimal frontier molecular orbital distributions and electrostatic potential patterns that correlate strongly with biological activity, while the molecular docking studies demonstrated specific interactions with key catalytic residues. These findings establish PHQ derivatives as promising leads for developing next-generation antidiabetic agents, with compound 17 representing an excellent candidate for further preclinical evaluation.

Keywords: Density functional theory; Molecular docking; Polyhydroquinoline ether; Structure activity relationship; α-amylase; α-glucosidase.