Dual-target inhibitors against α-amylase and α-glucosidase: novel anacardic acid depside derivatives

Inhibition of α-amylase and α-glucosidase enzymes are some of the crucial therapeutic targets in diabetes mellitus. The global shift toward sustainable utilization of natural resources has highlighted cashew nut shell liquid (CNSL), a by-product abundant in anacardic acids, as a promising natural source for developing new treatments for diabetes. In this study, two series of depside and pseudo-depside anacardic acid derivatives (4-19) were synthesized, evaluated against both α-amylase and α-glucosidase in vitro. All derivatives are newly synthesized and well-characterized using ¹H NMR, ¹³C NMR, IR and HRMS spectroscopic techniques. Some synthesized derivatives exhibited potential inhibitory activity against both enzymes, with IC₅₀ values in a range of 3.84-15.5 μM for α-amylase, and 0.13-1.16 μM for α-glucosidase, compared to the positive control acarbose with IC₅₀ values of 7.42 and 817.38 μM, respectively. Among the semisynthesized compounds, 19 had the strongest inhibitory effect for both α-amylase and α-glucosidase with an IC₅₀ 3.84, 0.13 μM, respectively. Kinetic analyses indicated competitive inhibition, with equilibrium constants K_i = 7.54 μM (α-amylase) and 0.170 μM (α-glucosidase). To rationalize these findings, we combined LB-PaCS-MD/FMO to delineate binding pathways and residue-level energetics with long classical MD and MM/GBSA to quantify binding stability and per-residue contributions. The simulations confirmed active-site engagement and hydrophobically driven stabilization, with slightly stronger and more consistent binding to α-glucosidase, aligning with experiment. The overall ADMET predictions suggested that 19 is a promising derivative for further development. This work contributes to a valuable source of lead antidiabetic compounds for developing new drugs to prevent or treat diabetes mellitus.