Design, synthesis and biological evaluation of hydroxycinnamoylamides derivatives as potent glucosidase inhibitors

Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by persistent hyperglycemia and impaired insulin sensitivity and α-glucosidase represents a key therapeutic target for managing T2DM. In this study, a series of hydroxycinnamoylamide derivatives (2a-2s) were designed and synthesized via straightforward chemical reactions. Most of the target compounds exhibited potent α-glucosidase inhibitory activity compared to the lead compound 5. Rational introduction of chlorine atoms into hydrophobic pockets enables potent halogen bonding with Asn412, significantly boosting glucosidase inhibitory activity. Remarkably, the most effective compound, dichlorophenyl derivative 2l (IC₅₀ = 0.0136 μM), was 382-fold more effective against α-glucosidase than quercetin. Mechanistic studies revealed that compound 2l inhibits α-glucosidase activity via active site binding, as demonstrated by fluorescence quenching and molecular docking. Liver microsomal assays indicated favorable pharmacokinetics, with slow clearance and prolonged efficacy. In vivo evaluations in T2DM mice showed that 2l significantly reduced fasting blood glucose, attenuated weight loss, and improved glucose tolerance and dyslipidemia. Histopathological analysis further confirmed its hepatoprotective effects, with HE staining revealing restored liver tissue architecture compared to the model group. These findings highlight 2l as a promising multifunctional agent for T2DM treatment.