Citronellyl Caffeate as a Novel α-Glucosidase Inhibitor with Potential Antidiabetic Activity

Abstract

ABSTRACT. Caffeic acid, a well-studied phenolic acid, has been extensively investigated for its diverse bioactivities, including antidiabetic, anti-inflammatory, antioxidant, antimicrobial, and antiviral properties. Esterification of caffeic acid has been explored to modulate its physicochemical and biological properties, however, optimization of lipophilicity while maintaining inhibitory activity remains a challenge. In this context, citronellyl caffeate was designed as a structurally optimized derivative that enhances α-glucosidase inhibition while improving lipophilicity and permeability. To enhance antidiabetic bioactivity through α-glucosidase inhibition, caffeic acid and citronellol were coupled using dicyclohexylcarbodiimide (DCC) as an activator and 4-dimethylaminopyridine (DMAP) as a catalyst with dimethylformamide (DMF) as the solvent. The synthesis was carried out under reflux conditions, followed by purification via liquid–liquid extraction and column chromatography, with thin-layer chromatography (TLC) used to confirm purity. The resulting compound, citronellyl caffeate, was characterized using ¹H NMR and ¹³C NMR spectroscopy. Evaluation through α-glucosidase inhibition assays demonstrated that citronellyl caffeate showed enhanced α-glucosidase inhibitory activity (IC₅₀ = 31.17 µg/mL) compared to its precursors, caffeic acid and citronellol, despite being less potent than quercetin (IC₅₀ = 2.43 µg/mL), it demonstrates biologically relevant inhibition consistent with successful structural optimization.

Keywords: antidiabetic, caffeic acid, citronellol, glucosidase, synthesis