Type 2 Diabetes mellitus is a chronic disease considered one of the most severe global health emergencies. Chlorogenic acid (1) has been shown to delay intestinal glucose absorption by inhibiting the activity of α-glucosidase (α-Glu) and α-amylase (α-Amy). In the present work, eleven chlorogenic acid amides have been synthesized and evaluated for their antioxidant properties (as DPPH and ORAC) and inhibition activity towards the two enzymes and, with the aim to obtain dual-action antidiabetic agents. The two most promising hypoglycemic compounds, bearing a tertiary amine function on an alkyl chain (8) and a benzothiazole scaffold (11), showed IC50 values lower than that of (1) (45.5 µM α-Glu; 105.2 µM α-Amy). Amides 8 and 11 were by far more potent α-Glu inhibitors than the antidiabetic drug acarbose (IC50 = 268.4 µM) and about twice less active toward α-Amy than acarbose (IC50 = 34.4 µM). Kinetics experiments on amides 8 and 11 indicated these compounds as mixed-type inhibitors of α-Glu with K'i values of 13.3 and 6.3 µM, respectively. The amylase inhibition occurred with a competitive mechanism in the presence of 8 (Ki = 79.7 µM) and with a mixed-type mechanism with 11 (Ki = 19.1 µM; K'i = 93.6 µM). Molecular docking analyses supported these results, highlighting the presence of additional binding sites in both enzymes. Fluorescence experiments confirmed the grater affinity of amides 8 and 11 towards the two enzymes respect to (1). Moreover, a significant enhancement in acarbose efficacy was observed when inhibition assays were performed adding acarbose and amide 11. The above outcomes pinpointed the benzothiazole-based amide 11 as a promising candidate for further studies on type 2 diabetes treatment, both alone or combined with acarbose.
Keywords: Amides; Chlorogenic acid derivatives; Diabetes; Inhibition kinetics; Intrinsic fluorescence; Molecular modeling; α-amylase inhibition; α-glucosidase inhibition.
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