New acridine-9-carboxamide linked to 1,2,3-triazole-N-phenylacetamide derivatives as potent α-glucosidase inhibitors: design, synthesis, in vitro, and in silico biological evaluations

Abstract

α-Glucosidase plays a major role in degradation of carbohydrates to glucose. Therefore, inhibition of this enzyme can be useful in the treatment of carbohydrate-related diseases such as diabetes, cancer, and viral infections. In this study, a new series of acridine-9-carboxamide linked to 1,2,3-triazole-N-phenylacetamide derivatives 5a–m were designed, synthesized, and evaluated as potent α-glucosidase inhibitors. All the synthesized compounds showed excellent to good inhibitory activity against α-glucosidase with IC50 values of 80.3 ± 0.9–564.3 ± 7.2 µM in comparison with standard drug acarbose (IC50 value = 750.0 ± 10.5 μM). Among the synthesized compounds, the most active compound was 3-bromo derivative 5h with inhibitory activity around 9.3 times more than acarbose. this compound was selected for farther biological evaluations. Kinetic study of compound 5h revealed that it is a competitive inhibitor against α-glucosidase. Docking study of compound 5h and its regioisomer 5i with 4-bromo substituent were also carried out in the active site of α-glucosidase to gain an insight into the interaction modes of the synthesized compounds and rationalized structure–activity relationship between these two compounds. Compound 5h was also evaluated against α-amylase and no activity was observed in comparison with acarbose. Furthermore, in vitro cytotoxic assay of compound 5h against human normal and cancer cell lines HDF and MCF-7, respectively, revealed that this compound is a noncytotoxic agent. In silico pharmacokinetic and toxicity assays of compound 5h was performed and obtained results were compared with acarbose.