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

• Published in: Medicinal chemistry research Vol. 29; no. 10; pp. 1836 - 1845
• Main Authors: Sepehri, Nima, Asemanipoor, Nafise, Mousavianfard, Seyed Ali, Hoseini, Seyedhamid, Faramarzi, Mohammad Ali, Adib, Mehdi, Biglar, Mahmood, Larijani, Bagher, Hamedifar, Haleh, Mohammadi-Khanaposhtani, Maryam, Mahdavi, Mohammad
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-10-2020; Springer Nature B.V
• Subjects: Acarbose; Acetanilide; Acridine; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Cancer; Carbohydrates; Cytotoxicity; Derivatives; Diabetes mellitus; Glucosidase; Inhibitors; Inorganic Chemistry; Medicinal Chemistry; Original Research; Pharmacokinetics; Pharmacology/Toxicology; Synthesis; Toxicity; Triazoles; Tumor cell lines; α-Amylase; α-Glucosidase; Acridine; In silico; α-Glucosidase inhibitor; 1,2,3-Triazole; Acetamide; In vitro
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-020-02603-7

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 IC
50
values of 80.3 ± 0.9–564.3 ± 7.2 µM in comparison with standard drug acarbose (IC
50
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.