Synthesis, α-glucosidase inhibition and antioxidant activity of the 7-carbo–substituted 5-bromo-3-methylindazoles

• Published in: Bioorganic chemistry 2020-04, Vol.97, p.103702, Article 103702
• Main Authors: Mphahlele, Malose J., Magwaza, Nontokozo M., Gildenhuys, Samantha, Setshedi, Itumeleng B.
• Format: Article
• Language: English
• Subjects: alpha-Glucosidases - metabolism; Antioxidant activity; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacology; Cytotoxicity; Glycoside Hydrolase Inhibitors - chemical synthesis; Glycoside Hydrolase Inhibitors - chemistry; Glycoside Hydrolase Inhibitors - pharmacology; Halogenation; HEK293 Cells; Humans; Indazoles - chemical synthesis; Indazoles - chemistry; Indazoles - pharmacology; MCF-7 Cells; Methylation; Molecular docking; Molecular Docking Simulation; Polysubstituted indazoles; Structure-Activity Relationship; α-Glucosidase
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.103702

[Display omitted] •Series of 3,5,7-trisubstituted indazoles were prepared and evaluated against α-glucosidase.•Their antioxidant properties were evaluated through 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay.•The most active compounds exhibit dual anti-α-glucosidase and antioxidant properties.•Their cytotoxicity was evaluated against breast MCF-7 cancer cell line and the human embryonic kidney (Hek293-T) cells. Series of 7-aryl- (3a–f), 7-arylvinyl- (3g–k) and 7-(arylethynyl)-5-bromo-3-methylindazoles (4a–f) have been evaluated through enzymatic assay in vitro for inhibitory effect against α-glucosidase activity and for antioxidant potential through the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Compounds 3a–k and 4a–f showed significant to moderate α-glucosidase inhibition with IC50 values in the range of 0.50–51.51 μM and 0.42–23.71 μM compared with acarbose drug (IC50 = 0.82 μM), respectively. 5-Bromo-3-methyl-7-phenyl-1H-indazole (3a), 5-bromo-3-methyl-7-styryl-1H-indazole (3h) and 5-bromo-3-methyl-7-styryl-1H-indazole (4a) exhibited moderate to significant antigrowth effect against the breast MCF-7 cancer cell line and reduced cytotoxicity against the human embryonic kidney derived Hek293-T cells when compared to doxorubicin as reference standard. Non-covalent (alkyl, π-alkyl and π-π T shaped), electrostatic (π-sulfur and/or π-anion) and hydrogen bonding interactions are predicted to increase interactions with protein residues, thereby enhancing the inhibitory effect of these compounds against α-glucosidase.