New carbazole linked 1,2,3-triazoles as highly potent non-sugar α-glucosidase inhibitors

• Published in: Bioorganic chemistry 2017-10, Vol.74, p.72-81
• Main Authors: Iqbal, Shazia, Khan, Maria Aqeel, Javaid, Kulsoom, Sadiq, Rabia, Fazal-ur-Rehman, Saba, Choudhary, M. Iqbal, Basha, Fatima Z.
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Acetophenones; alpha-Glucosidases - metabolism; Animals; Carbazole; Carbazoles - chemistry; Carbazoles - pharmacology; Click chemistry; Diabetes; Dose-Response Relationship, Drug; Glycoside Hydrolase Inhibitors - chemical synthesis; Glycoside Hydrolase Inhibitors - chemistry; Glycoside Hydrolase Inhibitors - pharmacology; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Mice; Molecular Structure; Structure-Activity Relationship; Triazoles; Triazoles - chemistry; Triazoles - pharmacology; α-Glucosidase
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2017.07.006

[Display omitted] •A library of new carbazole linked 1H-1,2,3-triazoles were synthesized via copper catalyzed click reaction between N-propargyl-9H-carbazole and azides of appropriate acetophenones and heterocycles.•Most of the sythesized compounds showed potent α-glucosidase inhibitoy activity, and can be used as a starting point for the development of new antidiabetic drugs.•Among the series, most active triazole compound exhibited ∼1000-fold better α-glucosidase inhibitoy activity, while second-most active compound is 800 times better than that of the standard drug, acarbose. Both compounds are found inactive when tested for cytotoxicity against 3T3 cell lines, hence these triazoles are considered as safe. In the present study, a series of new carbazole linked 1H-1,2,3-triazoles (2–27) were synthesized via click reaction of N-propargyl-9H-carbazole (1) and azides of appropriate acetophenones and heterocycles. Synthesized carbazole triazoles including 7, 9, 10, 19, 20, and 23–26 (IC50=0.8±0.01–100.8±3.6μM), exhibited several folds more potent α-glucosidase inhibitory in vitro activity as compared to standard drug, acarbose. Compounds 2–5, 7–13, and 17–27 did not show any cytotoxicity against 3T3 cell lines, except triazoles 6, and 14–16. Among the series, carbazole triazoles 23 (IC50=1.0±0.057μM) and 25 (IC50=0.8±0.01μM) were found to be most active, and could serve as an attractive building block in the search of new non-sugar derivatives as anti-diabetic agents.