Synthesis of benzotriazoles derivatives and their dual potential as α-amylase and α-glucosidase inhibitors in vitro: Structure-activity relationship, molecular docking, and kinetic studies

• Published in: European journal of medicinal chemistry 2019-12, Vol.183, p.111677, Article 111677
• Main Authors: Hameed, Shehryar, Kanwal, Seraj, Faiza, Rafique, Rafaila, Chigurupati, Sridevi, Wadood, Abdul, Rehman, Ashfaq Ur, Venugopal, Vijayan, Salar, Uzma, Taha, Muhammad, Khan, Khalid Mohammed
• Format: Article
• Language: English
• Subjects: alpha-Amylases - antagonists & inhibitors; alpha-Glucosidases - metabolism; Benzotriazoles; Diabetes; Diabetes Mellitus - drug therapy; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; In silico studies; Kinetic studies; Molecular Docking Simulation; Molecular Targeted Therapy; Structure-Activity Relationship; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; α-Amylase inhibition; α-glucosidase inhibition
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111677

Benzotriazoles (4–6) were synthesized which were further reacted with different substituted benzoic acids and phenacyl bromides to synthesize benzotriazole derivatives (7–40). The synthetic compounds (7–40) were characterized via different spectroscopic techniques including EI-MS, HREI-MS, 1H-, and 13C NMR. These molecules were examined for their anti-hyperglycemic potential hence were evaluated for α-glucosidase and α-amylase inhibitory activities. All benzotriazoles displayed moderate to good inhibitory activity in the range of IC50 values of 2.00–5.6 and 2.04–5.72 μM against α-glucosidase and α-amylase enzymes, respectively. The synthetic compounds were divided into two categories “A” and “B”, in order to understand the structure-activity relationship. Compounds 25 (IC50 = 2.41 ± 1.31 μM), (IC50 = 2.5 ± 1.21 μM), 36 (IC50 = 2.12 ± 1.35 μM), (IC50 = 2.21 ± 1.08 μM), and 37 (IC50 = 2.00 ± 1.22 μM), (IC50 = 2.04 ± 1.4 μM) with chloro substitution/s at aryl ring were found to be most active against α-glucosidase and α-amylase enzymes. Molecular docking studies on all compounds were performed which revealed that chloro substitutions are playing a pivotal role in the binding interactions. The enzyme inhibition mode was also studied and the kinetic studies revealed that the synthetic molecules have shown competitive mode of inhibition against α-amylase and non-competitive mode of inhibition against α-glucosidase enzyme. [Display omitted] •Benzotriazoles (1–40) were synthesized.•The synthetic molecules were screened for α-glucosidase and α-amylase inhibitory activity.•The synthetic molecules were divided into two categories to understand the better structure-activity relationship.•In silico studies were performed to confirm the binding interactions of synthetic molecules with the enzyme active site.•Kinetic studies determined the mechanism of action of both enzymes.