by Shilpi Aggarwal, PhD, Freelance Writer
A March 28, 2024 article in Nature Scientific Reports describes a successful study on the design, synthesis, and evaluation of novel coumarin-linked 2-phenylbenzimidazole derivatives as potent novel α-glucosidase inhibitors. The open-access article is titled “Coumarin Linked to 2-Phenylbenzimidazole Derivatives As Potent α-Glucosidase Inhibitors.” α-glucosidase inhibitors are a group of antidiabetic drugs used for the management of type-2 diabetes mellitus. They act by inhibiting α-glucosidase, a hydrolase enzyme that is found in the intestinal cells and is responsible for breaking down complex carbohydrates into absorbable monosaccharides, including glucose. The inhibitory effect of α-glucosidase inhibitors decelerates the breakdown of complex carbohydrates, resulting in decreased glucose absorption and a reduced glycemic response post meals. Acarbose is the most widely researched and used drug in this category. However, it exhibits several side effects such as abdominal pain, bloating, and diarrhea in patients.
Coumarin is an attractive pharmacophore for designing new therapeutic compounds as it is a naturally occurring compound and its derivatives have shown promising pharmacological activities such as antioxidation, anti-inflammation, antimicrobial, and anticancer properties. On the other hand, benzoimidazole has gained attention in medical chemistry due to its diverse biological activities and potential therapeutic use. It also exhibits pharmacological properties including antimicrobial, anticancer, anti-inflammatory, and antioxidant activities.
The derivatives of both coumarin and benzoimidazole have shown excellent α-glucosidase inhibitory activities compared to acarbose. Thus, in this study, a novel series of α-glucosidase inhibitors was designed by connecting coumarin and 2-phenylbenzimidazole (a derivative of benzoimidazole) by a carboxylate linker. Different moieties were substituted at the R position to design and synthesize 13 different compounds to obtain optimal α-glucosidase inhibition activity. The chemical structures of these derivatives were characterized using various analytical techniques, including 1H-NMR, 13C-NMR, and FTIR (Fourier-transform infrared spectroscopy).
The potencies of the synthesized compounds were evaluated in vitro against α-glucosidase and were compared with that of acarbose used as a positive control. The α-glucosidase inhibition activities of these compounds as demonstrated by their IC50 values ranging from 10.8 + 0.1 µM to 119.5 + 0.1 µM were significantly higher than that of acarbose (IC50 = 750 µM). This suggests that the designed compounds have a higher efficacy than acarbose.
The enzyme kinetics studies of these compounds showed that they bind to the active site of the enzyme and compete with the substrate for binding to the active site. Further, the molecular docking studies were performed using a new structure developed based on homology modeling. The comparison of binding energies of the novel compounds with that of acarbose showed that the coumarin-benzoimidazole derivatives can bind to the active site of the enzyme more easily compared to the standard inhibitor.
Based on these results, the coumarin-benzoimidazole derivatives show potential as being the promising backbone for the design of novel α-glucosidase inhibitors for the management of type-2 diabetes mellitus.
Posting based on:
Ganjeh, M.S., Mazlomifar, A., Shahvelayti, A.S. et al. Coumarin Linked to 2-Phenylbenzimidazole Derivatives As Potent α-Glucosidase Inhibitors. Sci Rep 14, 7408 (2024) [Scientific Reports article]
Akmal M, Wadhwa R. Alpha Glucosidase Inhibitors. [Updated 2022 Aug 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan.