# Sustainable Synthesis of 1,2-Disubstituted Benzimidazoles as Promising α-Glucosidase Inhibitors: In Vitro and In Silico Evaluation

## TL;DR

Researchers developed a green method to synthesize benzimidazoles that effectively inhibit α-glucosidase, a target for diabetes treatment, with some compounds showing strong activity and safety in cell tests.

## Contribution

The study introduces a sustainable, metal-free synthesis method for benzimidazoles and identifies potent α-glucosidase inhibitors with antioxidant properties.

## Key findings

- Compounds 8s, 8k, and 8r showed significant α-glucosidase inhibition with low IC50 values.
- Selected compounds did not affect Caco-2 cell viability at tested concentrations.
- Compounds 8r and 8s exhibited antioxidant activity, potentially beneficial for diabetes-related oxidative stress.

## Abstract

Background: Inhibiting α-glucosidase and α-amylase is a well-established strategy for managing postprandial hyperglycemia in type 2 diabetes mellitus. However, the adverse effects of current α-glucosidase inhibitors (α-GIs) underscore the need for safer alternatives. Methods: This study introduces an efficient, metal-free, and environmentally friendly protocol for the selective, high-yield synthesis of 1,2-disubstituted benzimidazoles. The reaction between o-phenylenediamine and various aromatic aldehydes proceeds smoothly in water at room temperature, using cost-effective and eco-friendly catalysts such as acetylsalicylic acid (ASA) or salicylic acid (SA). The methodology exhibits broad versatility, enabled by the use of different o-phenylenediamines and a wide range of aromatic and heteroaromatic aldehydes. Results: Selected compounds were assessed for their inhibitory activity against α-glucosidase and α-amylase. While all exhibited low α-amylase inhibition, several showed significant α-glucosidase inhibition, with compounds 8s (IC50 = 0.39 ± 0.04 μM), 8k (IC50 = 7.4 ± 1.6 μM) and 8r (IC50 = 13.8 ± 2.7 μM) emerging as the most promising candidates. Notably, none of these compounds affected Caco-2 cell viability at concentrations up to 30 μM. Additionally, compounds 8r and 8s exhibited antioxidant properties, which may be relevant in counteracting the excessive production of free radicals associated with diabetes. Preliminary molecular docking and 500 ns molecular dynamics (MD) simulations were carried out on compounds 3k, 8i, 8k, and 8p–8s to support and interpret the experimental biological findings qualitatively.