Efficient Microwave-Mediated Synthesis of Disubstituted Benzimidazoles: A One-Pot Green Approach with Biological Evaluation

Abstract

The benzimidazole nucleus represents a privileged scaffold in medicinal chemistry, underpinning a wide array of therapeutic agents. However, conventional synthetic routes to disubstituted benzimidazoles often suffer from harsh conditions, prolonged reaction times, and environmentally detrimental reagents. In response, this study delineates the development of an efficient, one-pot, and environmentally benign methodology for the synthesis of a novel series of disubstituted benzimidazole derivatives utilizing microwave irradiation. The optimized protocol employs ethanol as a green solvent and operates under catalyst-free conditions, facilitating rapid cyclocondensation between *o*-phenylenediamine and various aryl aldehydes. This method offers remarkable advantages, including significantly reduced reaction times (2-8 minutes), excellent yields (85-96%), and minimal waste production, as evidenced by a low E-factor. The reaction demonstrated broad substrate scope and generality, tolerating a range of electron-donating and electron-withdrawing substituents. All newly synthesized compounds were fully characterized by spectroscopic techniques (¹H NMR, ¹³C NMR, IR, MS). The biological potential of the compounds was evaluated through in vitro antimicrobial and cytotoxic assays. Several derivatives exhibited promising antibacterial activity against Gram-positive and Gram-negative strains, with minimum inhibitory concentration (MIC) values comparable to standard drugs, and displayed significant cytotoxicity against MCF-7 and A549 cancer cell lines. A preliminary structure-activity relationship (SAR) was deduced, indicating the influence of specific substituents on bioactivity. Collectively, this microwave-mediated strategy embodies key principles of green chemistry, providing a sustainable, rapid, and high-yielding pathway to biologically relevant disubstituted benzimidazoles, thereby holding substantial promise for future pharmaceutical development.