Aromatic carbothioamide-, triazole-, thiadiazole-, and thiazolidinone-derived benzimidazoles: synthesis, characterization, urease and AChE inhibition properties, and docking study

Abstract

In this study, we synthesized a series of aromatic carbothioamide derivatives bearing a benzimidazole scaffold. Subsequently, their thiadiazole and triazole analogs were prepared through intramolecular cyclization under acidic and basic conditions. Additionally, thiazolidinone derivatives were synthesized via cyclization in the presence of ethyl bromoacetate. The in vitro inhibitory activities of all synthesized compounds against urease and acetylcholinesterase (AChE) were evaluated. All compounds showed significant inhibitory effects, with IC50 values ranging from 7.50 ± 0.20 to 9.05 ± 0.10 μg/mL against urease (standard: thiourea, 15.75 ± 0.15 μg/mL) and from 7.25 ± 0.15 to 9.35 ± 0.05 μg/mL against AChE (standard: galantamine, 20.75 ± 0.25 μg/mL). Among them, the triazole derivative 3b was identified as the most potent urease inhibitor (IC50 = 7.50 ± 0.20 μg/mL). Notably, carbothioamide derivative 2c exhibited superior dual inhibitory activity, with IC50 values of 7.25 ± 0.15 μg/mL for AChE and 7.80 ± 0.10 μg/mL for urease, making it a promising candidate for multi-target enzyme inhibition. Molecular docking studies further supported these findings by revealing strong and stable interactions of 2c within the active sites of both enzymes, which correlates well with its experimental potency. These results highlight compound 2c as a compelling lead structure for the development of dual-target therapeutic agents, combining significant experimental activity with theoretical validation.