Cyanuric Chloride Mediated One-Pot Three-Component Reaction of Benzoylhydrazinyl-N-Alkyl Acetamide Derivatives as a New Urease Inhibitor Scaffold: Docking Study and Enzyme Inhibitory Activity

Helicobacter pylori (H. pylori) have infected half of the world’s population and led to pathological conditions. The urease plays anessential role in H. pylori pathogenesis. In this regard, and based on the antimicrobial properties of different hydrazides, we synthesized a set of benzoyl hydrazinyl-N-alkyl-acetamide derivatives through a multi-component method using cyanuric chloride as the acid catalyst, which acts as a proton supplier to enhance the reaction. The final compounds were obtained in good yield. All synthesized compounds could efficiently inhibit the urease enzyme with IC50 ranging from 10.75 ± 0.91 to 208.9 ± 0.4 μM. The compound 4A was the most potent compound with IC50 = 10.75 ± 0.91 μM that is much higher than thiourea (IC50 = 21.00 ± 0.11 μM) and hydroxyurea (IC50 = 100.00 ± 0.01 μM). Docking results showed that compounds 4A, 4H, 4M, 4J have efficient steric and chemical complementarily with urease and make interactions with critical residues at the entrance of the binding pocket. In agreement with in vitro results, the most potent compounds were also capable of efficiently (i) making hydrophobic interactions with Ala 636, Ala 440, His 409, Met 637, Asp 494, and (ii) forming Ala 636 hydrogen bonds with Gln 635, Met 637, and Arg 439.