Methimazole Analogs as Urease Inhibitors: Synthesis, In Silico and In Vitro Evaluation

Abstract Urease plays a key role in urinary tract and gastrointestinal infections for which inhibition of it could prove to be substantial as a potential therapeutic option. Here, synthesized thirty novel compounds in four different series based on methimazole skeleton, also known as thiamazole, a drug that is used for the treatment of hyperthyroidism. Characterization of novel compounds consisting oxadiazoles, hydrazine‐1‐carbothioamides and N ′‐arylidenebenzohydrazides were performed by 1 H‐, 13 C‐NMR and high resolution mass spectrometry (HRMS). The synthesized molecules were examined for structure‐activity relationship in urease inhibition and found to exhibit inhibitory potency in a range of IC50=3.56–14.08 μM compared to urea and acetohydroxamic acid used as standard. Moreover, molecular docking was performed to understand ligand binding interactions in the active site of the enzyme (Jack bean urease, Protein Data Bank ID 3LA4). The promise of addressing urinary tract and gastrointestinal disorders through urease inhibition is discussed.