Synthesis, Molecular Docking and Biological Evaluation of Diaryl Pyrimidine Derivatives as Urease Inhibitors.

Urease is a dinickel enzyme that is responsible for the hydrolysis of urea to ammonia and carbon dioxide. A series of bacteria like Helicobacter pylori produce urease in order to release ammonia via urea hydrolysis and survive in acidic environments. Urease inhibitors are often used as a part of the medical treatment of infections by ureolytic bacteria. In this work, a series of diaryl pyrimidine derivatives (compounds 6a–6i) have been synthesized as urease inhibitors, their inhibitory activities against Jack bean urease have been investigated in vitro, and the obtained values of IC₅₀ showed potent urease inhibitory activity. Cytotoxic activity of the synthesized compounds was evaluated against four cell lines (HT-29, MCF-7, T47D, and NIH3T3). Many of the tested compounds did not show significant cytotoxicity, and compounds 6d, 6g, and 6i did not show any cytotoxic activity against these cell lines. Among these, compound 6d showed the most pronounced urease inhibitory activity (IC₅₀ = 780 ± 50nM), being over 28-fold more potent than thiourea (IC₅₀ = 22.01 ± 0.08 ìM) and 128-fold more potent than hydroxyurea (IC₅₀ = 100.00 ± 0.08 ìM) as standard inhibitors, respectively. The results of molecular docking studies showed that compound 6b had the best binding energy and exhibited proper interaction with the active site of urease. [ABSTRACT FROM AUTHOR]