New 1,2,3-triazole-(thio)barbituric acid hybrids as urease inhibitors: Design, synthesis, in vitro urease inhibition, docking study, and molecular dynamic simulation

A new series of 1,2,3-triazole-(thio)barbituric acid hybrids8a-nwas designed and synthesized on the basis of potent pharmacophores with urease inhibitory activity. Therefore, these compounds were evaluated againstHelicobacter pyloriurease. The obtained result demonstrated that all the synthesized compounds,8a-n, were more potent than the standard urease inhibitor, hydroxyurea. Moreover, among them, compounds8a,8c-e,8g,h, and8k,lexhibited higher urease inhibitory activities than the other standard inhibitor used: thiourea. Docking studies were performed with the synthesized compounds. Furthermore, molecular dynamic simulation of the most potent compounds,8eand8l, showed that these compounds interacted with the conserved residues Cys592 and His593, which belong to the active site flap and are essential for enzymatic activity. These interactions have two consequences: (a) blocking the movement of a flap at the entrance of the active site channel and (b) stabilizing the closed active site flap conformation, which significantly reduces the catalytic activity of urease. Calculation of the physicochemical and topological properties of the synthesized compounds8a-npredicted that all these compounds can be orally active. The ADME prediction of compounds8a-nwas also performed.