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A new series of arylmethylene hydrazine derivatives bearing 1,3-dimethylbarbituric moiety  7a–o  were designed, synthesized, and evaluated for their in vitro urease inhibitory activity. All the title compounds displayed high anti-urease activity, with IC 50  values in the range of 0.61 ± 0.06–4.56 ± 0.18 µM as compared to the two standard inhibitors hydroxyurea (IC 50  = 100 ± 0.15 μM) and thiourea (IC 50  = 23 ± 1.7 μM). Among the synthesized compounds, compound  7h  with 2-nitro benzylidene group was found to be the most potent compound. Kinetic study of this compound revealed that it is a mix-mode inhibitor against urease. Evaluation of the interaction modes of the synthesized compounds in urease active site by molecular modeling revealed that that compounds with higher urease inhibitor activity ( 7h ,  7m, 7c, 7l ,  7i , and  7o,  with IC 50  of 0.61, 0.86, 1.2, 1.34, 1.33, 1.94 μM, respectively) could interact with higher number of residues, specially Arg609, Cys592 (as part of urease active site flap) and showed higher computed free energy, while compounds with lower urease activity ( 7f ,  7n ,  7g , and  7a  with IC 50  of 3.56, 4.56, 3.62 and 4.43 μM, respectively) and could not provide the proper interaction with Arg609, and Cys592 as the key interacting residues along with lower free binding energy. MD investigation revealed compound  7h  interacted with Arg609 and Cys592 which are of the key residues at the root part of mobile flap covering the active site. Interacting with the mentioned residue for a significant amount of time, affects the flexibility of the mobile flap covering the active site and causes inhibition of the ureolytic activity. Furthermore, in silico physico-chemical study of compounds  7a–o  predicted that all these compounds are drug-likeness with considerable orally availability.

Arylmethylene hydrazine derivatives containing 1,3-dimethylbarbituric moiety as novel urease inhibitors