Different Barbiturate Derivatives Linked to Aryl Hydrazone Moieties As Urease Inhibitors; Design, Synthesis, Urease Inhibitory Evaluations, and Molecular Dynamic Simulations Publisher



Mollazadeh M¹ ; Azizian H² ; Fakhrioliaei A³ ; Iraji A^{4, 5} ; Avizheh L¹ ; Valizadeh Y¹ ; Zomorodian K⁶ ; Elahi F¹ ; Moazzam A¹ ; Kazemzadeh H⁷ ; Amanlou M^{7, 8} ; Garmciri F⁹ ; Hamidian E⁷ ; Biglar M¹ Show All Authors Show Affiliations
Source: Medicinal Chemistry Research Published:2023

Abstract

New series of barbiturates linked to aryl hydrazone derivatives 4a-n were designed and synthesized. Briefly, aniline derivatives in the presence of HBF4 and NaNO2 convert to aryl diazonium tetrafluoroborate which is further attacked to barbituric acid derivatives in water. Finally, with tautomerization, the desired products were achieved. Next, compounds were evaluated as possible urease inhibitors and all the synthesized compounds (IC50 = 8.43 ± 0.14–10.91 ± 0.42 μM) were more potent than standard inhibitors hydroxyurea (IC50 = 100.00 ± 0.15 μM) and thiourea (IC50 = 23 ± 1.7 μM) against urease. It was shown that 4-bromo substitution on the phenyl ring of barbiturate improved the inhibitory potency. Furthermore, based on the molecular dynamic studies, compound 4g depicted noticeable interaction with the urease active site and mobile flap residues through the barbituric acid moiety by coordinating toward the metal bi-nickel center and the essential residues at the active site flap-like Cys592, His593, His594, respectively. These interactions cause interfering catalytic activity of the active site and reduce the flexibility of the mobile flap at the entrance of the active site channel, which significantly decreases the ureolytic activity of urease. © 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.