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Different barbiturate derivatives linked to aryl hydrazone moieties as urease inhibitors; design, synthesis, urease inhibitory evaluations, and molecular dynamic simulations.

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Title: Different barbiturate derivatives linked to aryl hydrazone moieties as urease inhibitors; design, synthesis, urease inhibitory evaluations, and molecular dynamic simulations.
Authors: Mollazadeh, Marjan, Azizian, Homa, Fakhrioliaei, Azadeh, Iraji, Aida, Avizheh, Laya, Valizadeh, Yousef, Zomorodian, Kamiar, Elahi, Fateme, Moazzam, Ali, Kazemzadeh, Houman, Amanlou, Massoud, Garmciri, Farnia, Hamidian, Elham, Biglar, Mahmood, Larijani, Bagher, Mahdavi, Mohammad
Source: Medicinal Chemistry Research; May2023, Vol. 32 Issue 5, p930-943, 14p
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. [ABSTRACT FROM AUTHOR]
Copyright of Medicinal Chemistry Research is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Different barbiturate derivatives linked to aryl hydrazone moieties as urease inhibitors; design, synthesis, urease inhibitory evaluations, and molecular dynamic simulations.
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  Data: Medicinal Chemistry Research; May2023, Vol. 32 Issue 5, p930-943, 14p
– Name: Abstract
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  Data: New series of barbiturates linked to aryl hydrazone derivatives 4a-n were designed and synthesized. Briefly, aniline derivatives in the presence of HBF<subscript>4</subscript> and NaNO<subscript>2</subscript> 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 (IC<subscript>50</subscript> = 8.43 ± 0.14–10.91 ± 0.42 μM) were more potent than standard inhibitors hydroxyurea (IC<subscript>50</subscript> = 100.00 ± 0.15 μM) and thiourea (IC<subscript>50</subscript> = 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. [ABSTRACT FROM AUTHOR]
– Name: Abstract
  Label:
  Group: Ab
  Data: <i>Copyright of Medicinal Chemistry Research is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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