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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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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.

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Authors and Affiliations

  1. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

    Marjan Mollazadeh, Laya Avizheh, Yousef Valizadeh, Fateme Elahi, Ali Moazzam, Mahmood Biglar, Bagher Larijani & Mohammad Mahdavi

  2. Department of Medicinal Chemistry, School of Pharmacy, Iran University of Medical Sciences, Tehran, Iran

    Homa Azizian

  3. Faculty of Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad Univesity, Tehran, Iran

    Azadeh Fakhrioliaei

  4. Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Aida Iraji

  5. Central Research Laboratory, Shiraz University of Medical Sciences, Shiraz, Iran

    Aida Iraji

  6. Department of Medical Mycology and Parasitology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    Kamiar Zomorodian

  7. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Houman Kazemzadeh, Massoud Amanlou & Elham Hamidian

  8. Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Massoud Amanlou

  9. Department of Biology, Payame Noor University (PNU), Tehran, Iran

    Farnia Garmciri

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  1. Marjan Mollazadeh
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  9. Ali Moazzam
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Correspondence to Mohammad Mahdavi.

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Mollazadeh, M., Azizian, H., Fakhrioliaei, A. et al. Different barbiturate derivatives linked to aryl hydrazone moieties as urease inhibitors; design, synthesis, urease inhibitory evaluations, and molecular dynamic simulations. Med Chem Res 32, 930–943 (2023). https://doi.org/10.1007/s00044-023-03050-w

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