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Synthesis, crystal structure and biological evaluation of new phosphoramide derivatives as urease inhibitors using docking, QSAR and kinetic studies.
Bioorg Chem. 2019 05; 86:482-493.BC

Abstract

In an attempt to achieve a new class of phosphoramide inhibitors with high potency and resistance to the hydrolysis process against urease enzyme, we synthesized a series of bisphosphoramide derivatives (01-43) and characterized them by various spectroscopic techniques. The crystal structures of compounds 22 and 26 were investigated using X-ray crystallography. The inhibitory activities of the compounds were evaluated against the jack bean urease and were compared to monophosphoramide derivatives and other known standard inhibitors. The compounds containing aromatic amines and their substituted derivatives exhibited very high inhibitory activity in the range of IC50 = 3.4-1.91 × 10-10 nM compared with monophosphoramides, thiourea, and acetohydroxamic acid. It was also found that derivatives with PO functional groups have higher anti-urease activity than those with PS functional groups. Kinetics and docking studies were carried out to explore the binding mechanism that showed these compounds follow a mixed-type mechanism and, due to their extended structures, can cover the entire binding pocket of the enzyme, reducing the formation of the enzyme-substrate complex. The quantitative structure-activity relationship (QSAR) analysis also revealed that the interaction between the enzyme and inhibitor is significantly influenced by aromatic rings and PO functional groups. Collectively, the data obtained from experimental and theoretical studies indicated that these compounds can be developed as appropriate candidates for urease inhibitors in this field.

Authors+Show Affiliations

Department of Chemistry, Faculty of Science, Tarbiat Modares University, Tehran, Iran. Electronic address: gholi_kh@modares.ac.ir.Department of Chemistry, Faculty of Science, Tarbiat Modares University, Tehran, Iran.Department of Chemistry, Faculty of Science, Tarbiat Modares University, Tehran, Iran.Department of Chemistry, Faculty of Science, Tarbiat Modares University, Tehran, Iran.College of Science & Engineering, James Cook University, Townsville, Queensland 4811, Australia.College of Science & Engineering, James Cook University, Townsville, Queensland 4811, Australia.Department of Chemistry, Faculty of Science, Tarbiat Modares University, Tehran, Iran.Department of Chemistry, Faculty of Science, Tarbiat Modares University, Tehran, Iran.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30772649

Citation

Gholivand, Khodayar, et al. "Synthesis, Crystal Structure and Biological Evaluation of New Phosphoramide Derivatives as Urease Inhibitors Using Docking, QSAR and Kinetic Studies." Bioorganic Chemistry, vol. 86, 2019, pp. 482-493.
Gholivand K, Pooyan M, Mohammadpanah F, et al. Synthesis, crystal structure and biological evaluation of new phosphoramide derivatives as urease inhibitors using docking, QSAR and kinetic studies. Bioorg Chem. 2019;86:482-493.
Gholivand, K., Pooyan, M., Mohammadpanah, F., Pirastefar, F., Junk, P. C., Wang, J., Ebrahimi Valmoozi, A. A., & Mani-Varnosfaderani, A. (2019). Synthesis, crystal structure and biological evaluation of new phosphoramide derivatives as urease inhibitors using docking, QSAR and kinetic studies. Bioorganic Chemistry, 86, 482-493. https://doi.org/10.1016/j.bioorg.2019.01.064
Gholivand K, et al. Synthesis, Crystal Structure and Biological Evaluation of New Phosphoramide Derivatives as Urease Inhibitors Using Docking, QSAR and Kinetic Studies. Bioorg Chem. 2019;86:482-493. PubMed PMID: 30772649.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis, crystal structure and biological evaluation of new phosphoramide derivatives as urease inhibitors using docking, QSAR and kinetic studies. AU - Gholivand,Khodayar, AU - Pooyan,Mahsa, AU - Mohammadpanah,Fahimeh, AU - Pirastefar,Foroogh, AU - Junk,Peter C, AU - Wang,Jun, AU - Ebrahimi Valmoozi,Ali Asghar, AU - Mani-Varnosfaderani,Ahmad, Y1 - 2019/02/08/ PY - 2018/11/01/received PY - 2019/01/20/revised PY - 2019/01/27/accepted PY - 2019/2/18/pubmed PY - 2020/4/14/medline PY - 2019/2/18/entrez KW - Bisphosphoramide derivatives KW - Docking KW - Inhibitory activity KW - Kinetics KW - QSAR KW - Urease enzyme SP - 482 EP - 493 JF - Bioorganic chemistry JO - Bioorg Chem VL - 86 N2 - In an attempt to achieve a new class of phosphoramide inhibitors with high potency and resistance to the hydrolysis process against urease enzyme, we synthesized a series of bisphosphoramide derivatives (01-43) and characterized them by various spectroscopic techniques. The crystal structures of compounds 22 and 26 were investigated using X-ray crystallography. The inhibitory activities of the compounds were evaluated against the jack bean urease and were compared to monophosphoramide derivatives and other known standard inhibitors. The compounds containing aromatic amines and their substituted derivatives exhibited very high inhibitory activity in the range of IC50 = 3.4-1.91 × 10-10 nM compared with monophosphoramides, thiourea, and acetohydroxamic acid. It was also found that derivatives with PO functional groups have higher anti-urease activity than those with PS functional groups. Kinetics and docking studies were carried out to explore the binding mechanism that showed these compounds follow a mixed-type mechanism and, due to their extended structures, can cover the entire binding pocket of the enzyme, reducing the formation of the enzyme-substrate complex. The quantitative structure-activity relationship (QSAR) analysis also revealed that the interaction between the enzyme and inhibitor is significantly influenced by aromatic rings and PO functional groups. Collectively, the data obtained from experimental and theoretical studies indicated that these compounds can be developed as appropriate candidates for urease inhibitors in this field. SN - 1090-2120 UR - https://www.unboundmedicine.com/medline/citation/30772649/Synthesis_crystal_structure_and_biological_evaluation_of_new_phosphoramide_derivatives_as_urease_inhibitors_using_docking_QSAR_and_kinetic_studies_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0045-2068(18)31251-3 DB - PRIME DP - Unbound Medicine ER -