title: Dihydropyrimidine based hydrazine dihydrochloride derivatives as potent urease inhibitors.
abstract: Four series of heterocyclic compounds 4-dihydropyrimidine-2-thiones 7-12 (series A), N,S-dimethyl-dihydropyrimidines 13-18 (series B), hydrazine derivatives of dihydropyrimidine 19-24 (series C), and tetrazolo dihydropyrimidine derivatives 25-30 (series D), were synthesized and evaluated for in vitro urease inhibitory activity. The series B-D were first time examined for urease inhibition. Series A and C were found to be significantly active with IC50 values between 34.7-42.9 and 15.0-26.0 μM, respectively. The structure-activity relationship showed that the free S atom and hydrazine moiety are the key pharmacophores against urease enzyme. The kinetic studies of the active series A (7-12) and C (19-24) were carried out to determine their modes of inhibition and dissociation constants Ki. Compounds of series A (7-12) and series C (19-24) showed a mixed-type of inhibition with Ki values ranging between 15.76-25.66 and 14.63-29.42 μM, respectively. The molecular docking results showed that all the active compounds of both series have significant binding interactions with the active sites specially Ni-ion of the urease enzyme. Cytotoxicity of all series A-D was also evaluated against mammalian mouse fibroblast 3T3 cell lines, and no toxicity was observed in cellular model.
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan.
authors.forename: Ajmal
authors.initials: A
authors.lastname: Khan
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan. Electronic address: jamshed.hashim@iccs.edu.
authors.forename: Jamshed
authors.initials: J
authors.lastname: Hashim
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Department of Chemistry, NED University of Engineering & Technology, Karachi 75270, Pakistan.
authors.forename: Nuzhat
authors.initials: N
authors.lastname: Arshad
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Ijaz
authors.initials: I
authors.lastname: Khan
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Naureen
authors.initials: N
authors.lastname: Siddiqui
authors.affiliation: Computational Medicinal Chemistry Laboratory, Department of Biochemistry, Abdul Wali Khan University, Mardan, Mardan 23200, Pakistan.
authors.forename: Abdul
authors.initials: A
authors.lastname: Wadood
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Muzaffar
authors.initials: M
authors.lastname: Ali
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Fiza
authors.initials: F
authors.lastname: Arshad
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Khalid Mohammed
authors.initials: KM
authors.lastname: Khan
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21412, Saudi Arabia. Electronic address: iqbal.choudhary@iccs.edu.
authors.forename: M Iqbal
authors.initials: MI
authors.lastname: Choudhary
mesh_terms: D016475:3T3 Cells; D000818:Animals; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D062105:Molecular Docking Simulation; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014510:Urease / Q000037:antagonists & inhibitors*
chemical_list: D006834:Hydrazines; D011743:Pyrimidines; D014510:Urease
keywords: 4-Dihydropyrimidine-2-thione; Cytotoxicity; Helicobacter pylori; Hydrazine derivatives of dihydropyrimidine; Peptic ulcer; Proteus mirabilis; Urease inhibition; Urolithiasis