Dihydropyrimidine based hydrazine dihydrochloride derivatives as potent urease inhibitors

Ajmal Khan; Jamshed Hashim; Nuzhat Arshad; Ijaz Khan; Naureen Siddiqui; Abdul Wadood; Muzaffar Ali; Fiza Arshad; Khalid Mohammed Khan; M Iqbal Choudhary

doi:10.1016/j.bioorg.2015.12.007

Dihydropyrimidine based hydrazine dihydrochloride derivatives as potent urease inhibitors

Bioorg Chem. 2016 Feb:64:85-96. doi: 10.1016/j.bioorg.2015.12.007. Epub 2015 Dec 31.

Authors

Affiliations

¹ 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.
² 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.
³ 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.
⁴ H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
⁵ Computational Medicinal Chemistry Laboratory, Department of Biochemistry, Abdul Wali Khan University, Mardan, Mardan 23200, Pakistan.
⁶ 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.

PMID: 26771129
DOI: 10.1016/j.bioorg.2015.12.007

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.

Keywords: 4-Dihydropyrimidine-2-thione; Cytotoxicity; Helicobacter pylori; Hydrazine derivatives of dihydropyrimidine; Peptic ulcer; Proteus mirabilis; Urease inhibition; Urolithiasis.

Publication types

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

MeSH terms

3T3 Cells
Animals
Hydrazines / chemical synthesis
Hydrazines / chemistry
Hydrazines / pharmacology*
Kinetics
Mice
Molecular Docking Simulation
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship
Urease / antagonists & inhibitors*

Substances

Hydrazines
Pyrimidines
Urease