Dihydropyrimidine based hydrazine dihydrochloride derivatives as potent urease inhibitors

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

来源：Bioorganic Chemistry, 2016, 64: 85-96.

DOI：10.1016/j.bioorg.2015.12.007

• 4-Dihydropyrimidine-2-thione
• Hydrazine derivatives of dihydropyrimidine
• Urease inhibition
• Helicobacter pylori
• Peptic ulcer
• Proteus mirabilis
• Urolithiasis
• Cytotoxicity

Four series of heterocyclic compounds 4-dihydropyrimidine-2-thiones 7-12 (series A), N,S-dimethyldihydropyrimidines 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 mu M, 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 K-i. 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 mu M, 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.

• 出版日期2016-2