Dihydropyrimidine based hydrazine dihydrochloride derivatives as potent urease inhibitors

• Urease inhibitory activity of our recently designed four different DHPM series.
• Among them two series were identified as significant inhibitors of urease enzyme.
• Molecular docking and kinetics in order to understand their mode of inhibition.
• The cytotoxicity was also examined and no toxicity was observed.
• These compounds are interesting for urease inhibitory developments.

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.

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