Dihydropyrimidine based hydrazine dihydrochloride derivatives as potent urease inhibitors |
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| Institution: | 1. H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;2. Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan;3. Department of Chemistry, NED University of Engineering & Technology, Karachi 75270, Pakistan;4. Computational Medicinal Chemistry Laboratory, Department of Biochemistry, Abdul Wali Khan University, Mardan, Mardan 23200, Pakistan;5. Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21412, Saudi Arabia;1. Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education of China, Lanzhou 730070, China;2. Gansu Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, China;1. Department of Chemistry, National Institute of Technology, Warangal 506 004, India;2. Department of Chemistry, Osmania University, Hyderabad 500 007, India;1. Department of Chemistry, Goa University, Taleigao Plateau, Goa 403206, India;2. Department of Biotechnology, Goa University, Taleigao Plateau, Goa 403206, India;1. Faculty of Pharmacy, Yasuda Women’s University, 6-13-1, Yasuhigashi, Asaminami-ku, Hiroshima 731-0153, Japan;2. Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Keyakidai, Sakado, Saitama 350-0295, Japan;3. Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan;1. H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;2. Dr. Panjwani Centre for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;3. Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 21412, Saudi Arabia;4. PCSIR Laboratories Complex, Karachi, Shahra-e-Dr. Salimuzzaman Siddiqui, Karachi 75280, Pakistan;5. Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia;1. School of Chemistry, The University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom;2. Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, United Kingdom;3. Natural and Medical Sciences Research Center, University of Nizwa, P.O Box 33, Postal Code 616, Birkat Al Mauz, Nizwa, Oman;4. Department of Chemistry, Quaid-i-Azam University-45320, Islamabad, Pakistan;5. Department of Chemistry, Abbottabad University of Science and Technology, Havelian, Abbottabad, Pakistan;6. Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany |
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| 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. |
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| Keywords: | 4-Dihydropyrimidine-2-thione Hydrazine derivatives of dihydropyrimidine Urease inhibition Peptic ulcer Urolithiasis Cytotoxicity |
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