Synthesis and pharmacological evaluation of novel N-Mannich bases derived from 5,5-diphenyl and 5,5-di(propan-2-yl)imidazolidine-2,4-dione core |
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| Institution: | 1. Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland;2. Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland;1. Food and Pharmacy College, Zhejiang Ocean University, Zhejiang, Zhoushan 316022, PR China;2. Donghai Science and Technology College, Zhejiang Ocean University, Zhejiang, Zhoushan 316000, PR China;1. Faculty of Chemical Engineering and Technology, Institute of Organic Chemistry and Technology, Cracow University of Technology, 24 Warszawska Street, Cracow 31-155, Poland;2. Department of Medicinal Chemistry, Institute of Pharmacology – Polish Academy of Sciences, 12 Smętna Street, Cracow 31-343, Poland;1. Department of Chemistry, Sri Venkateswara University, Tirupati 517502, Andhra Pradesh, India;2. Department of Zoology, Sri Venkateswara University, Tirupati 517502, Andhra Pradesh, India;1. Universidad de Navarra, Department of Pharmaceutical Technology and Chemistry, Instituto de Salud Tropical, Pamplona, 31008, Spain;2. Department of Parasitology, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/University of Granada, Granada, 18071, Spain;3. Department of Pharmaceutical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, 21949-900, Brazil;4. Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale, Viale T. Michel 11, 15121, Alessandria, Italy |
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| Abstract: | The aim of this study was to design and synthesize two series of N-Mannich bases with imidazolidine-2,4-dione core as a potential anticonvulsant with reduced toxicity and broad antiseizure activity. Preliminary screening revealed that the majority of synthesized compounds were effective in the maximal electroshock seizure (MES) and/or subcutaneous pentylenetetrazole (scPTZ) test. The most active in vivo compound, 18 (3-((4-methylpiperazin-1-yl)methyl)-5,5-diphenylimidazolidine-2,4-dione), exhibited an ED50 value comparable to that of phenytoin in the MES test (38.5 mg/kg vs 28.1 mg/kg), and more importantly, it showed four times higher potency than phenytoin in the 6 Hz test (12.2 mg/kg vs > 60 mg/kg). Additionally, 18 exhibited antiallodynic properties in the von Frey test in neuropathic (oxaliplatin-treated) mice. Compound 18 also demonstrated a broader spectrum of anticonvulsant activity than phenytoin and showed statistically significant antinociceptive properties in selected models of chronic pain. |
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| Keywords: | Anticonvulsants Antinociceptive Imidazolidine-2 4-dione Hydantoin |
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