Synthesis, central nervous system activity and structure-activity relationships of novel 1-(1-Alkyl-4-aryl-4,5-dihydro-1H-imidazo)-3-substituted urea derivatives.
A series of 10 novel urea derivatives has been synthesized and evaluated for their central nervous system activity. Compounds 3a-3h were prepared in the reaction between the respective 1-alkyl-4-aryl-4,5-dihydro-1H-imidazol-2-amines 1a and 1b and appropriate benzyl-, phenethyl-isocyanate or ethyl 4-isocyanatobenzoate and ethyl isocyanatoacetate 2 in dichloromethane. Derivatives 4c and 4g resulted from the conversion of 3c and 3g into the respective amides due to action of an aqueous ammonia solution. The results obtained in this study, based on literature data suggest a possible involvement of serotonin system and/or the opioid system in the effects of tested compounds, and especially in the effect of compound 3h. The best activity of compound 3h may be primarily attributed to its favourable ADMET properties, i.e., higher lipophilicity (related to lower polar surface area and greater molecular surface, volume and mass than for other compounds) and good blood-brain permeation. This compound has also the greatest polarizability and ovality. The HOMO and LUMO energies do not seem to be directly related to activity.
Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4a Chodźki St., Lublin PL-20093, Poland. elzbieta.szacon@umlub.pl.
Elżbieta
E
Szacoń
Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4a Chodźki St., Lublin PL-20093, Poland. marzena.rzadkowska@umlub.pl.
Marzena
M
Rządkowska
Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4a Chodźki St., Lublin PL-20093, Poland. agnieszka.kaczor@umlub.pl.|School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, Kuopio FI-70211, Finland. agnieszka.kaczor@umlub.pl.
Agnieszka A
AA
Kaczor
Department of Pharmacology and Pharmacodynamics, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodźki St., Lublin PL-20093, Poland. ewa.kedzierska@umlub.pl.
Ewa
E
Kędzierska
Department of Pharmacology and Pharmacodynamics, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodźki St., Lublin PL-20093, Poland. sylwia.fidecka@umlub.pl.
Sylwia
S
Fidecka
Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4a Chodźki St., Lublin PL-20093, Poland. dariusz.matosiuk@umlub.pl.
Dariusz
D
Matosiuk
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002490:Central Nervous System / Q000187:drug effects*; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D059225:Nociception / Q000187:drug effects*; D011597:Psychomotor Performance / Q000187:drug effects; D012640:Seizures / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
C000604397:1-(1-methyl-4-(4-methylphenyl)-4,5-dihydro-1H-imidazo)-3-(4-ethoxycarbonylphenyl)urea; D007093:Imidazoles; C029899:imidazole; D014508:Urea