title: Synthesis, pharmacological activity and molecular modeling of 1-aryl-7- hydroxy-2,3-dihydroimidazo[1,2-a]pyrimidine-5(1H)-ones and their 6-substituted derivatives.
abstract: Pain management is an important medical problem with social and economic consequences. Opioid receptors are among the most important molecular targets involved in antinociception. We have previously reported several series of antinociceptive compounds with the affinity to opioid receptors. In search for novel compounds acting on central nervous system with antinociceptive activity we synthesized a series of 1-aryl-7-hydroxy-2,3-dihydroimidazo[1,2- a]pyrimidine-5(1H)-ones and their 6-phenyl derivatives. The novel compounds were subjected to extensive pharmacological studies to assess their effect on motor coordination, body temperature, clonic seizures and tonic convulsions and their antinociceptive activity. In the writhing test the antinociceptive activity of some derivatives was reversed by naloxone, thus we can assume that their activity may be associated with opioid system. We also used molecular modeling to describe active conformations of the studied compounds and to build a pharmacophore model. As in the previously reported series of the compounds, the studied substances exerted antinociceptive activity probably associated with the opioid system without possessing a protonable nitrogen atom. Furthermore, we calculated structural, electronic and ADMET parameters (volume, surface area, polar surface area, ovality, dipole moment, HOMO and LUMO energies, polarizaibility, molar refractivity, lipophilicity, the charges on the heteroatoms, aqueous solubility, and blood-brain barrier permeation parameter) for novel compounds in order to address the observed structure-activity relationship.
authors.forename: Marzena
authors.initials: M
authors.lastname: Rzadkowska
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Szacon
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Kaczor
authors.forename: Sylwia
authors.initials: S
authors.lastname: Fidecka
authors.forename: Ewa
authors.initials: E
authors.lastname: Kedzierska
authors.affiliation: 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 Chodzki St., PL-20093 Lublin, Poland. marzena.rzadkowska@umlub.pl.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Matosiuk
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D011743:Pyrimidines; C030986:pyrimidine