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
Marzena Rzadkowska, Elzbieta Szacon, Agnieszka A. Kaczor, Sylwia Fidecka, Ewa Kedzierska and Dariusz Matosiuk
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.
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.
Keywords: Antinociceptive compounds, central nervous system activity, cyclocondensation, imidazo[1, 2-a]pyrimidines.
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