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.

Synthesis, central nervous system activity and structure–activity relationship of N-substituted derivatives of 1-arylimidazolidyn-2-ylideneurea and products of their cyclization

“…Parameters to evaluate drug-likeness were calculated using VegaZZ v. 3.0.1 26 (number of atoms), Discovery Studio v. 3.1. 27 (molar mass, number of rings, lipophilicity, number of rotatable bonds), ACDLabs (molar refractivity, number of hydrogen bond donors and acceptors), and MOE Molecular Environment 28 (a number of rigid bonds) as described previously 2,12 . Drug-likeness was also evaluated with Osiris Property Explorer 29 .…”

“…The prediction of toxicity by this tool relies on a precomputed set of structural fragment that give rise to toxicity alerts in case they are encountered in the investigated structure. For structure-activity relationship studies, HOMO and LUMO energies and polar surface area were calculated with Discovery Studio 3.1 as reported earlier 2,12 . Molar volume and polarizability were calculated with ACDLabs software 2,12 .…”

“…Efficient treatment of pain requires more effective medications devoid of side effects of current drugs. For morphine and related antinociceptive compounds the most severe side effects are euphoria/dysphoria, sedation, depression of respiratory center, depression of vasomotor center with hypotension, nausea, convulsions, tolerance and serious dependence 2 . There are two main approaches which are exploited in searching for new antinociceptive drugs: elaboration of more selective and safer substances acting through the well-established molecular targets and identification of new molecular targets thanks to progress in proteomics and bioinformatics.…”

“…the phenyl ring, tertiary nitrogen atom and the two carbon fragment (e.g. as a part of the piperidine ring), which are required by the receptor cavity [2][3][4] . These shared structural features can be found in bezitramide, fentanyl and petidine, and their analogues, Figure 1 2 .…”

“…These shared structural features can be found in bezitramide, fentanyl and petidine, and their analogues, Figure 1 2 . This ''pharmacophore'' model was proposed by Beckett (with its subsequent modifications [5][6][7] ) and was one of the first models used to explain the antinociceptive activity of morphine derivatives 2 . Discovery of pharmacological properties of salvinorin A wich is k opioid receptor agonist lacking a protonable nitrogen atom capable to interact with the conserved Asp(3.32) led to revisiting of the classical opioid receptor pharmacophore model.…”