Synthesis, central nervous system activity, and structure–activity relationship of 1-aryl-6-benzyl-7-hydroxy-2,3-dihydroimidazo[1,2-a]pyrimidine-5(1H)-ones

Abstract

A series of 24 1-aryl-6-benzyl-7-hydroxy-2,3-dihydroimidazo[1,2-a]pyrimidine-5(1H)-ones was designed as antinociceptive compounds acting through opioid receptors with additional serotoninergic activity. The compounds, similarly as previously published series, lack the protonable nitrogen atom which is a part of classical opioid receptor pharmacophore and is necessary to interact with the conserved Asp(3.32) in the opioid receptor binding pocket. The compounds were obtained in one-step cyclocondensation of 1-aryl-4,5-dihydro-1H-imidazol-2-amines diethyl 2-benzylmalonate or diethyl 2-(2-chlorobenzyl)malonate under basic conditions. Almost all the tested compounds exerted strong antinociceptive activity, but surprisingly, it was not reversed by naloxone; thus, it is not mediated through opioid receptors. It makes it possible to conclude that addition of one more aromatic moiety to the non-classical opioid receptor pharmacophore results in the compounds which are not opioid receptor ligands. The lack of activity of one of the tested compounds may be attributed to low blood–brain barrier permeation or unfavorable distribution of electrostatic potential and HOMO and LUMO orbitals.Electronic supplementary materialThe online version of this article (doi:10.1007/s00044-014-0993-1) contains supplementary material, which is available to authorized users.

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 .…”

“…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 . The maps of the electrostatic potential (ESP) onto a surface of the electron density were visualized with ArgusLab 30 .…”

“…Drug-likness was assessed using Lipinski's rule as well as the placement of the investigated compounds in the chemical space determined by the databases of the pharmacologically active compounds (CMC, Comprehensive Medicinal Chemistry Database, containing about 7000 compounds and MDDR, MACCS-II Drug Data Report, containing about 100 000 compounds) according to the methodology of PREADMET 38 service as described previously 12 . Concerning Lipinski's rule, all the compounds possess the molar mass below 500, the number of hydrogen bond donors below 5, the number of hydrogen bond acceptors below 10, and the lipophilicity below 5.…”

“…Regarding subsequent criteria of drug-likeness, most compounds collected in the CMC database has lipophilicity from À0.4 to 5.6, molar refractivity in the range of 40-130, molar mass from 160 to 480, and the number of atoms from 20 to 70 12 . All the investigated compounds fulfill this criterion.…”