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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.

Rządkowska M, Szacoń E, Kaczor AA, Fidecka S, Kędzierska E, Matosiuk D - Med Chem Res (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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 Chodźki St, 20093 Lublin, Poland.

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.

No MeSH data available.


Related in: MedlinePlus

The scheme of synthesis of the investigated compounds
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Fig4: The scheme of synthesis of the investigated compounds

Mentions: The compounds 3a–3x were obtained in one-step cyclocondensation of 1-aryl-4,5-dihydro-1H-imidazol-2-amines (1a–1l) diethyl 2-benzylmalonate (2a) or diethyl 2-(2-chlorobenzyl)malonate (2b) under basic conditions (sodium methoxide), Fig. 4 cyclocondensation reaction. The cyclocondensation reaction of this type was earlier reported as a method of preparation of imidazo[1,2-a]pyrimidines (Matosiuk et al., 1996) as well as other derivatives of 1-aryl-4,5-dihydro-1H-imidazol-2-amines (Matosiuk et al., 2002a, b; Sztanke et al., 2005) and 1-aryl-4,5-dihydro-1H-imidazol-2-hydrazines (Sztanke, 2002, 2004). Reaction of imidazole-2-amines with electrophilic compounds represents one of the synthetic methods to build this heterocyclic system. The main alternative involves the imidazole ring closure by condensation of pyrimidin-2-amines with an appropriate compound.Fig. 4


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.

Rządkowska M, Szacoń E, Kaczor AA, Fidecka S, Kędzierska E, Matosiuk D - Med Chem Res (2014)

The scheme of synthesis of the investigated compounds
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4127001&req=5

Fig4: The scheme of synthesis of the investigated compounds
Mentions: The compounds 3a–3x were obtained in one-step cyclocondensation of 1-aryl-4,5-dihydro-1H-imidazol-2-amines (1a–1l) diethyl 2-benzylmalonate (2a) or diethyl 2-(2-chlorobenzyl)malonate (2b) under basic conditions (sodium methoxide), Fig. 4 cyclocondensation reaction. The cyclocondensation reaction of this type was earlier reported as a method of preparation of imidazo[1,2-a]pyrimidines (Matosiuk et al., 1996) as well as other derivatives of 1-aryl-4,5-dihydro-1H-imidazol-2-amines (Matosiuk et al., 2002a, b; Sztanke et al., 2005) and 1-aryl-4,5-dihydro-1H-imidazol-2-hydrazines (Sztanke, 2002, 2004). Reaction of imidazole-2-amines with electrophilic compounds represents one of the synthetic methods to build this heterocyclic system. The main alternative involves the imidazole ring closure by condensation of pyrimidin-2-amines with an appropriate compound.Fig. 4

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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 Chodźki St, 20093 Lublin, Poland.

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.

No MeSH data available.


Related in: MedlinePlus