title: Comparative computational studies of 3,4-dihydro-2,6-diaryl-4-oxo-pyrimidine-5-carbonitrile derivatives as potential antinociceptive agents.
abstract: In this study, the antinociceptive properties of 3,4-dihydro-2,6-diaryl-4-oxo-pyrimidine-5-carbonitrile derivatives 5a-i at doses of 25 and 50 mg/kg were evaluated in mice, using the abdominal constriction test. Molecular modeling studies were also performed using density functional theory calculations. These data provided information about the electrostatic and ionization potentials and were used to compare the antinociceptive activity of the title compounds. The most active compounds were 3,4-dihydro-2-(4-chlorophenyl)-6-(4-methoxyphenyl)-4-oxo-pyrimidine-5-carbonitrile (5b) and 3,4-dihydro-2,6-diphenyl-4-oxo-pyrimidine-5-carbonitrile (5i), which inhibited the number of abdominal constrictions, at 50 mg/kg dose, in 88.6% and 88% of the sample, respectively. A preliminary SAR study demonstrated that halogen replacement in the phenyl rings of the compounds under study reduces the antinociceptive activity. DFT calculations showed that there is a high correlation between the ionization potentials and the analgesic properties of the compounds. It was found that compounds with a positive ionization potential (compounds 5b and 5i) were found to be the best analgesic drugs in this series.
authors.affiliation: Departamento de Química Fundamental, Universidade Federal de Pernambuco, 50740-540, Recife, PE, Brazil.
authors.forename: Janaína V
authors.initials: JV
authors.lastname: dos Anjos
authors.forename: Rajendra M
authors.initials: RM
authors.lastname: Srivastava
authors.forename: João H
authors.initials: JH
authors.lastname: Costa-Silva
authors.forename: Luciana
authors.initials: L
authors.lastname: Scotti
authors.forename: Marcus T
authors.initials: MT
authors.lastname: Scotti
authors.forename: Almir G
authors.initials: AG
authors.lastname: Wanderley
authors.forename: Elisa Soares
authors.initials: ES
authors.lastname: Leite
authors.forename: Sebastião J
authors.initials: SJ
authors.lastname: de Melo
authors.forename: Francisco J B
authors.initials: FJ
authors.lastname: Mendonça Junior
mesh_terms: D019342:Acetic Acid; D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009570:Nitriles / Q000494:pharmacology* / Q000627:therapeutic use; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C571657:3,4-dihydro-2-(4-chlorophenyl)-6-(4-methoxyphenyl)-4-oxo-pyrimidine-5-carbonitrile; C571656:3,4-dihydro-2-phenyl-6-para-fluorophenyl-4-oxo-pyrimidine-5-carbonitrile; D000700:Analgesics; D009570:Nitriles; D011743:Pyrimidines; D019342:Acetic Acid