title: Design, synthesis and pharmacological screening of a series of N1-(substituted) aryl-5,7-dimethyl-2-(substituted)pyrido(2,3-d)-pyrimidin-4(3H)-ones as potential histamine H1-receptor antagonists.
abstract: A series of N1-(substituted)aryl-5,7-dimethyl-2-(substituted)pyrido(2,3-d)pyrimidin-4(3H)-one was designed on the basis of the triangular pharmacophoric requirement of histamine H1-receptor antagonists. The designed series was synthesized by cyclo-condensation of monoaryl thiourea with ethyl cyanoacetate in the presence of dry HCl gas to give N1-(substituted aryl)-2-mercaptopyrimidine-4(3H)-one, which on cyclo-condensation with acetylacetone gave the pyridopyrimidinone. Further methylation of the mercapto group at C-2 with methyl iodide followed by nucleophilic displacement of the methylmercapto group by various amines gave the targeted compounds. All the synthesized compounds were screened for histamine H1-receptor antagonistic activity by the in vitro method of inhibition of the isotonic contraction induced by histamine on isolated guinea pig ileum using cetirizine as a standard drug. All the compounds exhibited potent histamine H1-receptor antagonistic activity with pA2 values from 7.30- 9.75 (cetirizine, pA2 value 9.40). The potent compounds were screened for their in vivo antihistaminic activity by protection of animal from asphyxic shock. The sedative potential of potent compounds was checked on albino mice by photoactometer and they had comparative sedative potential to the standard drug cetirizine. None of the compound exhibited anticholinergic activity in the in vitro rat ileum model.
authors.affiliation: Department of Pharmaceutical Chemistry, L.M. College of Pharmacy, Navrangpura, Ahmedabad-380009, Gujarat, India.
authors.forename: Bhanubhai N
authors.initials: BN
authors.lastname: Suhagia
authors.forename: Mahesh T
authors.initials: MT
authors.lastname: Chhabria
authors.forename: Ashlesha G
authors.initials: AG
authors.lastname: Makwana
mesh_terms: D000818:Animals; D017332:Cetirizine / Q000494:pharmacology; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D039563:Histamine H1 Antagonists, Non-Sedating / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011969:Receptors, Histamine H1 / Q000378:metabolism*
chemical_list: D006634:Histamine H1 Antagonists; D039563:Histamine H1 Antagonists, Non-Sedating; D011744:Pyrimidinones; D011969:Receptors, Histamine H1; D017332:Cetirizine