Design, Synthesis and Histamine H₁-Receptor Antagonistic Activity of Some Novel 4-Amino-2-(substituted)-5-(substituted) aryl-6-[(substituted aryl)amino]pyrimidines

Abstract

A series of 4-amino-2-(substituted)-5-(substituted)aryl-6-[(substituted)aryl)-amino]pyrimidines was designed based on the triangular pharmacophoric requirements for histamine Hi-receptor antagonists. The designed molecules were synthesized by condensation of arylacetonitriles with respective arylisothiocyanates to form corresponding acrylonitriles followed by cyclocondensation with carboxamidines to afford substituted pyrimidines. All compounds were screened for their histamine H₁-receptor antagonistic activity using the model “Inhibition of the isotonic contraction induced by histamine on isolated guinea pig ileum”. Target compounds were also evaluated for their sedative potential as well as their anticholinergic activities as these two are known to be the common adverse effects of histamine H₁-receptor antagonists. Compounds 2 h, 2 i, 2 j and 2 k exhibited potent histamine H₁-receptor antagonistic activity, which was found to be comparable with the standard drug, cetirizine (CAS 83881-51-0) and more potent than the conventional drug mepyramine (CAS 91-84-9). Some of the compounds have displayed very low sedative potential compared to diphenhydramine (CAS 58-73-1), but was found higher than cetirizine. None of them showed anticholinergic activity indicating potentialities of this series to be developed as second-generation histamine H₁-receptor antagonists.

Key words

4-Aminopyrimidines - Antihistamines - Histamine antagonists - Histamine H₁-receptor antagonists, anticholinergic effects, sedative potential

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