Abstract
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•Conformational analysis, geometric disposition, and SAR (Structure Activity Relationship) led to design oxazolo/thiazolo/imidazole pyrimidin-3-one derivatives.•Green approach to Biginelli Condensation with tetra butyl ammonium bromide as catalyst yielded near quantitative yields.•95.46%, and 92.02% Mean-Arterial-Blood Pressure-reduction compared to nifedipine in 6, and12 h, respectively, with 3 mg/kg body-weight dose.•MABP-reduction at 79.78% and 92.95% in 6 and 12 h as compared to nifedipine, respectively, at 1.5 mg/kg body-weight dose.•An extended pharmacophore model incorporating receptor-site’s molecular and geometric attributes is propositioned.
An improved pharmacophore model, molecular properties, geometric analyses, and SAR led to synthesize oxazolo/thiazolo-[3,2-a]-pyrimidin-3(2H)-one, and 1,5-dihydroimidazo-[1,2-a]-pyrimidin-3(2H)-one derivatives exhibiting potent anti-hypertensive activity. The 6-ethoxycarbonyl-2,7-dimethyl-5-phenyl-1,5-dihydroimidazo[3,2-a]pyrimidin-3(2H)-one (4g), and 6-ethoxycarbonyl-2,7-dimethyl-5-(3-methyl-phenyl)-1,5-dihydroimidazo[3,2-a]pyrimidin-3(2H)-one (4h) showed significant reduction in mean arterial blood pressure (MABP, mm/Hg) of 79.78%, and 92.95% in 6 and 12 h durations, respectively, at 1.5 mg/kg body-weight dose, while at 3.0 mg/kg body-weight dose, the MABP reduction was achieved at 95.46%, and 92.02%, respectively, in 6 and 12 h durations, as compared to the standard drug, nifedipine.