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.