| Summary: | Pyrimidines play an important role in modern medical fields. They have a wide spectrum of biological activities such as antimicrobial, anticancer, anti-allergic, anti-leishmanial, antioxidant agents and others. Moreover, in recent years, 3,4-dihydropyrimidin-2(1H)ones have attracted researchers to synthesize them via Biginelli reaction and evaluate their antihypertensive activities as bioisosters of Nifedipine, which is a famous calcium channel blocker. Our new target compounds were prepared through one-pot reaction of thiourea <b>1</b>, ethyl acetoacetate <b>2</b> and/or 1H-indole-2-carbaldehyde, 2-chloroquinoline-3-carbaldehyde, 1,3-diphenyl-1H-pyrazole-4-carbaldehyde, <b>3a</b>–<b>c</b> in acid medium (HCl) yielding pyrimidines <b>4a</b>–<b>c</b>, which in turn were hydrolyzed to carboxylic acid derivatives <b>5a</b>–<b>c</b> which were chlorinated by SOCl<sub>2</sub> to give acyl chlorides <b>6a</b>–<b>c</b>. Finally, the latter were reacted with some selected aromatic amines, namely, aniline, p-toluidine and p-nitroaniline, producing amides <b>7a</b>–<b>c, 8a</b>–<b>c,</b> and <b>9a</b>–<b>c</b>. The purity of the prepared compounds was examined via TLC monitoring, and structures were confirmed by different spectroscopic techniques such as IR, <sup>1</sup>HNMR, <sup>13</sup>CNMR, and mass spectroscopy. The in vivo evaluation of the antihypertensive activity revealed that compounds <b>4c, 7a, 7c, 8c, 9b</b> and <b>9c</b> had comparable antihypertensive properties with Nifedipine. On the other hand, the in vitro calcium channel blocking activity was evaluated by IC<sub>50</sub> measurement and results revealed that compounds <b>4c, 7a, 7b, 7c, 8c, 9a, 9b,</b> and <b>9c</b> had comparable calcium channel blocking activity with the reference Nifedipine. Based on the aforementioned biological results, we selected compounds <b>8c</b> and <b>9c</b> to be docked onto Ryanodine and dihydropyridine receptors. Furthermore, we developed a structure–activity relationship. The designed compounds in this study show promising activity profiles in reducing blood pressure and as calcium channel blockers, and could be considered as new potential antihypertensive and/or antianginal agents.
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