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 thiourea1, ethyl acetoacetate2and/or 1H-indole-2-carbaldehyde, 2-chloroquinoline-3-carbaldehyde, 1,3-diphenyl-1H-pyrazole-4-carbaldehyde,3a–cin acid medium (HCl) yielding pyrimidines4a–c, which in turn were hydrolyzed to carboxylic acid derivatives5a–cwhich were chlorinated by SOCl2to give acyl chlorides6a–c. Finally, the latter were reacted with some selected aromatic amines, namely, aniline, p-toluidine and p-nitroaniline, producing amides7a–c, 8a–c,and9a–c. The purity of the prepared compounds was examined via TLC monitoring, and structures were confirmed by different spectroscopic techniques such as IR,1HNMR,13CNMR, and mass spectroscopy. The in vivo evaluation of the antihypertensive activity revealed that compounds4c, 7a, 7c, 8c, 9band9chad comparable antihypertensive properties with Nifedipine. On the other hand, the in vitro calcium channel blocking activity was evaluated by IC50measurement and results revealed that compounds4c, 7a, 7b, 7c, 8c, 9a, 9b,and9chad comparable calcium channel blocking activity with the reference Nifedipine. Based on the aforementioned biological results, we selected compounds8cand9cto 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.