Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Pyrimidine Derivatives as Potential Calcium Channel Blockers

Abstract

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 1, ethyl acetoacetate 2 and/or 1H-indole-2-carbaldehyde, 2-chloroquinoline-3-carbaldehyde, 1,3-diphenyl-1H-pyrazole-4-carbaldehyde, 3a-c in acid medium (HCl) yielding pyrimidines 4a-c, which in turn were hydrolyzed to carboxylic acid derivatives 5a-c which were chlorinated by SOCl₂ to give acyl chlorides 6a-c. Finally, the latter were reacted with some selected aromatic amines, namely, aniline, p-toluidine and p-nitroaniline, producing amides 7a-c, 8a-c, and 9a-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 compounds 4c, 7a, 7c, 8c, 9b and 9c had comparable antihypertensive properties with Nifedipine. On the other hand, the in vitro calcium channel blocking activity was evaluated by IC₅₀ measurement and results revealed that compounds 4c, 7a, 7b, 7c, 8c, 9a, 9b, and 9c had comparable calcium channel blocking activity with the reference Nifedipine. Based on the aforementioned biological results, we selected compounds 8c and 9c 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.

Keywords: 3,4-dihydropyrimidin-2(1H)ones; antihypertensive; calcium channel blocking; nifedipine isosters.

Scheme 1

Synthesis of target dihydropyrimidines with three different starting aldehydes (a) 1H-indole-3-carbaldehyde; (b) 2-chloroquinoline-3-carbaldehyde and (c) 1,3-diphenyl-1H-pyrazole-4-carbaldehyde.

Figure 1

DHP analogue and aza analogues.

Figure 2

Comparison of (a) antihypertensive activity in terms of percent inhibition in blood pressure, (b) CCB in terms of IC₅₀ values between the standard drug and the target compounds showing similar efficacy to that of standard.

Figure 3

The 2D visualization of (a) compound 8c and (b) compound 9c ligand interaction with dihydropyridine using the MOE 2015.10th version software.

Figure 4

Docking mode of co-crystalized ligand (KN93). (A) A 3D interaction map between co-crystalized ligand and binding sites. (B) A 2D molecular docking model of the co-crystalized ligand.

Figure 5

Docking mode of compound 8c. (A) A 3D interaction map between compound 8c and binding sites. (B) A 2D molecular docking model of compound 8c.

Figure 6

Docking mode of compound 9c. (A) A 3D interaction map between compound 9c and binding sites. (B) A 2D molecular docking model of compound 9c.