Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Pyrimidine Derivatives as Potential Calcium Channel Blockers
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 s...
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MDPI AG
2023-06-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/12/4869 |
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| author | Yasser M. Zohny Samir M. Awad Maha A. Rabie Omar Awad Alsaidan |
| author_facet | Yasser M. Zohny Samir M. Awad Maha A. Rabie Omar Awad Alsaidan |
| author_sort | Yasser M. Zohny |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T02:06:48Z |
| format | Article |
| id | doaj.art-fa41e8f2662249daa32f4e084bdb4d95 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T02:06:48Z |
| publishDate | 2023-06-01 |
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| series | Molecules |
| spelling | doaj.art-fa41e8f2662249daa32f4e084bdb4d952023-11-18T11:51:30ZengMDPI AGMolecules1420-30492023-06-012812486910.3390/molecules28124869Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Pyrimidine Derivatives as Potential Calcium Channel BlockersYasser M. Zohny0Samir M. Awad1Maha A. Rabie2Omar Awad Alsaidan3Pharmaceutical Sciences Department, College of Pharmacy, Shaqra University, Dawadmi 11911, Saudi ArabiaPharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Cairo 11795, EgyptPharmacy Practice Department, College of Pharmacy, Shaqra University, Dawadmi 11911, Saudi ArabiaDepartment of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka 72341, Saudi ArabiaPyrimidines 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.https://www.mdpi.com/1420-3049/28/12/48693,4-dihydropyrimidin-2(1H)onesnifedipine isostersantihypertensivecalcium channel blocking |
| spellingShingle | Yasser M. Zohny Samir M. Awad Maha A. Rabie Omar Awad Alsaidan Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Pyrimidine Derivatives as Potential Calcium Channel Blockers Molecules 3,4-dihydropyrimidin-2(1H)ones nifedipine isosters antihypertensive calcium channel blocking |
| title | Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Pyrimidine Derivatives as Potential Calcium Channel Blockers |
| title_full | Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Pyrimidine Derivatives as Potential Calcium Channel Blockers |
| title_fullStr | Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Pyrimidine Derivatives as Potential Calcium Channel Blockers |
| title_full_unstemmed | Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Pyrimidine Derivatives as Potential Calcium Channel Blockers |
| title_short | Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Pyrimidine Derivatives as Potential Calcium Channel Blockers |
| title_sort | design synthesis molecular modeling and biological evaluation of novel pyrimidine derivatives as potential calcium channel blockers |
| topic | 3,4-dihydropyrimidin-2(1H)ones nifedipine isosters antihypertensive calcium channel blocking |
| url | https://www.mdpi.com/1420-3049/28/12/4869 |
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