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Synthesis of novel calcium channel blockers with ACE2 inhibition and dual antihypertensive/anti-inflammatory effects: A possible therapeutic tool for COVID-19.
Mahgoub, Shahenda; Kotb El-Sayed, Mohamed-I; El-Shehry, Mohamed F; Mohamed Awad, Samir; Mansour, Yara E; Fatahala, Samar S.
  • Mahgoub S; Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, P.O. Box, 11795 Cairo, Egypt. Electronic address: Shahenda.Mahgoub@pharm.helwan.edu.eg.
  • Kotb El-Sayed MI; Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, P.O. Box, 11795 Cairo, Egypt; Department of Biochemistry, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt.
  • El-Shehry MF; Pesticide Chemistry Department, National Research Centre, P.O. Box, 12622 Dokki, Egypt.
  • Mohamed Awad S; Pharmaceutical Organic Chemistry Department, Helwan University, P.O. Box, 11795 Cairo, Egypt.
  • Mansour YE; Pharmaceutical Organic Chemistry Department, Helwan University, P.O. Box, 11795 Cairo, Egypt.
  • Fatahala SS; Pharmaceutical Organic Chemistry Department, Helwan University, P.O. Box, 11795 Cairo, Egypt. Electronic address: Samar_Saleh@pharm.helwan.edu.eg.
Bioorg Chem ; 116: 105272, 2021 11.
Article in English | MEDLINE | ID: covidwho-1370451
ABSTRACT
Hypertension has been recognized as one of the most frequent comorbidities and risk factors for the seriousness and adverse consequences in COVID-19 patients. 3,4-dihydropyrimidin-2(1H) ones have attracted researchers to be synthesized via Beginilli reaction and evaluate their antihypertensive activities as bioisosteres of nifedipine a well-known calcium channel blocker. In this study, we report synthesis of some bioisosteres of pyrimidines as novel CCBs with potential ACE2 inhibitory effect as antihypertensive agents with protective effect against COVID-19 infection by suppression of ACE2 binding to SARS-CoV-2 Spike RBD. All compounds were evaluated for their antihypertensive and calcium channel blocking activities using nifedipine as a reference standard. Furthermore, they were screened for their ACE2 inhibition potential in addition to their anti-inflammatory effects on LPS-stimulated THP-1 cells. Most of the tested compounds exhibited significant antihypertensive activity, where compounds 7a, 8a and 9a exhibited the highest activity compared to nifedipine. Moreover, compounds 4a,b, 5a,b, 7a,b, 8a,c and 9a showed promising ACE2SARS-CoV-2 Spike RBD inhibitory effect. Finally, compounds 5a, 7b and 9a exerted a promising anti-inflammatory effect by inhibition of CRP and IL-6 production. Ultimately, compound 9a may be a promising antihypertensive candidate with anti-inflammatory and potential efficacy against COVID-19 via ACE2 receptor inhibition.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Angiotensin-Converting Enzyme Inhibitors / Calcium Channel Blockers / Anti-Inflammatory Agents, Non-Steroidal / COVID-19 / Antihypertensive Agents Type of study: Risk factors Limits: Humans Language: English Journal: Bioorg Chem Year: 2021 Document Type: Article

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Angiotensin-Converting Enzyme Inhibitors / Calcium Channel Blockers / Anti-Inflammatory Agents, Non-Steroidal / COVID-19 / Antihypertensive Agents Type of study: Risk factors Limits: Humans Language: English Journal: Bioorg Chem Year: 2021 Document Type: Article