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Exploring the dual effect of novel 1,4-diarylpyranopyrazoles as antiviral and anti-inflammatory for the management of SARS-CoV-2 and associated inflammatory symptoms.
Malebari, Azizah M; E A Ahmed, Hany; Ihmaid, Saleh K; Omar, Abdelsattar M; Muhammad, Yosra A; Althagfan, Sultan S; Aljuhani, Naif; A A El-Sayed, Abdel-Aziz; Halawa, Ahmed H; El-Tahir, Heba M; Turkistani, Safaa A; Almaghrabi, Mohammed; K B Aljohani, Ahmed; El-Agrody, Ahmed M; Abulkhair, Hamada S.
  • Malebari AM; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi Arabia.
  • E A Ahmed H; Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City 11884, Cairo, Egypt. Electronic address: heahmad@azhar.edu.eg.
  • Ihmaid SK; Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Jadara University Irbid, Jordan.
  • Omar AM; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi Arabia; Center for Artificial Intelligence in Precision Medicines, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Pharmaceutical Chemistry, Faculty of Pharmacy,
  • Muhammad YA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi Arabia.
  • Althagfan SS; Clinical and Hospital Pharmacy Department, Taibah University, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia.
  • Aljuhani N; Pharmacology and Toxicology Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia.
  • A A El-Sayed AA; Biology Department, Faculty of Science, Islamic University of Madinah, Madinah, Saudi Arabia; Zoology Department, Faculty of Science, Zagazig University, Zagazig, Egypt.
  • Halawa AH; Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt.
  • El-Tahir HM; Pharmacology and Toxicology Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia.
  • Turkistani SA; Fakeeh College for Medical Sciences, Jeddah, Saudia Arabia.
  • Almaghrabi M; Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia.
  • K B Aljohani A; Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia.
  • El-Agrody AM; Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt.
  • Abulkhair HS; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City 11884, Cairo, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Horus University-Egypt, International Coastal Road, New Damietta 34518, Egypt. Electronic address: hamadaorganic@azhar.edu.e
Bioorg Chem ; 130: 106255, 2023 01.
Article in English | MEDLINE | ID: covidwho-2120216
ABSTRACT
COVID-19 and associated substantial inflammations continue to threaten humankind triggering death worldwide. So, the development of new effective antiviral and anti-inflammatory medications is a major scientific goal. Pyranopyrazoles have occupied a crucial position in medicinal chemistry because of their biological importance. Here, we report the design and synthesis of a series of sixteen pyranopyrazole derivatives substituted with two aryl groups at N-1 and C-4. The designed compounds are suggested to show dual activity to combat the emerging Coronaviruses and associated substantial inflammations. All compounds were evaluated for their in vitro antiviral activity and cytotoxicity against SARS-CoV infected Vero cells. As well, the in vitro assay of all derivatives against the SARS-CoV Mpro target was performed. Results revealed the potential of three pyranopyrazoles (22, 27, and 31) to potently inhibit the viral main protease with IC50 values of 2.01, 1.83, and 4.60 µM respectively compared with 12.85 and 82.17 µM for GC-376 and lopinavir. Additionally, in vivo anti-inflammatory testing for the most active compound 27 proved its ability to reduce levels of two cytokines (TNF-α and IL-6). Molecular docking and dynamics simulation revealed consistent results with the in vitro enzymatic assay and indicated the stability of the putative complex of 27 with SARS-CoV-2 Mpro. The assessment of metabolic stability and physicochemical properties of 27 have also been conducted. This investigation identified a set of metabolically stable pyranopyrazoles as effective anti-SARS-CoV-2 Mpro and suppressors of host cell cytokine release. We believe that the new compounds deserve further chemical optimization and evaluation for COVID-19 treatment.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / COVID-19 Drug Treatment Type of study: Experimental Studies / Randomized controlled trials Limits: Animals / Humans Language: English Journal: Bioorg Chem Year: 2023 Document Type: Article Affiliation country: J.bioorg.2022.106255

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / COVID-19 Drug Treatment Type of study: Experimental Studies / Randomized controlled trials Limits: Animals / Humans Language: English Journal: Bioorg Chem Year: 2023 Document Type: Article Affiliation country: J.bioorg.2022.106255