Phenylpyrazolone-1,2,3-triazole Hybrids as Potent Antiviral Agents with Promising SARS-CoV-2 Main Protease Inhibition Potential

Arafa Musa; Hamada S Abulkhair; Ateyatallah Aljuhani; Nadjet Rezki; Mohamed A Abdelgawad; Khaled Shalaby; Ahmed H El-Ghorab; Mohamed R Aouad

doi:10.3390/ph16030463

Phenylpyrazolone-1,2,3-triazole Hybrids as Potent Antiviral Agents with Promising SARS-CoV-2 Main Protease Inhibition Potential

Pharmaceuticals (Basel). 2023 Mar 20;16(3):463. doi: 10.3390/ph16030463.

Authors

Arafa Musa¹, Hamada S Abulkhair^{2

3}, Ateyatallah Aljuhani⁴, Nadjet Rezki⁴, Mohamed A Abdelgawad⁵, Khaled Shalaby⁶, Ahmed H El-Ghorab⁷, Mohamed R Aouad⁴

Affiliations

¹ Department of Pharmacognosy, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia.
² Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo 11884, Egypt.
³ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Horus University-Egypt, International Coastal Road, New Damietta 34518, Egypt.
⁴ Chemistry Department, College of Sciences, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia.
⁵ Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia.
⁶ Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia.
⁷ Department of Chemistry, College of Science, Jouf University, Sakaka 72341, Saudi Arabia.

Abstract

COVID-19 infection is now considered one of the leading causes of human death. As an attempt towards the discovery of novel medications for the COVID-19 pandemic, nineteen novel compounds containing 1,2,3-triazole side chains linked to phenylpyrazolone scaffold and terminal lipophilic aryl parts with prominent substituent functionalities were designed and synthesized via a click reaction based on our previous work. The novel compounds were assessed using an in vitro effect on the growth of SARS-CoV-2 virus-infested Vero cells with different compound concentrations: 1 and 10 μM. The data revealed that most of these derivatives showed potent cellular anti-COVID-19 activity and inhibited viral replication by more than 50% with no or weak cytotoxic effect on harboring cells. In addition, in vitro assay employing the SARS-CoV-2-Main protease inhibition assay was done to test the inhibitors' ability to block the common primary protease of the SARS-CoV-2 virus as a mode of action. The obtained results show that the one non-linker analog 6h and two amide-based linkers 6i and 6q were the most active compounds with IC₅₀ values of 5.08, 3.16, and 7.55 μM, respectively, against the viral protease in comparison to data of the selective antiviral agent GC-376. Molecular modeling studies were done for compound placement within the binding pocket of protease which reveal conserved residues hydrogen bonding and non-hydrogen interactions of 6i analog fragments: triazole scaffold, aryl part, and linker. Moreover, the stability of compounds and their interactions with the target pocket were also studied and analyzed by molecular dynamic simulations. The physicochemical and toxicity profiles were predicted, and the results show that compounds behave as an antiviral activity with low or no cellular or organ toxicity. All research results point to the potential usage of new chemotype potent derivatives as promising leads to be explored in vivo that might open the door to rational drug development of SARS-CoV-2 Main protease potent medicines.

Keywords: 1,2,3-triazole; SARS-CoV-2; antiviral activity; click chemistry; molecular dynamics simulation; molecular modeling; pyrazolone.

Grants and funding

DSR2022-RG-0151/Al Jouf University