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

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.

Introducing the antibacterial and photocatalytic degradation potentials of biosynthesized chitosan, chitosan-ZnO, and chitosan-ZnO/PVP nanoparticles

“…The FTIR spectrum of PVP showed a band below cm -1 , which is attributed to the amidic C=O stretching of the pyrrolidone ring [39][40][41]. The interaction between ZnO molecules and chitosan and PVP functional groups was investigated by means of Fourier transform infrared spectroscopy.…”

CuFe2O4 Magnetic Nanoparticles as Heterogeneous Catalysts for Synthesis of Dihydropyrimidinones as Inhibitors of SARS-CoV-2 Surface Proteins—Insights from Molecular Docking Studies

“…Among these, nitrogen-containing heterocycles have emerged as particularly promising antivirals against coronaviruses, demonstrating their efficacy through the specific targeting of the primary protease of the virus (the main protease). The ability of these nitrogenous heterocycles to establish essential hydrogen bonds with specific biological targets makes them valuable candidates for drug development [39].…”

“…Based on a comprehensive literature review [37][38][39][40]54], proteins that play a crucial role in the pathogenesis of SARS-CoV-2 were selected as molecular targets. The crystal structures of the COVID-19 main protease (PDB: 6LU7) at a resolution of 2.16 Å, pre-fusion spike glycoprotein with a single receptor-binding domain (PDB: 6VSB) at a resolution of 3.46 Å, and the papain-like protease of SARS-CoV-2 (PDB: 6W9C) at a resolution of 2.7 Å were obtained from the Protein Data Bank and analyzed.…”

Exploring of N-phthalimide-linked 1,2,3-triazole analogues with promising ­anti-SARS-CoV-2 activity: synthesis, biological screening, and molecular modelling studies

“…Our previous investigation introduced efficient anti-SARS-CoV-2 analogues of molecular hybrids of rigid terminal scaffold bonded through heterocyclic basic triazole ring and ended with lipophilic-substituted fragments ( Figure 2 ) 46 . Chemically, this compound and its congeners composed of phenylpyrazolone scaffold connected to lipophilic aryl moiety (4-acetamidobenzoic acid for active derivative) through 1,2,3-triazole linker.…”