tetano
Editor, Senior Moderator
Bioorg Chem
. 2024 Apr 8:147:107353.
doi: 10.1016/j.bioorg.2024.107353. Online ahead of print. Design, synthesis, docking, and antiviral evaluation of some novel pyrimidinone-based α-aminophosphonates as potent H1N1 and HCoV-229E inhibitors
Hend A Hekal[SUP] 1 [/SUP], Omar M Hammad[SUP] 2 [/SUP], Nasser R El-Brollosy[SUP] 3 [/SUP], Maha M Salem[SUP] 4 [/SUP], Abdou K Allayeh[SUP] 5 [/SUP]
Affiliations
Dialkyl/aryl aminophosphonates, 3a-g and 4a-e were synthesized using the LiClO[SUB]4[/SUB] catalyzed Kabachnic Fields-type reaction straightforwardly and efficiently. The synthesized phosphonates structures were characterized using elemental analyses, FT-IR, [SUP]1[/SUP]H NMR, [SUP]13[/SUP]C NMR, and MS spectroscopy. The new compounds were subjected to in-silico molecular docking simulations to evaluate their potential inhibition against Influenza A Neuraminidase and RNA-dependent RNA polymerase of human coronavirus 229E. Subsequently, the compounds were further tested in vitro using a cytopathic inhibition assay to assess their antiviral activity against both human Influenza (H1N1) and human coronavirus (HCoV-229E). Diphenyl ((2-(5-cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl) hydrazinyl) (furan-2-yl) methyl) phosphonate (3f) and diethyl ((2-(5-cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl) hydrazinyl) (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) methyl) phosphonate (4e) were demonstrated direct inhibition activity against Influenza A Neuraminidase and RNA-dependent RNA polymerase. This was supported by their highly favorable binding energies in-silico, with top-ranked values of -12.5 kcal/mol and -14.2 kcal/mol for compound (3f), and -13.5 kcal/mol and -9.89 kcal/mol for compound (4e). Moreover, they also displayed notable antiviral efficacy in vitro against both viruses. These compounds demonstrated significant antiviral activity, as evidenced by selectivity indices (SI) of 101.7 and 51.8, respectively against H1N1, and 24.5 and 5.1 against HCoV-229E, respectively.
Keywords: Antiviral activity; Coronavirus; Influenza; Molecular Docking; Pyrimidinones; α-Aminophosphonates.
. 2024 Apr 8:147:107353.
doi: 10.1016/j.bioorg.2024.107353. Online ahead of print. Design, synthesis, docking, and antiviral evaluation of some novel pyrimidinone-based α-aminophosphonates as potent H1N1 and HCoV-229E inhibitors
Hend A Hekal[SUP] 1 [/SUP], Omar M Hammad[SUP] 2 [/SUP], Nasser R El-Brollosy[SUP] 3 [/SUP], Maha M Salem[SUP] 4 [/SUP], Abdou K Allayeh[SUP] 5 [/SUP]
Affiliations
- PMID: 38615475
- DOI: 10.1016/j.bioorg.2024.107353
Dialkyl/aryl aminophosphonates, 3a-g and 4a-e were synthesized using the LiClO[SUB]4[/SUB] catalyzed Kabachnic Fields-type reaction straightforwardly and efficiently. The synthesized phosphonates structures were characterized using elemental analyses, FT-IR, [SUP]1[/SUP]H NMR, [SUP]13[/SUP]C NMR, and MS spectroscopy. The new compounds were subjected to in-silico molecular docking simulations to evaluate their potential inhibition against Influenza A Neuraminidase and RNA-dependent RNA polymerase of human coronavirus 229E. Subsequently, the compounds were further tested in vitro using a cytopathic inhibition assay to assess their antiviral activity against both human Influenza (H1N1) and human coronavirus (HCoV-229E). Diphenyl ((2-(5-cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl) hydrazinyl) (furan-2-yl) methyl) phosphonate (3f) and diethyl ((2-(5-cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl) hydrazinyl) (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) methyl) phosphonate (4e) were demonstrated direct inhibition activity against Influenza A Neuraminidase and RNA-dependent RNA polymerase. This was supported by their highly favorable binding energies in-silico, with top-ranked values of -12.5 kcal/mol and -14.2 kcal/mol for compound (3f), and -13.5 kcal/mol and -9.89 kcal/mol for compound (4e). Moreover, they also displayed notable antiviral efficacy in vitro against both viruses. These compounds demonstrated significant antiviral activity, as evidenced by selectivity indices (SI) of 101.7 and 51.8, respectively against H1N1, and 24.5 and 5.1 against HCoV-229E, respectively.
Keywords: Antiviral activity; Coronavirus; Influenza; Molecular Docking; Pyrimidinones; α-Aminophosphonates.