Spiroindole-containing compounds bearing phosphonate group of potential Mpro-SARS-CoV-2 inhibitory properties
- Eur J Med Chem. 2023 Oct 5;258:115563. doi: 10.1016/j.ejmech.2023.115563.
- 1. Department of Pesticide Chemistry, National Research Centre, Dokki, Giza, 12622, Egypt.
- 2. Department of Chemistry and Physics, Augusta University, Augusta, GA, 30912, USA.
- 3. School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, UK.
- 4. Center of Scientific Excellence for Influenza Viruses, National Research Centre, Giza, 12622, Egypt.
- 5. Department of Pesticide Chemistry, National Research Centre, Dokki, Giza, 12622, Egypt. Electronic address: [email protected].
Microwave-assisted reaction of 3,5-bis((E)-ylidene)-1-phosphonate-4-piperidones 3a‒g with azomethine ylide (produced through interaction of isatins 4 and sarcosine 5) cycloaddition afforded the corresponding (dispiro[indoline-3,2'-pyrrolidine-3',3″-piperidin]-1″-yl)phosphonates 6a‒l in excellent yields (80-95%). Structure of the synthesized agents was evidenced by single crystal X-ray studies of 6d, 6i and 6l. Some of the synthesized agents revealed promising anti-SARS-CoV-2 properties in the viral infected Vero-E6 cell technique with noticeable selectivity indices. Compounds 6g and 6b are the most promising agents synthesized (R = 4-BrC6H4, Ph; R' = H, Cl, respectively) with considerable selectivity index values. Mpro-SARS-CoV-2 inhibitory properties supported the anti-SARS-CoV-2 observations of the potent analogs synthesized. Molecular docking studies (PDB ID: 7C8U) are consistent with the Mpro inhibitory properties. The presumed mode of action was supported by both experimentally investigated Mpro-SARS-CoV-2 inhibitory properties and explained by docking observations.
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