Spiroindole-containing compounds bearing phosphonate group of potential Mpro-SARS-CoV-2 inhibitory properties

Mohamed S Bekheit; Siva S Panda; Benson M Kariuki; Sara H Mahmoud; Ahmed Mostafa; Adel S Girgis

doi:10.1016/j.ejmech.2023.115563

Spiroindole-containing compounds bearing phosphonate group of potential M^pro-SARS-CoV-2 inhibitory properties

Eur J Med Chem. 2023 Oct 5:258:115563. doi: 10.1016/j.ejmech.2023.115563. Epub 2023 Jun 10.

Authors

Mohamed S Bekheit¹, Siva S Panda², Benson M Kariuki³, Sara H Mahmoud⁴, Ahmed Mostafa⁴, Adel S Girgis⁵

Affiliations

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: girgisas10@yahoo.com.

Abstract

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. M^pro-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 M^pro inhibitory properties. The presumed mode of action was supported by both experimentally investigated M^pro-SARS-CoV-2 inhibitory properties and explained by docking observations.

Keywords: Azomethine ylide; COVID-19; Phosphonate; SARS-CoV-2; Spiroindole.

MeSH terms

Animals
Antiviral Agents / chemistry
Antiviral Agents / pharmacology
COVID-19*
Chlorocebus aethiops
Molecular Docking Simulation
Molecular Dynamics Simulation
Protease Inhibitors / chemistry
SARS-CoV-2*
Vero Cells

Substances

Antiviral Agents
Protease Inhibitors