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

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.

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