3-Alkenyl-2-oxindoles: Synthesis, antiproliferative and antiviral properties against SARS-CoV-2

Sets of 3-alkenyl-2-oxindoles (6,10,13) were synthesized in a facile synthetic pathway through acid dehydration (EtOH/HCl) of the corresponding 3-hydroxy-2-oxoindolines (5,9,12). Single crystal (10a,c) and powder (12a,26f) X-ray studies supported the structures. Compounds 6c and 10b are the most effective agents synthesized (about 3.4, 3.3 folds, respectively) against PaCa2 (pancreatic) cancer cell line relative to the standard reference used (Sunitinib). Additionally, compound 10b reveals antiproliferative properties against MCF7 (breast) cancer cell with IC50 close to that of Sunitinib. CAM testing reveals that compounds 6 and 10 demonstrated qualitative and quantitative decreases in blood vessel count and diameter with efficacy comparable to that of Sunitinib, supporting their anti-angiogenic properties. Kinase inhibitory properties support their multitargeted inhibitory activities against VEGFR-2 and c-kit in similar behavior to that of Sunitinib. Cell cycle analysis studies utilizing MCF7 exhibit that compound 6b arrests the cell cycle at G1/S phase while, 10b reveals accumulation of the tested cell at S phase. Compounds 6a and 10b reveal potent antiviral properties against SARS-CoV-2 with high selectivity index relative to the standards (hydroxychloroquine, chloroquine). Safe profile of the potent synthesized agents, against normal cells (VERO-E6, RPE1), support the possible development of better hits based on the attained observations.

Automated summary

Sets of 3-alkenyl-2-oxindoles were synthesized through acid dehydration of the corresponding 3-hydroxy-2-oxoindolines. Compounds 6c and 10b showed effective inhibition against pancreatic cancer cells and potential antiviral properties against SARS-CoV-2, with compound 10b also exhibiting antiproliferative properties against breast cancer cells. The compounds also demonstrated anti-angiogenic properties and multitargeted inhibitory activities against VEGFR-2 and c-kit, supporting their potential as therapeutic agents.