Development of spiro-3-indolin-2-one containing compounds of antiproliferative and anti-SARS-CoV-2 properties.

A series of 1″-(alkylsulfonyl)-dispiro[indoline-3,2'-pyrrolidine-3',3″-piperidine]-2,4″-diones 6a‒o has been synthesized through regioselective multi-component azomethine dipolar cycloaddition reaction of 1-(alkylsulfonyl)-3,5-bis(ylidene)-piperidin-4-ones 3a‒h. X-ray diffraction studies (6b‒d,h) confirmed the structures. The majority of the synthesized analogs reveal promising antiproliferation properties against a variety of human cancer cell lines (MCF7, HCT116, A431 and PaCa2) with good selectivity index towards normal cell (RPE1). Some of the synthesized agents exhibit potent inhibitory properties against the tested cell lines with higher efficacies than the standard references (sunitinib and 5-fluorouracil). Compound 6m is the most potent. Multi-targeted inhibitory properties against EGFR and VEGFR-2 have been observed for the synthesized agents. Flow cytometry supports the antiproliferation properties and shows the tested agents as apoptosis and necrosis forming. Vero cell viral infection model demonstrates the anti-SARS-CoV-2 properties of the synthesized agents. Compound 6f is the most promising (about 3.3 and 4.8 times the potency of the standard references, chloroquine and hydroxychloroquine). QSAR models explain and support the observed biological properties.

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 multi-targeted 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.