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

Nehmedo G. Fawazy; Siva S. Panda; Ahmed Mostafa; Benson M. Kariuki; Mohamed S. Bekheit; Yassmin Moatasim; Omnia Kutkat; Walid Fayad; May A. El-Manawaty; Ahmed A.F. Soliman; Riham A. El-Shiekh; Aladdin M. Srour; Reham F. Barghash; Adel S. Girgis

doi:10.1038/s41598-022-17883-9

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

Nehmedo G. Fawazy, Siva S. Panda, Ahmed Mostafa, Benson M. Kariuki, Mohamed S. Bekheit, Yassmin Moatasim, Omnia Kutkat, Walid Fayad, May A. El-Manawaty, Ahmed A.F. Soliman, Riham A. El-Shiekh, Aladdin M. Srour, Reham F. Barghash, Adel S. Girgis

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Abstract

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.

Original language	English (US)
Article number	13880
Journal	Scientific reports
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41598-022-17883-9
State	Published - Dec 2022

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Fawazy, N. G., Panda, S. S., Mostafa, A., Kariuki, B. M., Bekheit, M. S., Moatasim, Y., Kutkat, O., Fayad, W., El-Manawaty, M. A., Soliman, A. A. F., El-Shiekh, R. A., Srour, A. M., Barghash, R. F., & Girgis, A. S. (2022). Development of spiro-3-indolin-2-one containing compounds of antiproliferative and anti-SARS-CoV-2 properties. Scientific reports, 12(1), Article 13880. https://doi.org/10.1038/s41598-022-17883-9

Fawazy, NG, Panda, SS, Mostafa, A, Kariuki, BM, Bekheit, MS, Moatasim, Y, Kutkat, O, Fayad, W, El-Manawaty, MA, Soliman, AAF, El-Shiekh, RA, Srour, AM, Barghash, RF & Girgis, AS 2022, 'Development of spiro-3-indolin-2-one containing compounds of antiproliferative and anti-SARS-CoV-2 properties', Scientific reports, vol. 12, no. 1, 13880. https://doi.org/10.1038/s41598-022-17883-9

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title = "Development of spiro-3-indolin-2-one containing compounds of antiproliferative and anti-SARS-CoV-2 properties",

abstract = "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.",

author = "Fawazy, {Nehmedo G.} and Panda, {Siva S.} and Ahmed Mostafa and Kariuki, {Benson M.} and Bekheit, {Mohamed S.} and Yassmin Moatasim and Omnia Kutkat and Walid Fayad and El-Manawaty, {May A.} and Soliman, {Ahmed A.F.} and El-Shiekh, {Riham A.} and Srour, {Aladdin M.} and Barghash, {Reham F.} and Girgis, {Adel S.}",

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year = "2022",

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doi = "10.1038/s41598-022-17883-9",

language = "English (US)",

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AU - Fawazy, Nehmedo G.

AU - Panda, Siva S.

AU - Mostafa, Ahmed

AU - Kariuki, Benson M.

AU - Bekheit, Mohamed S.

AU - Moatasim, Yassmin

AU - Kutkat, Omnia

AU - Fayad, Walid

AU - El-Manawaty, May A.

AU - Soliman, Ahmed A.F.

AU - El-Shiekh, Riham A.

AU - Srour, Aladdin M.

AU - Barghash, Reham F.

AU - Girgis, Adel S.

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

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ER -

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

Abstract

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