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. 2022 Aug 16;12(1):13880.
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  1 , Siva S Panda  2 , Ahmed Mostafa  3 , Benson M Kariuki  4 , Mohamed S Bekheit  1 , Yassmin Moatasim  3 , Omnia Kutkat  3 , Walid Fayad  5 , May A El-Manawaty  5 , Ahmed A F Soliman  5 , Riham A El-Shiekh  6 , Aladdin M Srour  7 , Reham F Barghash  1 , Adel S Girgis  8
Affiliations

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

Nehmedo G Fawazy et al. Sci Rep. .

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Natural spiro-indole containing compounds.
Figure 2
Figure 2
Approved antitumor sulfonamide-containing drugs.
Figure 3
Figure 3
Drugs for treatment of COVID-19.
Figure 4
Figure 4
Synthesis of the targeted compounds 6a‒o.
Figure 5
Figure 5
The molecular structures of (a) 6b, (b) 6c (c) 6d and (d) 6h.
Figure 6
Figure 6
Cell cycle analysis of compounds 6l, 6m and control experiment for MCF7 (breast cancer cell line).
Figure 7
Figure 7
% DNA content of compounds 6l, 6m and control experiment for MCF7 (breast cancer cell line) at G0-G1, S and G2/M phases through PI-FC cell cycle studies.
Figure 8
Figure 8
% Apoptosis and necrosis of compounds 6l, 6m and control experiment for MCF7 (breast cancer cell line).
Figure 9
Figure 9
Dose–response curves for the synthesized agents against SARS-CoV-2.
See this image and copyright information in PMC

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