3-Arylidene-2-oxindoles as Potent NRH:Quinone Oxidoreductase 2 Inhibitors

Abstract

The enzyme NRH:quinone oxidoreductase 2 (NQO2) plays an important role in the pathogenesis of various diseases such as neurodegenerative disorders, malaria, glaucoma, COVID-19 and cancer. NQO2 expression is known to be increased in some cancer cell lines. Since 3-arylidene-2-oxindoles are widely used in the design of new anticancer drugs, such as kinase inhibitors, it was interesting to study whether such structures have additional activity towards NQO2. Herein, we report the synthesis and study of 3-arylidene-2-oxindoles as novel NRH:quinone oxidoreductase inhibitors. It was demonstrated that oxindoles with 6-membered aryls in the arylidene moiety were obtained predominantly as E-isomers while for some 5-membered aryls, the Z-isomers prevailed. The most active compounds inhibited NQO2 with an IC50 of 0.368 µM. The presence of a double bond in the oxindoles was crucial for NQO2 inhibition activity. There was no correlation between NQO2 inhibition activity of the synthesized compounds and their cytotoxic effect on the A549 cell line.

3-Arylidene-2-oxindoles as GSK3β inhibitors and anti-thrombotic agents

“…Studied 2-oxindole derivatives were obtained from the Department of Chemistry of Moscow State University. Synthesis and characterization data were described previously 16 , 24 , 25 .…”

Polymorphisms and Pharmacogenomics of NQO2: The Past and the Future

“…This is in strong contrast to the emerging evidence suggesting that plenty of known drugs interact with NQO2. In fact, the literature is full of examples of drugs and compounds that have been found to work as NQO2 inhibitors including imatinib and other ABL kinase inhibitors [105], imiquimod [106], chloroquine and hydroxychloroquine [107], imidazole derivatives and other cancer drug candidates [108][109][110][111]. Many drugs or their quinone metabolites are known NQO2 substrates such as mitomycin, tretazicar and other anti-cancer drugs [40], paracetamol, clozapine, carbamazepine and others [47].…”