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

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.

Design, Synthesis and Pharmacological Evaluation of Novel C2,C3-Quinoxaline Derivatives as Promising Anxiolytic Agents.

A new series of quinoxaline derivatives, 2a-4b, were synthesized and their anxiolytic potential was evaluated in vivo using elevated plus maze (EPM), open field (OF) and light-dark box (LDB) techniques. According to the results of the EPM, four active compounds were found in 2a, 2b, 2c, 4b. Their anxiolytic properties were confirmed in terms of LDB and the most active was compound 2b. In the OF, only 2c had an influence on the locomotor activity of the rodents. Thus, the most promising substance was determined; this was 2b, which has the structure of 2-(2-{[3-(4-tert-butylphenyl)quinoxaline-2-yl]methyl}-4,5-dimethoxyphenyl)-N-methylethan-1-amine hydrochloride. The obtained data were analyzed with the pharmacophore feature prediction approach, which made it possible to compare the structures of the studied compounds with the reference drug diazepam, and to determine the contribution of pharmacophores to the manifestation of the activity under study. ADMET analysis was carried out for compound 2b and the acute oral toxicity of this substance was also tested in vivo. As a result of the study, a promising compound with a high anxiolytic effect and low level of toxicity 2b was found, which is of interest for further preclinical study of its properties.

Towards multi-target antidiabetic agents: In vitro and in vivo evaluation of 3,5-disubstituted indolin-2-one derivatives as novel α-glucosidase inhibitors.

Type 2 diabetes mellitus is a chronic progressive disease that usually requires polypharmacological treatment approaches. Previously we have described a series of 2-oxindole derivatives as GSK3ß inhibitors with in vivo antihyperglycemic activity. α-Glucosidase is another antidiabetic target that prevents postprandial hyperglycemia and corresponding hyperinsulinemic response. Herein we report a study of 3,5-disubstituted indolin-2-one derivatives as potent α-glucosidase inhibitors. These inhibitors were identified via efficient synthesis, in vitro screening, and biological evaluation. The most active compound 5f inhibits yeast α-glucosidase with IC50 of 6.78 µM and prevents postprandial hyperglycemia in rats after maltose and sucrose challenge at 5.0 mg/kg dose. Two lead glucosidase inhibitors, 5f and 5m, are also GSK3ß inhibitors with submicromolar potency. Hence, structure-activity studies elucidate foundation for development of dual GSK3ß/α-glucosidase inhibitors for treatment of type 2 diabetes.

Synthesis, in vitro and in vivo evaluation of 2-aryl-4H-chromene and 3-aryl-1H-benzo[f]chromene derivatives as novel α-glucosidase inhibitors.

Herein we report a study of novel arylchromene derivatives as analogs of naturally occurring flavonoids with prominent α-glucosidase inhibitory properties. Novel inhibitors were identified via simple stepwise in silico screening, efficient synthesis, and biological evaluation. It is shown that 2-aryl-4H-chromene core retains pharmacophore properties while being readily available synthetically. A lead compound identified through screening inhibits yeast α-glucosidase with IC50 of 62.26 µM and prevents postprandial hyperglycemia in rats at 2.2 mg/kg dose.