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Resume. Aim. Glaucoma is a whole group of diseases caused by increased intraocular pressure (IOP), leading to atrophy of the optic nerve and irreversible blindness. Melatonin has a wide range of biological activity, including antioxidant and antiglaucoma, but its use is limited by insufficient stability and duration of action. To search for new, more effective antiglaucoma agents among derivatives of 3-arylidene-2-oxindole, melatonin analogues, a search for quinonoxidoreductase 2 (NQO2) inhibitors was performed, antioxidant activity was determined and the effect of active compounds on intraocular pressure was studied. Materials and methods. The study of inhibitory activity against NQO2 was evaluated kinetically using menadione and N-benzyl-dihydronicotinamide as substrate and co-substrate, respectively. Antiradical activity was studied for reducing superoxide-dependent luminescence in a reaction medium containing hemoglobin, luminol and hydrogen peroxide using the Infinite M200 PRO microplate reader (Tecan, Austria), as well as for free radical binding tests OH, ABTS and DPPH. Cytotoxicity assessment was carried out using a standard MTT test on MCF-7 and HepG2 line cells. Intraocular pressure in laboratory animals was measured using a contact veterinary tonometer Tonovet (Finland). Results. Derivatives of 3-arylidene-2-oxindole have demonstrated significant antioxidant activity. A number of NQO2 inhibitors have also been identified. The most active compound inhibits human NQO2 with an IC50 of 0,4 pM. The compound also showed antiradical activity, binding the superoxide anion to IC50 of 6,1 pM, superior to melatonin on both counts, and low cytotoxicity. With topical application of a 0,4% solution, the compound reduced the intraocular pressure of intact rats by (40,9 ± 6,4) %, while not having a systemic hypotensive effect. Conclusion. Derivatives of 3-arylidene-2-oxindole are promising for drug discovery for the treatment of eye diseases associated with increased intraocular pressure or oxidative stress, such as glaucoma, uveitis and diabetic retinopathy.

A series of 24-ethylcholest-4-ene-3,6-dione 2

A series of 24-ethylcholest-4-ene-3,6-dione 2E-arylidene-derivatives has been synthesized by a Claisen-Schmidt reaction from a natural phytosterol β-sitosterol with yields of 80–85%. The structure of the obtained compounds was confirmed by NMR spectroscopy, including two-dimensional correlation experiments. The synthesized compounds were evaluated for their in vitro cytotoxicity and α-glucosidase inhibitory activity. It was established that compound 3 with pyridin-3-ylmethylene moiety exhibited a selective cytotoxic effect against the U251 cancer cell line with 99.31% inhibition of cancer cell growth. Compounds with pyridin-4-ylmethylene 4 and furan-2-ylmethylene-5 fragments were the most active inhibitors of α-glucosidase with IC50 64.00 and 38.95 µM, being 3- and 5-times more active than acarbose. Binding mode to α-glucosidase and ADMET characteristics for the lead molecule 5 were proposed computationally. To sum up, an efficient approach to the derivatives with promising antidiabetic activity based on available natural product β-sitosterol is suggested.

Nonenzymatic glycosylation of lens proteins in diabetes mellitus is one of the pathogenetic mechanisms of cataract formation. According to the results of this study, aminoguanidine, which has anti-glycation activity, inhibits cataractogenesis in experimental diabetes. Laboratory animals with streptozotocin-induced diabetes mellitus treated with aminoguanidine showed less clouding in the lenses, and the content of advanced glycation end products, in particular, carboxymethyllysine, in the lenses was found to be reduced compared to the same parameters in animals from the control diabetic group.

The method of similarity to standards is used to calculate the spectrum of targeted hypoglycemic activities of a series of natural compounds of terpenoid and polyphenol classes. Some compounds are shown to be promising multitargeted hypoglycemic agents. Primary action targets are identified.

Several 5-aminouracil derivatives that have previously been shown to inhibit Mycobacterium tuberculosis growth at concentrations of 5–40 μg/mL are demonstrated to act also as noncompetitive non-nucleoside inhibitors of HIV-1 reverse transcriptase without causing toxicity in vitro (MT-4 cells) and ex vivo (human tonsillar tissue).