3-ARILIDENE-2-OXYNDOLE DERIVATIVESAS MELATONIN ANALOGUES WITH ANTIOXIDANT AND INTRAOCULAR PRESSURE LOWERING PROPERTIES

Abstract

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 assubstrate and co-substrate, respectively. Antiradical activity was studied for reducing superoxide-dependentluminescence 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 contactveterinary 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 IC50of 0,4 μM. The compound also showed anti-radical activity, binding the superoxide anion to IC50of 6,1 μM, 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 associatedwith increased intraocular pressure or oxidative stress, such as glaucoma, uveitis and diabetic retinopathy.