Discovery of Novel 2‐Oxindoles as Compounds with Antiglaucoma Activity

Oxindole‐based natural indoles analogues retain the rigidity and size of the original indole ring system whilst introducing more 3‐dimensionality and potential increased water solubility. We report the first preparation of a diverse series of new melatonin analogues 4, 6, 11, 12 based on 3‐hydroxy‐2‐oxindoles (11) and hydroxy‐free 2‐oxindoles (4, 6, 12) and evaluated their ability to reduce intraocular pressure as well as their neuroprotective and antioxidant properties. Reductive amination was used to obtain new 5‐(benzylamino)‐substituted (indolin‐3‐yl)acetonitriles 11 and (indolin‐3‐yl)acetic acids 12 with high yields. Compounds 4 a, c, 6 a and 11 a, d, h, j–l demonstrated IOP reduction effect in range 15–27 % similar to the effect of reference compounds melatonin and timolol (12 % and 18 % reduction, respectively). 5‐(Benzylamino)‐substituted 3‐hydroxy‐2‐oxindoles 11, unlike compounds 4, 6, inhibited lipid peroxidation in range 2.075–13.012 μM. Inhibition of NQO2 associated with antioxidant properties of melatonin was also evaluated for synthesized compounds and it was found that compound 11 h showed the best NQO2 inhibitory activity with an IC₅₀=39 μM (vs. melatonin IC₅₀=64 μM). All synthesized compounds 4, 6, 11, 12 at a concentration of 30 μM do not possess the mitochondrial toxicity. Moreover, no disruption of tubulin polymerization was observed even in the presence of 100 μM of the compounds. Thus, 3‐hydroxy‐2‐oxindole derivatives 11 can be used for drug design of first‐in‐class antiglaucoma drugs with antioxidant and neuroprotective properties.