Naphthoquinones and tricyclic derivatives: in vitro evaluation as xanthine oxidase inhibitors

Abstract

The enzyme, xanthine oxidase (XO), is a complex flavoprotein that catalyzes the sequential oxidation of hypoxanthine and xanthine to ultimately yield uric acid as the final steps in the catabolism of adenine nucleotides. In this process molecular oxygen is reduced to yield the superoxide anion radical and hydrogen peroxide. The overproduction of uric acid could lead to hyperuricemia and the deposition of urate crystals in joints and surrounding tissues. This condition is known as gout and is the most common cause of inflammatory arthritis. XO inhibitors are well-known treatment for the prevention of hyperuricemia and gout, and may find application in various other disease states that are associated with XO-induced production of reactive oxygen species. To discover new inhibitors of XO, the present study investigated 55 diverse compounds from an in-house library. The results showed that seven compounds inhibited bovine milk XO with IC₅₀ < 10 µM: juglone (IC₅₀ = 2.45 µM); menadione (IC₅₀ = 4.38 µM); benz(g)isoquinoline-5,10-dione (IC₅₀ = 2.07 µM); 2-chloro-7-methoxy-10H-phenothiazine (IC₅₀ = 2.17 µM); cinnabarinic acid (IC₅₀ = 3.41 µM); 9,10-phenanthrenequinone (IC₅₀ = 0.726 µM); quinalizarin (IC₅₀ = 8.54 µM). These potencies were comparable to that recorded for the reference inhibitor, chrysin (IC₅₀ = 13.6 µM). This study therefore discovered naphthoquinone and tricyclic derivatives as small molecule XO inhibitors for the development of treatments for hyperuricemia and other disorders that are associated with the overactivity of XO.