Ten Years Milestones in Xanthine Oxidase Inhibitors Discovery: Febuxostat-Based Inhibitors Trends, Bifunctional Derivatives, and Automatized Screening Assays

Abstract

Xanthine oxidase (XO) is an enzyme involved in the oxidative process of hypoxanthine and xanthine to uric acid (UA). This process also produces reactive oxygen species (ROS) as byproducts. Both UA and ROS are dangerous for human health, and some health conditions trigger upregulation of XO activity, which results in many diseases (cancer, atherosclerosis, hepatitis, gout, and others) given the worsened scenario of ROS and UA overproduction. So, XO became an attractive target to produce and discover novel selective drugs based on febuxostat, the most recent XO inhibitor out of only two approved by FDA. Under this context, high-performance liquid chromatography (HPLC) and capillary electrophoresis (CE) have been successfully applied to rapidly and easily screen for bioactive compounds, isolated or in complex natural matrixes, that act as enzyme inhibitors through the use of an immobilized enzyme reactor (IMER). This article’s goal is to present advances comprising febuxostat-based XO inhibitors as a new trend, bifunctional moieties capable of inhibiting XO and modulating ROS activity, and in-flow techniques employing an IMER in HPLC and CE to screen for synthetic and natural compounds that act as XO inhibitors.

Identification of Anastatica hierochuntica L. Methanolic Leaves Extract-Derived Metabolites Exhibiting Xanthine Oxidase Inhibitory Activities: In Vitro and in Silico Approaches

“…Other adverse side effects such as musculoskeletal symptoms, upper respiratory tract infections, and discrete liver and renal functions were documented in patients receiving synthetic XO inhibitors [14], which poses a restriction to the broad use of these inhibitors in patients. In addition, drug resistance, target enzyme mutations, pharmacokinetic properties, toxicity and off-targets due to selectivity and specificity failure remain as a major concern in the development of XO inhibitor [15]. Thus, there has been an emerging interest in the discovery and development of novel XO inhibitors having very fewer side effects for the treatment of gout and other diseases such as cancer [16].…”