Drug-like Properties and ADME of Xanthone Derivatives: The Antechamber of Clinical Trials

Abstract

Xanthone derivatives have been described as compounds with a privileged scaffold exhibiting diverse biological/pharmacological activities, what directed the interest to pursue the development of these derivatives into drug candidates. Nevertheless, to achieve this purpose it is crucial to study their pharmacokinetics and toxicity (PK/tox) properties as decision endpoints to continue or interrupt the development investment. This review aims to expose the most relevant analytical methods used in the physicochemical and PK/tox studies in order to detect, quantify, and identify different bioactive xanthones. Analyzing the main results from in vitro and in vivo systems towards ADME properties such as solubility, lipophilicity, pKa, chemical and metabolic stability, permeability, transporters modulation, and plasma protein binding, it is possible to uncover some threats governing the PK properties and to understand the bioavailability and drugability of xanthone derivatives. The last section of this review focuses on a case-study of the development of the drug candidate DMXAA, which has reached clinical trials, to provide the paths and the importance of PK/tox parameters of this scaffold. The data assembled in this review intends to guide for tackling issues in the design of potential lead compounds and drug candidates with a xanthone scaffold.

Chemical and Biological Research on Herbal Medicines Rich in Xanthones

“…As a class of secondary metabolites obtained from a number of herbal medicines, xanthones are playing more and more important roles in new drug research and development. The pharmacokinetics and toxicity (PK/tox) properties of xanthones, as part of the most crucial preclinical studies, have proved that xanthones are promising drug candidates owing to their high efficacy and low toxicity [ 186 , 187 ].…”

Chiral Derivatives of Xanthones with Antimicrobial Activity

“…Xanthones (9 H -xanthen-9-one) comprise a family of O -heterocycle symmetrical compounds with a dibenzo-γ-pyrone scaffold (Figure 1). The interest of this structure in drug development comes from the wide range of different substitutions that can generate a diverse library of compounds able to modulate several biological responses, and as such, is a privileged structure for drug development [6,7,8].…”

Structures, Activities and Drug-Likeness of Anti-Infective Xanthone Derivatives Isolated from the Marine Environment: A Review

“…Our group have been devoting special attention to xanthone derivatives, namely to their synthesis, PK behavior and biological activities [34,35,36]. Considering the anti-infective activity, several xanthone derivatives have been isolated from distinct natural sources [37,38,39,40,41,42].…”