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

Abstract

Marine organisms represent almost half of total biodiversity and are a very important source of new bioactive substances. Within the varied biological activities found in marine products, their antimicrobial activity is one of the most relevant. Infectious diseases are responsible for high levels of morbidity and mortality and many antimicrobials lose their effectiveness with time due to the development of resistance. These facts justify the high importance of finding new, effective and safe anti-infective agents. Among the variety of biological activities of marine xanthone derivatives, one that must be highlighted is their anti-infective properties. In this work, a literature review of marine xanthones with anti-infective activity, namely antibacterial, antifungal, antiparasitic and antiviral, is presented. Their structures, biological activity, sources and the methods used for bioactivity evaluation are described. The xanthone derivatives are grouped in three sets: xanthones, hydroxanthones and glycosylated derivatives. Moreover, molecular descriptors, biophysico-chemical properties, and pharmacokinetic parameters were calculated, and the chemical space occupied by marine xanthone derivatives is recognized. The chemical space was compared with marketed drugs and framed accordingly to the drug-likeness concept in order to profile the pharmacokinetic of anti-infective marine xanthone derivatives.

Keywords: ADME; antimicrobial; marine; physicochemical properties; xanthones.

Figure 1

Xanthone Scaffold.

Figure 2

Structures of xanthone derivatives with anti-infective activity.

Figure 3

Structures of hydroxanthones, glycosylated and other derivatives with anti-infective activity.

Figure 4

Mean (bar) and median (diamond) values of MW (a), stereogenic centers (b), PSA (c), HBA (d), HBD (e), rotatable bond (f) for marine xanthone derivatives (blue), hydroxanthone derivatives (orange), glycosylated derivatives (yellow), marketed drug types accordingly to its origin (greys).

Figure 5

PSA values of the marine xanthone derivatives vs molecular weight (MW).

Figure 6

(a) Mean (bars) and median (diamonds) log P values of each category of marine xanthone derivatives calculated by different methods. (b) Difference between log P and log D_7.4 calculated using ACDlabs.

Figure 7

(a) Log S (SILICOS-IT) of the marine xanthone derivatives vs molecular weight. (b) Log S (SILICOS-IT) of the marine xanthone derivatives vs Log P (SILICOS-IT).

Figure 8

Colormap of the compliance with rules of drug-likeness: L—Lipinski, G—Ghose, V—Veber, E—Egan, M—Muegge. Xanthone derivatives (ID: 1–19, 37–47, 49–52) are represented on the upper quadrant, hydroxanthone derivatives (ID: 20–31, 48, 53) on the lower left and glycosylated derivatives (ID: 32–36) on the middle. Green means ≤100% of compliance, yellow means ≤75% of compliance, orange means ≤50% of compliance, and red means ≤25% of compliance.

Figure 9

(a) GI absorption for the identified marine xanthone derivatives (left pie chart). Marine xanthone derivatives with high GI absorption were classified accordingly to its category (upper pie chart) and as P-gp substrate (lower pie chart). (b) BBB permeability of the identified xanthone derivatives. (c) Cumulative percentage of compounds identified as inhibitors of the five major isoforms of CYP450.

Figure 10

Polar plot of the marine xanthone chemical space. For each category, mean of RB (flexibility), mean of MW (size), mean of log P SILICOS-IT (lipophilicity), mean of PSA (Polarity), mean of log S SILICOS-IT (solubility), and mean Fsp³ (unsaturation) plotted in polar coordinates. Green colored zone: 0 < RB < 9; 150 < MW < 500; 0 < log P < 5; 20 < PSA < 130; -5 < log S < 0; 1 > Fsp³ > 0.25.