Marine endoperoxides as antimalarial lead compounds

Abstract

Malaria, a pathology caused by protozoa belonging to the genus Plasmodium, is one of the major threats to global health, with about 300-500 million new clinical cases occurring every year and 1-3 million annual deaths. The recrudescence in the number of fatal cases registered in recent years can be attributed to the diffusion of multi-drug resistant strains of Plasmodium, which make less effective the limited armamentarium of available drugs. Living organisms are a recognized source of potentially bioactive molecules and, among them, marine natural products are emerging as one of the most interesting sources to be exploited for the discovery of new antimalarial compounds. In this article we will report results obtained for a single class of marine metabolites, namely endoperoxide-containing derivatives. Many of these molecules possess a simple six-membered 1,2-dioxygenated ring bearing two or three alkyl/aryl groups of different complexity. They can be divided according to the group linked at one of the two endoperoxide-oxygen bearing carbons: peroxyketal derivatives (methoxy group) or non-peroxyketal derivatives (methyl/ethyl groups). Molecules belonging to these classes show in vitro antimalarial activity in the nanomolar range on chloroquine-resistant strains. A number of investigations gave insights into the mechanism of action of these molecules, suggesting structural changes to optimize their antimalarial activity

Structural diversity and chemical synthesis of peroxide and peroxide-derived polyketide metabolites from marine sponges

“…Since the discovery of 1 and 2, a suite of related metabolites have been isolated from marine sponges. These include plakorin (3), 4 xestins A (4), B (5), 5 manadoperoxides A-C, D (6), E-K, [15][16][17] manadodioxans A-E, 18 haterumadioxins A (7), B (8), 19 plakortenone (9), 20 plakortides E-O, P (10), Q-U, Z, AA, [20][21][22][23][24][25][26][27][28][29][30][31][32] plakorstatin 1 and 2 (11), 33 monotriajaponides B, C, D (12), 34 plakinic acids A (13), B-P, 32,[35][36][37][38][39][40][41][42][43] plakortolides A-O, P (14), Q-W, [40][41][42][43][44][45][46][47][48] plakortoperoxides A1 (15), A2 (16), B-D, 48…”

“…6,7,13,[51][52][53][54][55][56][57][58][59][60][61][62] Following global interest in antimalarial peroxide natural products such as artemisinin, 63,64 compounds in this class are routinely screened for in vitro activity against strains of Plasmodia (Section 5.1). 11,12,65,66 Testing for cytotoxic action against cancer cell types is also commonplace (Section 5.2). [8][9][10] Despite many encouraging results, the availability of marine endoperoxides is usually very poor and methods for their chemical synthesis are still in development.…”

“…A number of review articles on this topic have appeared in recent years. Most have focused on structural determination and biological analyses of marine endoperoxides; [6][7][8][9][10][11][12][13] and one, from 2004 focused on methods developed for their chemical synthesis. 14 However, none have detailed the complex biosynthetic interrelationships of these compounds beyond enzymatic polyketide synthesis.…”

Analysis of In Vivo Existence Forms of Nardosinone in Mice by UHPLC-Q-TOF-MS Technique

“…Natural peroxides have multiple biological activities and are one of the important natural product types. For example, a large number of chemical components, such as polyketones with six-membered or five-membered peroxide rings, have been found in sponges [ 19 , 20 , 21 ], and the great majority of components have pharmacological effects such as anticancer, antibacterial, and antimalarial [ 21 ]; two diterpenoids with seven-membered peroxy rings were found in rhizomes of Hedychium coronarium [ 22 ]; a peroxydimer monoterpene was isolated from Amomum cardamomum , which has powerful antimalarial activity [ 23 ]. Furthermore, there were also a large number of studies on sesquiterpene peroxides, such as artemisinin compounds (artemisinin, dihydroartemisinin, and artemether).…”

Marine natural products

“…34 A review of marine endoperoxides as antimalarial lead compounds has been published. 35 The structure of untenolide A 14, isolated from an Okinawan marine sponge of the genus Plakortis, was established by X-ray analysis. 36 The authors propose that the pentacyclic skeleton of untenolide A 14 is formed by cyclisation of two units of the diketo-fatty acid 15.…”