Natural and Semisynthetic Analogues of Manadoperoxide B Reveal New Structural Requirements for Trypanocidal Activity

Abstract

Chemical analysis of the Indonesian sponge Plakortis cfr. lita afforded two new analogues of the potent trypanocidal agent manadoperoxide B (1), namely 12-isomanadoperoxide B (2) and manadoperoxidic acid B (3). These compounds were isolated along with a new short chain dicarboxylate monoester (4), bearing some interesting relationships with the polyketide endoperoxides found in this sponge. Some semi-synthetic analogues of manadoperoxide B (6–8) were prepared and evaluated for antitrypanosomal activity and cytotoxicity. These studies revealed crucial structure–activity relationships that should be taken into account in the design of optimized and simplified endoperoxyketal trypanocidal agents.

Marine natural products

“…Both 591 and the likely oxidative breakdown product 592 showed potent antitrypanocidal activity against T. b. rhodesiense. 619 Six new methylated peroxidic acids 593-598 were isolated from Plakortis simplex (Keomun Is., West Sea, S. Korea). All showed low moderate cytotoxic activity against RAW264.7 cells.…”

Marine Pharmacology in 2012–2013: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis, and Antiviral Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action

“…Chianese and colleagues completed structure-activity relationship studies with several natural and semisynthetic manadoperoxide B analogues ( 85 , 86 ), isolated from the Indonesian sponge Plakortis sfr. lita , and determined that both were highly active towards the parasite T. brucei rhodesiense , highlighting the 1,2-dioxane ring to be a key pharmacophore [90]. …”

The Role of Natural Products in Drug Discovery and Development against Neglected Tropical Diseases

“…A recent example is the semisynthetic analogue 25 ( Figure 5 ), derived from a very potent peroxide manadoperoxide B ( 7 , Figure 5 , see also Figure 2 ) originally isolated from a marine sponge Plakortis cfr. Lita [ 62 , 91 ]. The semisynthetic analogue demonstrated marked trypanocidal activity against the blood stream forms of T. brucei rhodesiense in the submicromolar range (IC 50 = 0.43 μM) while displaying appreciable selectivity against the L6 cells derived from rat skeletal myoblasts (IC 50 = 33.82 μM) [ 91 ].…”