In Vivo Antimalarial Activity of the Beta-Carboline Alkaloid Manzamine A

Abstract

Manzamine A, a ␤-carboline alkaloid present in several marine sponge species, inhibits the growth of the rodent malaria parasite Plasmodium berghei in vivo. More than 90% of the asexual erythrocytic stages of P. berghei were inhibited after a single intraperitoneal injection of manzamine A into infected mice. A remarkable aspect of manzamine A treatment is its ability to prolong the survival of highly parasitemic mice, with 40% recovery 60 days after a single injection. Oral administration of an oil suspension of manzamine A also produced significant reductions in parasitemia. The plasma manzamine A concentration peaked 4 h after injection and remained high even at 48 h. Morphological changes of P. berghei were observed 1 h after treatment of infected mice. (؊)-8-Hydroxymanzamine A also displayed antimalarial activity, whereas manzamine F, a ketone analog of manzamine A, did not. Our results suggest that manzamine A and (؊)-8-hydroxymanzamine A are promising new antimalarial agents.Malaria remains the most devastating infectious parasitic disease, inflicting both death and economic losses on at least half the world's population. Numerous attempts have been made to control the disease by using vector control measures and/or chemoprophylaxis, but they have had limited success (18). Immunoprophylaxis holds promise, but effective vaccines are still not available. Presently, the most effective way of dealing with malaria is the administration of chemotherapeutic agents. Although drug treatments of malaria are currently the best means of disease management, there is an urgent need for the development of structurally novel and effective antimalarial drugs because of increasing resistance to most presently available antimalarial drugs (15,16,19).Some of the most effective antimalarial drugs available, quinine and artemisinin, are natural products derived from terrestrial plants. However, recent research suggests that marine organisms may also produce compounds with activity against malaria parasites (4,11,21). Manzamines are a structurally unique group of ␤-carboline alkaloids isolated from several marine sponge species found in waters of the Indian Ocean and the Pacific Ocean. Manzamine A (Fig. 1) was initially isolated from a Haliclona sp. (17) but has been subsequently found in other genera of marine sponges, including Pellina (14), Pachypellina (7), Xestospongia (3, 8), Ircinia (10), and Amphimedon (9). In addition, more than 30 other compounds structurally related to manzamine A have been isolated from sponges and characterized; these include 8-hydroxymanzamine A and the ketone derivative manzamine F (Fig. 1). The origin, isolation, and chemistry of various manzamines have been reviewed (6, 13), with the complete synthesis of manzamine A being recently reported (20). The manzamines previously received considerable interest because of their potential as anticancer agents, with both manzamine A and manzamine F inhibiting the growth of P-388 mouse leukemia cells (6) and 8-hydroxymanzamine A showing moderate cytotoxici...

New Manzamine Alkaloids with Activity against Infectious and Tropical Parasitic Diseases from an Indonesian Sponge

“…8 Although compounds 3 and 5 were inactive against malaria and leishmania, these results provide valuable information on the structural moieties required for activity against malaria and leishmania. This observation further supports our previous report 4 which indicates that reduction of the C32-C33 olefin and oxidation of C-31 also significantly reduces the antimalarial activity for the manzamine alkaloids in vivo. These data combined strongly suggest that the ability of the C-34 allyliccarbon to form a stabilized carbocation after oxidation both in cell culture and in animals followed by the inherent nucleophilic attack may play a critical role in the biological activity of the manzamine alkaloids against the malarial parasite.…”

Manadomanzamines A and B: A Novel Alkaloid Ring System with Potent Activity against Mycobacteria and HIV-1

“…The 3 J coupling of H-37 and H-22 (δ 3.75) in the COSY spectrum indicated that the 2-ketopropyl group was connected to C-22. Additional significant evidence for the structure was provided by the natural abundance 1 H- 15 3 , although it may not be the preferred conformation in energy level. This will no doubt be helpful in future SAR studies, since the ligand-based drug design takes solvent effects into consideration.…”

“…A gradient HMBC pulse sequence with 1 ms Gaussian Z-axis gradient pulses (70:30:50) was used. Referencing of the indirectly detected 15 N dimension was accomplished using nitromethane as an external standard. A GHMBC experiment was performed with nitromethane, and the 15 N correlation was calibrated to 380.2 ppm.…”

“…Inverse detected 15 N NMR spectra were recorded using a 500 Hz NMR spectrometer equipped with a 3 mm inverse-detection gradient probe. A gradient HMBC pulse sequence with 1 ms Gaussian Z-axis gradient pulses (70:30:50) was used.…”

Manzamine B and E and Ircinal A Related Alkaloids from an Indonesian Acanthostrongylophora Sponge and Their Activity against Infectious, Tropical Parasitic, and Alzheimer's Diseases

“…10 As part of our ongoing investigations to identify new manzamines and to define the SAR as well as utilize the natural products as synthetic starting materials, [1][2][3][11][12][13] extracts of the Indonesian sponge Acanthostrongylophora sp. were investigated.…”