manzamine-a and Malaria

Malaria, even though an avoidable and treatable disease, can be fatal if ignored. Artemisinin Combination Therapy (ACT) and RTS, S/AS01 vaccine (Mosquirix™) are the only modest means available with humans to overcome malaria, a lethal affliction wreaking havoc across the globe. Employment of ACT is associated with problems such as 'Artemisinin Resistance' and the 'Hypnozoite conundrum' that hinder the complete eradication of malaria. In this view, the natural products specifically comprising β-carboline scaffold have shown good antiplasmodial responses against different strains of malaria. Taking these observations forward, researchers have performed structure-activity relationship (SAR) studies around three different β-carboline skeletons (tetrahydro β-carbolines, dihydro β-carbolines, β-carbolines) to design new β-carboline derived heterocyclic structures or modified naturally occurring derivatives. In addition, different approaches such as dimerization and linkage to other moieties have also been adopted to enhance the antimalarial activity. The present review describes a comprehensive SAR study encapsulating various natural and synthetic β-carbolines to elaborate upon the utility of these skeletons in designing drugs to subdue this deadly disease.

Topics: Antimalarials; Carbolines; Humans; Malaria; Molecular Structure

Manzamines are a unique class of β-carboline marine alkaloids with an unusual tetra- or pentacyclic system. These alkaloids have shown a variety of bioactivities against infectious diseases, cancer and inflammatory diseases. The greatest potential for the manzamine alkaloids appears to be against malaria, with improved potency relative to chloroquine and artemisinin. Over 80 manzamine-related alkaloids have been isolated from more than 16 species of marine sponges belonging to five families distributed from the Red Sea to Indonesia, which suggests a possible microbial origin for manzamine alkaloids. The current review summarizes marine literature, focusing on the biological activities of manzamines, the possible microbial origin of this class of compounds and the Red Sea as a possible source of manzamines from biosynthetic gene clusters of Red Sea microbes.

Topics: Actinobacteria; Animals; Anti-Infective Agents; Antimalarials; Biological Products; Biota; Carbazoles; Carbolines; Indian Ocean; Indole Alkaloids; Malaria; Marine Biology; Porifera

Manzamine A, a sponge-derived alkaloid, was recently shown to possess in vivo antimalarial activity against the blood stages of the rodent malaria parasite Plasmodium berghei. A single intraperitoneal dose of 100 micromol/kg of manzamine A suppressed parasite growth but was followed by parasite recrudescence. Forty percent of mice with recrudescing parasites were able to recover and clear the fulminating parasitaemia. Examination of sera from these mice revealed that infected mice treated with manzamine A had a suppressed IFN-gamma production but an increase in their IL-10 and IgG production. The prolonged survival of infected mice treated with manzamine A and the eventual clearance of recrudescing parasites in some of these mice involve a down-regulation of Thl responses and a switch to antibody dependent-Th2 responses.

Topics: Animals; Antibodies, Protozoan; Antimalarials; Carbazoles; Cytokines; Erythrocytes; Immunoglobulin G; Indoles; Malaria; Male; Mice; Parasitemia; Plasmodium berghei; Pyrroles

Manzamine A, a beta-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.

Topics: Animals; Antimalarials; Carbazoles; Indoles; Malaria; Male; Mice; Microscopy, Electron; Plasmodium berghei; Pyrroles