Heme polymerization inhibitor

Recent work has also highlighted two classes of inorganic complexes that have interesting antimalarial activity (1) metal-N402 Schiff base complexes and (2) porphyrins. The mechanism of action for these complexes is discussed. The use of these complexes as probes for the elucidation of structure-activity relationships in heme polymerization inhibitor design and the loci of drug resistance is also detailed. 

More recently, and based on the same concept, O Neill and coworkers have prepared a series of related systems (80a-c) based on Vennerstrom s adamantyl trioxolane unit". These derivatives, which are synthesized in only three steps from adamantan-2-one, have activity in the low nanomolar region (<3 nM versus K1 P. falciparum). Like the prototypes synthesized by the groups of Meunier" and Singh", these compounds can be formulated as water-soluble salts and it is anticipated that these agents may have the capacity to hit the parasite by two distinctive mechanisms. Indeed, any chemical or metabolic degradation of the endoperoxide bridge in these compounds will result in metabolites that may still have the ability to function as inhibitors of heme polymerization provided that they do not become covalently attached to proteins in the bioactivation process. 

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