We have found 2-iodo-L-histidine t be a potent antimalarial agent against drug-resistant Plasmodium falciparum. The compound is effective in monkeys for only 24-48 hrs, and we have shown that inactivation may be the result of nonenzymatic deiodination by any sulfhydryl compound present in serum or tissue. The facts that 2-iodohistidine does not block protein synthesis in the parasite, and that the corresponding 2- bromo and 2-chloro compounds are inactive, led us to speculate that the 2-iodo compound operates by plugging one or more holes in the erythrocyte membrane and, thus depriving the parasite of nonamino acid nutrients obtained by diffusion through such holes. We have, therefore, synthesized and tested a broad range of more metabolically stable derivatives of histidine and histamine, in which the ring substituents are close to iodine in size. Alkylation at C-2 is achieved by generation of an alkyl radical by one of several methods. In acidic media, the reaction is remarkably specific for C-2, providing the most efficient and least expensive method yet developed for synthesis of 2-alkylhistidines and histamines. In vitro activity appears to depend on the extent to which a substituent projects from the imidazole ring, with the optimum size being somewhat larger than that of iodine. On this basis, covalent affinity labels have been designed and are being prepared. Drug resistance by the parasite and multidrug resistance in cancer chemotherapy both involve drug ejection by an ATP-driven protein pump; in both cases, resistance can be partially overcome by calcium channel blockers. Accordingly, a number of our antimalarial candidates have been submitted for testing to overcome multidrug resistance.
