We have found 2-iodo-L-histidine to be a potent antimalarial agent against drug-resistant Plasmodium falciparum. However, the compound is effective in monkeys for only 24-48 hrs; we have shown that inactivation may be the result of nonenzymatic deiodination by any of the sulfhydryl compounds present in tissue or serum. The facts that 2-iodohistidine does not block protein synthesis in the parasite, and that the corresponding 2-chloro and 2-bromo 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. Indeed, the diameter of the holes has been estimated at 0.7 nm, almost exactly the width of 2-iodohistidine. We have, therefore, explored the antimalarial activities of more metabolically stable derivatives of histidine which have ring substituents offering similar steric sizes. New general synthetic methods were devised to provide these series of compounds: 1-R-histidines, 2-R'-histidines, 1-R-2-R' histidines (and the corresponding histamines), in which R need not equal R' and in which R and R' may be any saturated, unsaturated, cyclic, bicyclic, arylalkyl or heteroarylalkyl group, or any of their functionalized derivatives. Regiospecific alkylation at N-1 involves the use of cycloureidohistidine; despite the reduced nucleophilicity at N-1, alkylation occurs readily even with such hindered groups as cyclohexyl and t-butyl. Alkylation at C-2 involves the rarely used Minisci reaction, in which R'COOH is decarboxylated to R' radical by a catalytic amount of argentic ion (regenerated by a peroxy salt). In acidic media, the reaction is remarkably specific for alkylation at C-2 in good yield, providing the most efficient and least expensive method yet developed for the production of 2-alkylimidazoles in general, and 2-alkylhistidines or histamines in particular. In vitro screening of a random sampling of these compounds reveals modest inhibitory activity, but sufficient to support the concept of chemotherapy by membrane plugging, or """"""""permeatherapy."""""""" Screening of a large number of these histidine or histamine analogs is in process.
