title: In vitro and in vivo studies of the effects of halogenated histidine analogs on Plasmodium falciparum.
abstract: The effects of four halogenated analogs of histidine on in vitro growth of Plasmodium falciparum malaria parasites were monitored by measurement of the incorporation of 3H-labeled amino acids into parasite proteins and by light and electron microscopy. The uptake of [3H]isoleucine was reduced to 50% of the control value by addition of 70 microM 2-fluoro-L-histidine (2-F-HIS) or 420 microM 2-iodo-L-histidine (2-I-HIS). [3H]histidine uptake into acid-insoluble material was affected equally by these two compounds, 50% inhibition resulting at 200 microM concentration. Morphological analysis of parasite development proved a sensitive assay, since development of mature trophozoites was inhibited 50% by 25 microM 2-F-HIS or 100 2-I-HIS. Electron microscopy studies suggested different mechanisms of action of 2-F-HIS and 2-I-HIS on P. falciparum. 2-F-HIS produced a decrease in knob number at the erythrocyte surface and accumulation of electron-dense material under the parasite membrane. 2-I-HIS had no obvious effect on knobs or electron-dense material but affected parasite morphology. Surprisingly, 2-chloro-L-histidine and 2-bromo-L-histidine did not inhibit P. falciparum in vitro, even though their halogen atom substituents are intermediate in size between F and I atoms. 2-F-HIS and 2-I-HIS were tested in vivo against P. falciparum in owl monkeys (Aotus sp.) but were ineffective at doses that were nontoxic.
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892.
authors.forename: L J
authors.initials: LJ
authors.lastname: Panton
authors.forename: R N
authors.initials: RN
authors.lastname: Rossan
authors.forename: A
authors.initials: A
authors.lastname: Escajadillo
authors.forename: Y
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: A T
authors.initials: AT
authors.lastname: Lee
authors.forename: V M
authors.initials: VM
authors.lastname: Labroo
authors.forename: K L
authors.initials: KL
authors.lastname: Kirk
authors.forename: L A
authors.initials: LA
authors.lastname: Cohen
authors.forename: M
authors.initials: M
authors.lastname: Aikawa
authors.forename: R J
authors.initials: RJ
authors.lastname: Howard
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000962:Antimalarials; D001029:Aotus trivirgatus; D002462:Cell Membrane / Q000648:ultrastructure; D006639:Histidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D008288:Malaria / Q000517:prevention & control; D008854:Microscopy, Electron; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism / Q000469:parasitology
chemical_list: D000596:Amino Acids; D000962:Antimalarials; C060179:2-bromohistidine; C060178:2-chlorohistidine; C060180:2-iodohistidine; D006639:Histidine; C007749:2-fluorohistidine