Anion transport inhibitors as suppressors of Plasmodium falciparum growth in in vitro cultures

Z. I. Cabantchik, S. Kutner, M. Krugliak, H. Ginsburg

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

A series of inhibitors of red blood cell anion-transport were tested as possible inhibitors of intraerythrocytic growth of Plasmodium falciparum parasites in in vitro human cultures. Two classes of compounds were used in this study: Class I, hydrophilic compounds which are impermeant to uninfected cells (e.g., disulfonic stilbene derivatives and phlorizin), and Class II, relatively lipophilic compounds to which membranes are permeable (e.g., phloretin, furosemide, niflumic acid, and indacrinone (MK-196). Good correlation between the inhibitory power on anion transport and on parasite growth was obtained for the reversibly acting 4,4'-dinitro-2,2'-stilbenedisulfonic acid and the irreversibly acting analogue, 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid. Phlorizin, a potent inhibitor of sugar transport but a rather poor inhibitor of anion transport, was the most efficient antimalarial agent. Alternatively, niflumic acid and MK-196, both good inhibitors of anion transport, and phloretin, a potent inhibitor of anion and sugar transport, were relatively less efficient in arresting parasite growth. Studies of growth rates and of metabolic activities conducted with synchronously grown cultures indicate that the Class I inhibitors arrest parasite development and propagation by the two following modes of inhibition: at the host cell membrane level, by blocking the anion transport (Mode A), and at the cellular level, by direct interference with schizont development and propagation (Mode B). The latter is made possible by an observed permselectivity change in the host cell membrane, which appears after trophozoite formation and persists throughout schizogony. Stilbene disulfonates act by both modes, whereas phlorizin and niflumic acid act primarily by Mode B. Our work indicates that anion transport inhibitors which act in a reversible fashion and which are impermeant to uninfected cells are useful antimalarial agents in in vitro systems. The work provides a rational basis for the design of drugs of potential therapeutic use.

Original languageEnglish
Pages (from-to)92-99
Number of pages8
JournalMolecular Pharmacology
Volume23
Issue number1
StatePublished - 1983

Fingerprint

Dive into the research topics of 'Anion transport inhibitors as suppressors of Plasmodium falciparum growth in in vitro cultures'. Together they form a unique fingerprint.

Cite this