Various lysosomotropic detergents were tested in this work on in vitro cultures of Plasmodium falciparum and are shown to be potent antimalarial agents. The order of antimalarial potency was similar to that of cell toxicity on mammalian cells in culture (Miller DK et al., J Cell Biol 97, 1841-51 (1983]. The most efficient agents, N-dodecyl-imidazole (NDI) and N-dodecyl morpholine (NDM) displayed IC50 values of 6.7 +/- 0.7 microM and 23 +/- 5 microM. The mechanism of action of NDI measured at IC50 concentrations displayed the following features: irreversible antimalarial effect after 15 min exposure of cells to drug; alkalinization of the parasite food vacuole; inhibition of protein synthesis; inhibition of host cell protein digestion by the parasite; lack of vacuolar membrane disruption; lack of effect on the rate of constitutive autoproteolysis. No biochemical or ultrastructural indications were found to support a detergent-like action of NDI and its structural congeners on the major acidic compartment of the parasite, the food vacuole. Rather, alkalinization of that compartment by weak-base accumulation properties of the amphiphilic drugs and ensuing protonophoric effect are likely to play a major role in the various parasite-associated properties affected by these drugs.
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