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Antimicrobial Agents and Chemotherapy, August 2003, p. 2590-2597, Vol. 47, No. 8
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.8.2590-2597.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Potent Inhibitors of Plasmodium Phospholipid Metabolism with a Broad Spectrum of In Vitro Antimalarial Activities

Marie L. Ancelin,1 Michèle Calas,2 Valérie Vidal-Sailhan,2 Serge Herbuté,1 Pascal Ringwald,3 and Henri J. Vial1*

UMR 5539,1 LAPP, UMR 5810, CNRS, Université Montpellier II, 34095 Montpellier Cedex 5, France,2 Laboratoire de Recherche sur le Paludisme, OCEAC, IRD, Yaoundé, Cameroon3

Received 14 November 2002/ Returned for modification 12 March 2003/ Accepted 10 May 2003

We characterized the potent in vitro antimalarial activity and biologic assessment of 13 phospholipid polar head analogs on a comparative basis. There was a positive relationship between the abilities of the drugs to inhibit parasite growth in culture and their abilities to specifically inhibit phosphatidylcholine biosynthesis of Plasmodium falciparum-infected erythrocytes. Maximal activity of G25 was observed for the trophozoite stage of the 48-h erythrocytic cycle (50% inhibitory concentration, 0.75 nM), whereas the schizont and ring stages were 12- and 213-fold less susceptible. The compounds exerted a rapid nonreversible cytotoxic effect, with complete clearance of parasitemia after 5 h of contact with the mature stages. The compounds were highly specific against P. falciparum, with much lower toxicity against three other mammalian cell lines, and the in vitro therapeutic indices ranged from 300 to 2,500,000. Finally, the monoquaternary ammonium E10 and two bis-ammonium salts, G5 and G25, were similarly active against multiresistant strains and fresh isolates of P. falciparum. This impressive selective in vitro toxicity against P. falciparum strongly highlights the clinical potential of these quaternary ammonium salts for malarial chemotherapy.

* Corresponding author. Mailing address: UMR 5539, CNRS, Université Montpellier II, CP 107, Place Bataillon, 34095 Montpellier Cedex 5, France. Phone: 33 0 4 6714 3745. Fax: 33 0 4 6714 4286. E-mail: vial{at}univ-montp2.fr.

Antimicrobial Agents and Chemotherapy, August 2003, p. 2590-2597, Vol. 47, No. 8
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.8.2590-2597.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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