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Antimicrobial Agents and Chemotherapy, July 2004, p. 2502-2509, Vol. 48, No. 7
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.7.2502-2509.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Terpenes Arrest Parasite Development and Inhibit Biosynthesis of Isoprenoids in Plasmodium falciparum

Herbert Rodrigues Goulart,1 Emília A. Kimura,1 Valnice J. Peres,1 Alicia S. Couto,2 Fulgencio A. Aquino Duarte,3 and Alejandro M. Katzin*

Departamento de Parasitologia, Instituto de Ciências Biomédicas,1 Departamento de Engenharia Mecanica, Escola Politécnica, Universidade de São Paulo, São Paulo, Brazil,2 CIHIDECAR, Departamento de Química Orgánica. Pabellón II, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires 1428, Argentina3

Received 19 November 2003/ Returned for modification 31 December 2003/ Accepted 8 March 2004

Development of new drugs is one of the strategies for malaria control. The biosynthesis of several isoprenoids in Plasmodium falciparum was recently described. Interestingly, some intermediates and final products biosynthesized by this pathway in mammals differ from those biosynthesized in P. falciparum. These facts prompted us to evaluate various terpenes, molecules with a similar chemical structure to the intermediates of the isoprenoids pathway, as potential antimalarial drugs. Different terpenes and S-farnesylthiosalicylic acid were tested on cultures of the intraerythrocytic stages of P. falciparum, and the 50% inhibitory concentrations for each one were found: farnesol, 64 µM; nerolidol, 760 nM; limonene, 1.22 mM; linalool, 0.28 mM; and S-farnesylthiosalicylic acid, 14 µM. All the terpenes tested inhibited dolichol biosynthesis in the trophozoite and schizont stages when [1-(n)-3H]farnesyl pyrophosphate triammonium salt ([3H]FPP) was used as precursor. Farnesol, nerolidol, and linalool showed stronger inhibitory activity on the biosynthesis of the isoprenic side chain of the benzoquinone ring of ubiquinones in the schizont stage. Treatment of schizont stages with S-farnesylthiosalicylic acid led to a decrease in intensity of the band corresponding a p21ras protein. The inhibitory effect of terpenes and S-farnesylthiosalicylic acid on the biosynthesis of both dolichol and the isoprenic side chain of ubiquinones and the isoprenylation of proteins in the intraerythrocytic stages of P. falciparum appears to be specific, because overall protein biosynthesis was not affected. Combinations of some terpenes or S-farnesylthiosalicylic acid tested in this work with other antimalarial drugs, like fosmidomycin, could be a new strategy for the treatment of malaria.

* Corresponding author. Mailing address: Universidade de São Paulo, Av. Professor Lineu Prestes, 1374, CEP 05508-900 São Paulo, Brazil. Phone: (55) (11) 30917267. Fax: (55) (11) 30917417. E-mail: amkatzin{at}icb.usp.br.

Antimicrobial Agents and Chemotherapy, July 2004, p. 2502-2509, Vol. 48, No. 7
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.7.2502-2509.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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