New drugs are urgently required for the treatment of amoebiasis, leishmaniasis, malaria and trypanosomiasis. In this review the potential of natural plant products as a source of antiprotozoal drugs is discussed with respect to biochemical differences between protozoa and hosts. Some of the ways in which pathogenic protozoa differ biochemically from their human hosts are described, and the modes of action of some antiprotozoal drugs which exploit these differences are mentioned. A selection of natural products of plant origin (alkaloids, terpenes, quinones and miscellaneous compounds) is illustrated with emphasis on their modes of action and potential for the development of selective antiprotozoal agents.

Natural products and the development of selective antiprotozoal drugs

The challenge of Chagas' disease chemotherapy: an update of drugs assayed against Trypanosoma cruzi.

Chagas disease is one of the most important endemic diseases in Latin America, caused by Trypanosoma cruzi. The drugs used for the treatment of this disease, nifurtimox and benznidazole, are toxic and present severe side effects. The need of effective drugs, without adverse effects, has stimulated the search for new compounds with potential clinical utility. An overview of a number of natural naphthoquinones tested against T. cruzi parasites is provided. Among natural naphthoquinones, lapachol, β-lapachone and its α-isomer have demonstrated useful trypanocidal activities. In the search for new trypanocidal agents, this review outlines different structural modifications of natural quinones, as well as synthetic quinones, which have been subjected to trypanocidal studies. This review summarizes the mechanism of action and structure-activity relationships of the quinone derivatives, including some theoretical calculations that discuss the correlation of stereo electronic properties with the trypanocidal activity. In this context, this review will be useful for the development of new antichagasic drugs based mainly on structural modification of natural quinones.

Natural and synthetic naphthoquinones active against Trypanosoma cruzi: an initial step towards new drugs for Chagas disease

Pharmaceutical research in natural products represents a major strategy for discovering and developing new drugs. The use of medicinal plants for the treatment of parasitic diseases is well known and documented since ancient times e.g. by the use of Cinchona succiruba (Rubiaceae) as an antimalarial. This chapter provides a comprehensive review of the latest results in the field of antiparasitic drug development from biologic sources (plants, bacteria, fungi and marine organisms) focussing on the treatment of protozoal infections ( Plasmodium, Leishmania, Trypanosoma spp.). The status of validated in vitro and in vivo assays is reviewed, discussing theirdifferent features, problems and limitations. Because of the high number of natural products tested against the aforesaid protozoa in the last years, we limit the discussion to lignans, phenolics, terpenoids, and alkaloids as defined natural product classes. The review also covers essential research topics of recent publications on specific natural products (e.g. licochalcone A, benzyl- and naphthylisoquinoline alkaloids, and artemisinin) and gives an outlook to semi-synthetic approaches of drugsalready introduced in clinics or in clinical trial studies.

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Natural Products as potential antiparasitic drugs.

Standard midpoint potentials have been deter- mined for p-benxoquinone, methoxy-p-benzoquinone and 2,3-, 2,5-, and 2,6-dimethoxy-p-benxoquinones in aqueous solution. ESR studies have been made of the ascorbate and semiqninone radicals produced when these quinones interact with sodium as- corbate. Direct correlations are found between the electrocbem- ical potentials, generated semiquinone lifetimes, and cytotoxic action in Ehrlich ascites-bearing mice. This work follows from earher considerations of the oxidation- reduction and cytotoxic properties of some methoxyquinones (1) and ofcharge-transfer reactions and electronic delo~ization effects in biological systems (2-4). The compounds of interest in these particular studies have been the methoxy-substituted p-quinones, two of which (methoxy- and 2,6-dimethoxy-p-ben- zoquinone) occur naturally in wheat germ (5). Bachur et al (6) have suggested that the cytotoxic action of quinone anticancer drugs is mediated through their free-radical metabolites. An important first step in such activity is the pro- duction of relatively stable semiquinone free radicals. Radicals result from one-electron rather than two-electron redox reac- tions and the radical concentration and rate ofproduction should depend on the difference between the electrochemical poten- tials of the electron donor and acceptor molecules involved. In this work, electrochemical and ESR measurements have been made to determine the correlation between the cytotoxic activ- ity of several quinone/ascorbate mixtures and their ability to produce stable semiquinone radicals.

Ascorbate-quinone interactions: Electrochemical, free radical, and cytotoxic properties (redox potential/semiquinone radical/cancer drug/electron transfer/ascites)

Tingenone and horminone, two natural quinonoid substances, inhibited the in vitro growth of Trypanosoma cruzi, 30 microM drug concentration producing total inhibition of growth. Tingenone inhibited total uptake and incorporation of [3H]thymidine, [3H]uridine, L-[3H]leucine into parasite macromolecules. Other quinonoids assayed were either less effective (abruquinone A) or even quite inactive (visminone B and ferruginin B). Investigation of several mechanisms for the cytotoxic action of tingenone pointed to the interaction with DNA as the most likely factor involved. Tingenone also inhibited the growth of Crithidia fasciculata, but the drug was significantly less active on this organism than on T. cruzi.

G. B. Marini-Bettolo

Papers

Effect of tingenone, a quinonoid triterpene, on growth and macromolecule biosynthesis in Trypanosoma cruzi.

Inhibition of growth and macromolecular biosynthesis in Trypanosoma cruzi by natural products. Effects of miconidine and tingenone