A review of natural products with antileishmanial activity

Abstract

Infections caused by protozoa of the genus Leishmania are a major worldwide health problem, with high endemicity in developing countries. The incidence of the disease has increased since the emergence of AIDS. In the absence of a vaccine, there is an urgent need for effective drugs to replace/supplement those in current use. The plant kingdom is undoubtedly valuable as a source of new medicinal agents. The present work constitutes a review of the literature on plant extracts and chemically defined molecules of natural origin showing antileishmanial activity. The review refers to 101 plants, their families, and geographical distribution, the parts utilized, the type of extract and the organism tested. It also includes 288 compounds isolated from higher plants and microorganisms, classified into appropriate chemical groups. Some aspects of recent antileishmanial-activity-directed research on natural products are discussed.

Introduction

Leishmaniasis is regarded as a major public health problem (WHO, 2002), causing significant morbidity and mortality in Africa, Asia and Latin America. The disease currently threatens about 350 million women, men and children in 88 countries around the world, with about 2 million affected annually. In Brazil, studies report the occurrence of about 20.000 new cases of the illness annually. An increase in the incidence of leishmaniasis can be associated with urban development, forest devastation, environmental changes and migrations of people to areas where the disease is endemic (Carvalho et al., 2000; Patz et al., 2000; Ashford, 2000).

Species of the genus Leishmania, a protozoan member of the hemoflagellate group, are the causative agents of human leishmaniasis, which has a reservoir in rodents, dogs, saguins, marsupials and others in the wild animal population, and is transmitted by mosquitoes of the genera Lutzomia and Phlebotomus. The term leishmaniasis comprises three clearly distinguishable clinical manifestations: generalized visceral infection (visceral leishmaniasis or “Kala-azar”), cutaneous leishmaniasis (Oriental button), and mucocutaneous leishmaniasis (ulceration of the skin and hyperdevelopment of the mucous membranes) (Garcia-Granados et al., 1997; Ashford, 2000).

Members of the genus Leishmania differentiate from proliferative promastigotes in the sandfly vector gut to infective metacyclic promastigotes in the insect foregut. Parasites are inoculated by the vector as the flagellate promastigotes enter the mammalian host, where they infect macrophages, differentiating into nonmotile amastigotes and multiplying as such (Araújo et al., 1998; Carvalho et al., 2000). The mechanisms by which visceral and cutaneous manifestations develop have not been fully clarified.

The treatment of leishmaniasis is difficult because of the intramacrophagic location of the infectious form. Victims of this illness present an immune deficiency and are not able to eliminate the parasites through a natural mechanism of defense. Moreover, malnutrition is associated with certain cases of leishmaniasis. Parallel infection with diseases such as malaria and pneumonia increases the fatality of the illness if it is not diagnosed and treated in time. The problem of leishmaniasis has been worsened by the evolution of AIDS due to parallel infections in AIDS patients, as well as by the development of drug-resistance by parasites (Carvalho et al., 2000; Torres-Santos et al., 1999).

In the absence of a vaccine, there is an urgent need for effective drugs to replace/supplement those in current use. The clinically used drugs, many of which are based on pentavalent antimony compounds, were developed before 1959. The toxicity of these agents and the persistence of side-effects even after modification of the dose level and duration of treatment are, however, severe drawbacks. The search for antileishmanial agents has been exhaustive. Alternative drugs, such as amphotericin B and pentamidine, also have unpleasant side-effects (Balana et al., 1998; Carvalho et al., 2000). On the other hand, plant extracts or plant-derived compounds are likely to provide a valuable source of new medicinal agents (Carvalho and Ferreira, 2001; Kayser and Kiderlen, 2001) and the urgent need for alternative treatments has led to a program to screen natural products for potential use in the therapy of leishmaniasis. In fact, the WHO advocated the use of traditional medicine where appropriate health services are inaccessible (Tahir et al., 1998; Weniger et al., 2001; Bhadra, 1993).

Furthermore, the leads obtained from the search for natural products with antileshmanial activity give new impetus for obtaining valuable synthetic compounds (Carvalho et al., 2000).

With the objective of contributing to these studies, a literature search on the use of natural products (crude plant extracts, semi-purified fractions and chemically defined molecules) which have already been evaluated particularly for leishmaniasis, has been carried out.