New highly active agents against leishmaniasis

Parasitic diseases, especially leishmaniases and trypanosomiases, kill hundreds of thousands of people every year in the world, mainly in the countries of the South. The most severe form of leishmaniosis (kala-azar, the visceral form), induced by Leishmania donovani and L. infantum, affects about 500 000 people per year and proves fatal if no treatment is given.

Although drugs do exist for treating these diseases, they are not always effective, owing to the appearance of resistant parasites and to the toxicity of the products. Moreover, administration of the available treatments against leishmaniases is mainly by injection, which means that patients have to go to hospital. Most people infected live in areas either far from health-care facilities or completely devoid of them. Research for new substances with potential as therapeutic agents is consequently necessary.

IRD researchers conducted ethno-pharmacological studies in line with this search, in South America. These scientists, working with researchers from the CNRS, the University of Paris-Sud and the Institut Pasteur (1), have thus discovered and studied alkaloids of the chemical family of the quinolines, doted with antiparasitic properties. The quinolines, obtained by chemical synthesis, are analogues of quinolines initially isolated from a Bolivian plant, Galipea longiflora (Rutaceae). Experiments conducted on mice infected by visceral leishmaniasis showed that oral administration of these quinolines was effective for treating this severe form of the disease (2).

The general chemical structure of quinolines comprises two rings (the quinoleic nucleus), one aromatic and the other bearing nitrogen (pyridinic) on to which variable substitution groups can bind depending on their character and position. In order to select the most active molecule, the least toxic and the easiest to synthesize, about 100 substituted quinolines were prepared and tested in vitro on different parasites, particularly those responsible for the cutaneous and visceral forms of leishmaniasis, then on two retroviruses, HIV (responsible for the Aids pandemic) and HTLV-1 (human T-cell leukaemia virus).

HTLV-1, which was the first retrovirus discovered (1980), currently affects 15 to 20 million people in the world, essentially in South-West Japan, the Caribbean, Latin America and tropical Africa. It can cause a specific form of leukaemia and a slowly developing degradation of the nervous system (tropical spastic paraparesia).

The activity of these substances is closely linked to their chemical structure, and especially to the length of the substitution group (number of carbon atoms) located in position 2 on the quinoleic nucleus. Generally, the most active quinolines are those which carry a three-carbon-atom branch and an unsaturated (alkenyl) bond.

Among these compounds, some proved especially active against parasites of the genus Leishmania, showing an efficacy equal to or higher than that of the reference drug for treating leishmaniases, glucantime®. Experiments run on mice confirmed that oral administration of these quinolines was effective and that toxicity was low for this animal. The adoption of this administration route would simplify treatment of patients in regions devoid of hospital infrastructures. Three of these compounds were eventually chosen for their biological activity, their innocuousness and their ease of synthesis. They are currently the focus of investigations on their action mechanism, their behaviour in the human organism and their toxicity.

Among the quinolines active against leishmaniases, some were also able to block, in vitro, the replication of the retrovirus HIV-1, without manifesting any toxicity against their host cells. Others were revealed to be active against HTLV-1, one being capable of inhibiting retrovirus replication, at very small doses by reducing the viral load by 76% (3).

The quinolines consequently are compounds worthy of investigation in line with the search for new treatments for infections that are insufficiently combated by existing medicines. Research work and development of these compounds active against leishmaniases are planned, in partnership with Brazil, with the particular aim of perfecting their production at industrial scale. Furthermore, assessment of their antiretroviral activity (HTLV-1) is being continued in a joint scientific project set up between the scientists and a research laboratory of the FIOCRUZ (Fondation Oswaldo Cruz, Salvador).

Marie Guillaume – IRD
Translation : Nicholas Flay

(1) This research work stems from collaboration between the IRD, UMR C8076 CNRS (BioCIS) – Pharmacy Faculty of Châtenay-Malabry, the Pharmacognosy laboratory of the University Paris-Sud and the Institut Pasteur.

(2) Natural quinolines were the subject of a first IRD patent application in 1991. Reférence: Fournet A., Angelo Barrios A., Muñoz V., Hocquemiller R., Roblot F., Bruneton J., Richomme P., Gantier J. C. 1992. Quinoléines 2-substituées pour le traitement des leishmanioses. Brevet PCT/FR92/00903. The in vivo experiments were performed at the time by IRD researchers in partnership with Bolivian scientists. The work undertaken by researchers from the IRD, the Institut Pasteur and the CNRS (UMR C8076 CNRS (BioCIS), Pharmacy Faculty of Châtenay-Malabry) led to the filing of a new CNRS-IRD patent application in 2001.

(3) Some quinolines also show activity against Trypanosoma cruzi, the parasite responsible for Chagas’ disease, which indeed was at least as strong as the reference medicine used to treat the disease.