New active agents against leishmaniasis
family, which have proved effective against visceral leishmaniasis
treating this severe form of the disease with its antiparasitic
properties.
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, 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. However effective treatments against leishmaniases are mainly by injection and research into an oral drug treatment has proved necessary.
The quinolines, obtained by chemical synthesis, are analogues of quinolines initially isolated from a Bolivian plant, Galipea longiflora. 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.
In order to select the most active molecule, the least toxic and the easiest to synthesize, scientists prepared about 100 substituted quinolines and tested them in vitro on different parasites. Those that were 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 Southwest 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).
Amongst these compounds, some proved 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. Three of these compounds were eventually chosen for their biological activity and ease of synthesis.
The researchers, who are from the CNRS, the University of Paris-Sud and the Institut Pasteur, are currently the focusing on the mechanism of action, its behaviour in the human organism and its 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 per cent.
The quinolines have proved viable compounds for research into 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 its 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).
