WO2012019772A1

WO2012019772A1 - Method for treating protozoan parasitic diseases

Info

Publication number: WO2012019772A1
Application number: PCT/EP2011/004055
Authority: WO
Inventors: Denis Sereno; Elodie Gazanion; Baptiste Vergnes; Jean-François GUICHOU; Gilles Labesse
Original assignee: Institut De Recherche Pour Le Developpement (I.R.D)
Priority date: 2010-08-12
Filing date: 2011-08-12
Publication date: 2012-02-16

Abstract

The present invention relates to a method of treating, preventing or inhibiting parasitic disease, in particular leishmaniasis or trypanosomiasis in a subject, by a compound of formula (1): R₂-A-R₁ wherein: - A represents a group chosen from a phenyl, a triazolyl, and a thienyl, - R₁ represents -CO-CH₂OH or -CO-NHOH, - R₂ is chosen from H, triazolyl, methyltriazolyl, -CONHR₃, -CH₂-CONHR₃, - 'NHS0₂NHR₃, -CH₂-NHSO₂NHR₃, wherein R₃ represents H, a (C₁-C₈) alkyl group, an aryl group, a (C₃-C₈) cycloalkyl group, a heterocyclic group, or a heteroaryl group. Or a pharmaceutically acceptable salt thereof.

Description

METHOD FOR TREATING PROTOZOAN PARASITIC DISEASES

The present invention relates to a method of treating, preventing or inhibiting parasitic disease, in particular leishmaniasis or trypanosomiasis in a subject.

The protozoan Leishmania parasite is the causative agent of a wide spectrum of diseases termed leishmaniasis that concern more that 12 millions people, over 88 countries around the world. Leishmaniasis is caused by several species of Leishmania, such as L. aethiopica, L. donovani, L. infantum, L. major, L. mexicana or L. tropica. Around the Mediterranean and in France in particular, leishmaniasis is essentially caused by L. infantum. During the ife cycle of Leishmania parasites, two different hosts lodge the parasite. Promastigotes develop in the gut of a phlebotomine sandfly that transmits flagellated infectious metacyclic forms into a vertebrate host during the bloodmeal. They rapidly differentiate into non-flagellated amastigotes, which actively divide within the mononuclear phagocytes. These particular niches constitute specific environments where the parasite has to find essential nutrients required for its development.

Three main clinical variants of this disease are known: cutaneous, mucocutaneous, and visceral. Cutaneous leishmaniasis can manifest itself as a single skin ulceration at the site of the sandfly bite appearing soon after infection or month later as disseminated lesions. Mucocutaneous syndrome develop as the cutaneous form, but progresses months or years later to lesions of the mouth, nose, or pharynx. Visceral leishmaniasis, the most severe form, can prove fatal in the absence of treatment

Currently, basic treatment for all forms of leishmaniases consists of the administration of pentavalent antimony SbV (sodium stibogluconate Pentostam or meglumine antimoniate Glucantime) or more recently the liposomal formulation of amphotericin B in endemic mediterranean countries and for immunocompromised patients. Alternative drug options include pentamidine, miltefosine, paromomycin and allopurinol but their use is limited due to their toxicity or declined efficacy. These drugs are difficult to handle and have serious side effects. By the way, some compounds, such as amphotericin B, are only efficient for visceral leishmaniasis, but not for nonvisceral disease.

The trypanosomiasis is another current parasitic disease of humans and animals, caused by Trypanosoma. For example, Trypanosoma brucei can cause human African trypanosomiasis, also called sleeping sickness. Without treatment, the disease is invariably fatal, with progressive mental deterioration leading to coma and death. Damage caused in the neurological phase is irreversible. The current antiparasitic treatment need an intensive drug administration and is not always efficient.

Trypanosoma cruzi can cause American trypanosomiasis, also called Chagas disease. The infection of parasite can affect nervous system, digestive system and hear. The current antiparasitic treatment can only delay in poor level the development of disease symptoms during the chronic phase of the disease. By the way, the currently available antiparasitic treatments can cause side effects in many patients including skin disorders, brain toxicity, and digestive system irritation.

Thus, there is a need for providing new medicaments without the drawbacks of the currently used medicaments, for the treatment of protozoan parasitic diseases, such as leishmaniasis or trypanosomiasis.

Consequently, the present invention provides a compound of formula (1):

R2-A-R1,

wherein:

- A represents a group chosen from a phenyl, a triazolyl, and a thienyl,

- Ri represents -CO-CH₂OH or -CO-NHOH,

- R₂ is chosen from H, triazolyl, methyltriazolyl, -CONHR₃, -CH₂-CONHR₃, - NHS0₂NHR₃, -CH₂-NHS0₂NHR₃, wherein R₃ represents H, a (C]-C₈) alkyl group, an aryl group, a (C₃-C₈) cycloalkyl group, a heterocyclic group, or a heteroaryl group,

or a pharmaceutically acceptable salt thereof, for use as a drug.

The term "Cj-Cs alkyl" denotes a straight or branched chain hydrocarbon group with 1 to 8 carbon atoms, especially with 1 to 6 carbon atoms, more especially with 1 to 4 carbon atoms. Examples of such groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, -3,3-dimethylbutyl and 2-ethylbutyl.

The term (C3-C₈)cycloalkyl group represents a saturated cyclic hydrocarbon such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term "aryl" refers to a 6- to 18-membered monocyclic, bicyclic, tricyclic, or polycyclic aromatic hydrocarbon ring system. Examples of an aryl group include phenyl, naphthyl, pyrenyl, anthracyl, quinolyl, and isoquinolyl.

The term "heterocyclic group" represents 3- to 7-membered non-aromatic ring system containing 1 or 2 hetero atoms selected from nitrogen, oxygen and sulfur or sulfur oxidized to sulfones or sulfoxides. Examples of such groups are oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, mo holinyl, thiomorpholinyl and piperazinyl.

The term "heteroaryl group" represents 5- or 6- membered aromatic mono- or bicyclic heterocydic group having 1 to 4 heteroatoms chosen from N, O and S. Examples of such aromatic heterocydic groups include pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, 1,2,4- oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1,3,4- thiadiazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, 1,2,3-triazolyl and tetrazolyl; examples of bicyclic heteroaryl groups are benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H- indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzodioxolyl, IH-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl; quinoxalinyl or phthalazinyl.

In a particular embodiment, the present invention concerns a compound of formula (1), wherein:

- A represents a phenyl group,

- Ri represents -CO-CH₂OH or -CO-NHOH,

- R₂ in para-position of R is chosen from H, triazolyl, methyl triazolyl, -CONHR₃, -CH₂- CONHR₃, -NHS0₂NHR₃, -CH2-NHS0₂NHR₃, wherein R₃ represents H, a (d-C₈) alkyl group, an aryl group, a (C₃-C₈) cycloalkyl group, a heterocyclic group, or a heteroaryl group,

said compound corresponding to formula (la) :

The present invention concerns more particularly a compound of formula (1), wherein:

- A represents a phenyl group,

- R₂ represents H,

- Ri represents -CO-CH₂OH or -CO-NHOH,

said compound corresponding to formula I

In a preferred embodiment, Rl represents -CO-CH₂OH and said compound corresponds to the following formula (la):

named alpha-hydroxyacetophenone.

In another preferred embodiment, Rl represents -CO-NHOH and said compound corresponds to the following formula (lb):

named also N-hydroxyberizamide.

The compound according to the invention may be synthesized by any method known from the art or is commercially available.

Particularly, the compounds of the present invention are useful as a drug for treating, inhibiting or preventing parasitic diseases, in particular protozoan parasitic diseases of a subject.

More particularly, the parasitic disease is caused by a protozoan parasite of the family of the Trypanosomatidae selected from the genus Trypanosoma or the genus Leishmania.

The parasite of the genus Trypanosoma can cause various trypanosomiases, such as sleeping sickness caused by Trypanosoma brucei, or Chagas disease caused by Trypanosoma cruzi.

In a particular embodiment, the compound of the present invention is for use as drug for treating, inhibiting or preventing parasitic diseases caused by Trypanosoma. . brucei. Gambiense.

The parasite of the genus Leishmania is the parasite responsible for the disease leishmaniasis.

In a particular embodiment, the compound of the present invention is for use as drug for treating, inhibiting or preventing parasitic diseases caused by Leishmania. aethiopica, Leishmania. donovani, Leishmania. mexicana, Leishmania. infantum, Leishmania. tropica and Leishmania. major, preferably by Leishmania. infantum, Leishmania. tropica and Leishmania. major, more preferably by Leishmania. infantum.

In another particular embodiment, the above defined compound is used as drug for treating, inhibiting or preventing a leishmaniasis, in particular cutaneous leishmaniasis, mucocutaneous leishmaniasis, or visceral leishmaniasis, or a trypanosomiasis.

In a more particular embodiment of the above defined compound, the subject is a mammalian including human and dog, more preferably, human.

The present invention provides also a composition comprising:

- a compound of formula (1):

wherein:

- A represents a group chosen from a phenyl, a triazolyl, and a thienyl,

- Rj represents -COCH₂OH or -CO-NHOH,

- R₂ is chosen from H, triazolyl, methyltriazolyl, -CONHR₃, -CH₂-CONHR₃, - NHS0₂NHR₃, -CH₂-NHS0₂NHR₃, wherein R₃ represents H, a (C C₈) alkyl group, an aryl group, a (C₃-C₈) cycloalkyl group, a heterocyclic group, or a heteroaryl group,

or a pharmaceutically acceptable salt thereof, and

- at least one anti-parasitic compound, selected from the group comprising : miltefosin, antimony based drugs, like meglumine antimoniate or sodium stibogluconate, amphotericin B, benznidazol, nifurtimox, paromomycin, pentamidin and its derivatives, arsenic derivatives, melarsoprol and difluoromethylornithin.

The above defined composition can be used as a drug, in particular a drug for treating, inhibiting or preventing a parasitic disease, in particular a leishmaniasis, more particularly cutaneous leishmaniasis, mucocutaneous leishmaniasis, or visceral leishmaniasis, or a trypanosomiasis.

The administration of the above defined compound and the composition can be carried out by oral, rectal, nasal, topical (including buccal and sublingual), parenteral (including subcutaneous, intramuscular, intravenous and intradermal) or intralesional route. As intended herein "intralesional" means that the administration of the compound of formula (1) is carried out at the sites of parasite-caused skin lesions of patients, in particular in case of Leishmania infections.

The above defined compound or the composition is administrated to a subject in need thereof in a therapeutically effective amount.

The term "therapeutically effective amount" refers to an amount which prevents, inhibits, suppresses or reduces the amount of Leishmania or Trypanosoma amastigotes, promastigotes, or both in a subject as compared to a control. The therapeutically effective amount may be determined by conventional methods known in the art.

In a preferred embodiment, a therapeutically effective amount of a compound of formula (I) is about 5 mg/m²/day to about 5 g/m²/day, in particular of about 500 mg/m²/day to about 3 g/m /day. However, one skilled in the art will know that this standard amount could be influenced by certain factors, such as the severity of the disease or disorder, previous treatment, the general health and/or age of the subject accepting the treatment, and other disease present.

In other embodiments, the present invention provides a method for reducing, suppressing or inhibiting a protozoan parasite of the family of the Trypanosomatidae in a target comprising contacting the target with an effective amount of an above defined composition or compound.

The target is a mammal tissue or cells derived therefrom. Preferably, the mammal tissue is a human tissue, a dog tissue.

In a preferred embodiment, the protozoan parasite is chosen from Leishmania parasite, in particular Leishmania. aethiopica, Leishmania. donovani, Leishmania. mexicana, Leishmania. infantum, Leishmania, tropica and Leishmania. major, preferably from Leishmania. infantum, Leishmania. tropica and Leishmania. major, more preferably from Leishmania. Infantum, or trypanosome parasite, in . particular Trypanosoma, brucei. gambiense.

According to a preferred embodiment of said method, the aboved defined compound or composition reduces, suppresses, or inhibits the Leishmania or Trypanosoma parasite growth, infection or proliferation by about 50% at a concentration of about 350 μΜ or less, about 200 μΜ or less, about 100 μΜ or less, about 70 μΜ or less, about 50 μΜ or less. In other embodiments, the present invention provides a pharmaceutical composition comprising as active substance at least a therapeutically effective amount of a compound of formula (1):

wherein:

- A represents a group chosen from a phenyl, a triazolyl, and a thienyl,

- Ri represents -CO-CH₂OH or -CO-NHOH,

- R₂ is chosen from H, triazolyl, methyltriazolyl, -CONHR₃, -CH₂-CONHR₃, - NHS0₂NHR₃, -CH₂-NHS0₂NHR₃, wherein R₃ represents H, a (Ci-C₈) alkyl group, an aryl group, a (C₃-C₈) cycloalkyl group, a heterocyclic group, or a heteroaryl group,

or a pharmaceutically acceptable salt thereof,

for its use in the treatment or prevention or inhibition of a parasitic disease, in particular of protozoan parasitic diseases, more particularly of leishmaniasis or trypanosomiasis, in a subject in need thereof.

In other embodiments, the present invention provides a pharmaceutical composition comprising as active substance at least a therapeutically effective amount of a compound of formula (1) and at least one anti -parasitic compound, such as a compound selected from: miltefosin, antimony based drugs, like meglumine antimoniate or sodium stibogluconate, amphotericin B, benzimidazol, nifurtimox, paromomycin, pentamidin and its derivatives, arsenic derivatives, melarsoprol and difluoromethylornithin.

In other embodiments, the present invention provides a product containing:

- at least a therapeutically effective amount of a compound of formula (1), and

- at least one anti-parasitic compound, such as a compound selected from: miltefosin, antimony based drugs, like meglumine antimoniate or sodium stibogluconate, amphotericin B, benzimidazol, nifurtimox, paromomycin, pentamidin and its derivatives, arsenic derivatives, melarsoprol and difluoromethylornithin,

as a combined preparation for simultaneous, separate or sequential use in the prevention or the treatment of parasitic diseases, in particular of protozoan parasitic diseases, more particularly of leishmaniasis or trypanosomiasis. The above defined pharmaceutical compositions or separate parts of the above defined products could include pharmaceutically acceptable salts of the compound of formula (1) and/or pharmaceutically acceptable carriers.

The term "pharmaceutically acceptable salt" refers to salt forms that are pharmacologically acceptable and substantially non-toxic to the subject being treated with the compound of the invention. The pharmaceutically acceptable salt forms of the compound of formula (la) or formula (lb) may be prepared according to methods well known in the art.

The term "pharmaceutically acceptable carriers" refers to non-API substances such as disintegrators, binders, fillers, and lubricants used in formulating pharmaceutical products. They are generally non-toxic for administering to humans.

The above defined pharmaceutical compositions or separate parts of the above defined products could be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries or suspensions.

The administration of the above defined pharmaceutical compositions or products could be carried out by oral, rectal, nasal, topical (including buccal and sublingual), parenteral (including subcutaneous, intramuscular, intravenous and intradermal) or intralesional route.

The present invention provides also a method for treating, inhibiting, or preventing parasitic diseases, in particular protozoan parasitic diseases, more particularly leishmaniasis, or trypanosomiasis, in a subject in need thereof comprising administering to said subject at least a therapeutically effective amount of a compound of formula (1):

- R2-A-R1,

wherein:

- A represents a group chosen from a phenyl, a triazolyl, and a thienyl,

- R, represents -CO-CH₂OH or -CO-NHOH,

- R₂ is chosen from H, triazolyl, methyltriazolyl, -CONHR₃, -CH₂-CONHR₃, - NHS0₂NHR₃, -CH₂-NHS0₂NHR₃, wherein R₃ represents H, a (C C₄) alkyl group, an aryl group, a (C₃-C₈) cycloalkyl group, a heterocyclic group, or a heteroaryl group,

or a pharmaceutically acceptable salt thereof.

The present invention is illustrated by the following figures and examples.

Figure 1 illustrates the growth curves of promastigote of L. infantum parasites in presence of lb (represented by■), la (represented by A) and nicotinamide (represented by ·). Results are the mean of two to four experiments, each performed in triplicate. The mean percentage of survival promastigotes respectively treated by compounds la, lb or nicotinamide is marked on ordinate axis. The concentration of compounds la or lb or nicotinamide in different cell cultures is marked on abscissa axis.

Examples

1.1. Compounds

Alpha-hydroxyacetophenone (compound la) and N-hydroxybenzamide (compound lb) were dissolved in 100 % DMSO at a concentration of 100 mM and stored at +4°C. For in vitro tests, compounds were diluted in culture medium and used immediately.

1.2. Strains and culture conditions

Promastigotes of Leishmania infantum (MHOM/MA/67/ITMAP-263), L. major (MHOM/SU/73/5-ASKH), L. tropica (MHOM/SU/74/SAF-K27), L. amazonensis (MHOM/BR/73/M2269) and L. braziliensis (MHOM/BR/75/M2904) were maintained at 26°C in SDM-79 medium (Brun and Schonenberger, Acta Tropica 1979;36(3):289-292) supplemented with 10% heat-inactivated foetal calf serum (FCS; Lonza), 100 IU penicillin/ml, 100 μg streptomycin/ml and 5 mg/1 hemin.

The L. infantum RSb80 and RSM60 strains were selected from a wild-type population using a stepwise selection until they were resistant to 80 μg/ml and 160 μg/ml trivalent antimony (Sblll), respectively. The sensitivity towards Sblll was determined after 3 days of incubation in presence of growing concentrations of Sblll. The IC₅o values for Sblll are 132.3 ± 14.-6 μg/ml and 163.2 ± 3.7 μg/ml for RSb80 and RSM60 strains, respectively. Both strains are 10- fold less sensitive to Sblll than wild-type parental strain.

Epimastigotes of Trypanosoma brucei gambiense (MHOM/CI/86/DAL967) were maintained at 26°C in SM medium (Cunningham, J Protozool 1977;21(2):325-329) supplemented with 10% FCS, 2 mM glutamine, 100 IU penicillin/ml and 100 μg streptomycin/ml.

Human leukemia monocyte cell line (THP-1) was cultured in RPMI 1640 medium (Lonza) supplemented with 10% FCS, 2 mM glutamine, 100 IU penicillin/ml and 100 μg streptomycin/ml, and incubated at 37°C with 5% C0₂.

1.3. IC50 determination of selected compounds on parasites

Late-log phase parasites were seeded at 1 x 10⁶ cells/ml in 96-well plates and grown at 26°C in the presence of serial dilutions of each compound. Each concentration point was tested in triplicate and all experiments were performed two times. The final concentration of DMSO did not exceed 0.5%, which was not toxic for parasites. After 3 days of incubation for Leishmania strains and 5 days for T. b. gambiense, viability and growth of parasites were determined by flow cytometry analysis. Briefly, a sample of cells (5 μΐ) was taken from each well and diluted into 500 μΐ of PBS (pH 7.2). Propidium iodide was added at a final concentration of 1 μ /ηι1 and cells were analyzed on a flow cytometer (Facsalibur™; Becton Dickinson) for 52 s. The parasite concentration was determined using standard curves where parasite concentrations were plotted as a function of mean number of cells counted by the cytometer after 52 s.

1.4. Cellular toxicity of compounds against non-infected THP-1 differentiated monocytes

THP-1 cells were cultured in RPMI 1640 medium supplemented with 10% FCS, 2 mM glutamine, 100 IU of penicillin/ml, and 100 μg of streptomycin/ml. THP-1 cells in the log phase of growth were differentiated in macrophages by incubation for 2 days in medium containing 20 ng/ml of phorbol myristate acetate in 96-well plates, at 37°C with 5% C0₂. Cells were washed once and serial dilutions of compounds up to 1 mM were added in culture medium. Each concentration point was tested in triplicate. Cells were incubated for 4 days at 37°C with 5% C0₂. The cytotoxic effect of each compound on non-infected macrophages was ascertained using trypan blue coloration.

1.5. IC50 determination of selected compounds on L. infantum intracellular amastigotes

The capacity of parasites to infect and replicate within macrophage host cells was evaluated according to a method adapted from da Luz et al. (da Luz et al, Antimicrob Agents Chemother 2009;53(12):5197-5203). THP-1 cells in the log phase of growth were differentiated in Labtek chamber slides at a concentration of 5 ^χ 10⁴ cells/well by incubation for 2 days in medium containing 20 ng of phorbol myristate acetate/ml. Five-day-old promastigote cultures were transferred to Schneider's medium (Lonza) at pH 5.4 supplemented with 20% FCS and incubated 24 hours at 26°C. Parasites were then used for the infection of freshly differentiated macrophages at a parasite macrophage ratio of 10:1. Infection was allowed to occur during 24 hours at 37°C with 5% C02, after which non- internalized parasites were removed and compounds were added to the media. After 4 days of incubation, cells were fixed with methanol and stained with Giemsa. The parasitic index (PI) was defined as the percentage of infected macrophages x number of intracellular parasites/ macrophage . 2. Results and discussion

In this study, the in vitro antiprotozoal activity of two compounds is evaluated, the alpha-hydroxyacetophenone, designed as compound la, and a hydroxamate-based compound, N-hydroxybenzamide, designed as compound lb.

The in vitro bioactivity of both compounds is determined on L. infantum promastigotes and intracellular amastigotes. The IC₅₀ values are presented in Table 1. The results show that the two compounds have potent inhibitory activities against both developmental stages with IC₅₀ values ranging from 29.3 μΜ to 348.0 μΜ. The cellular toxicity on non-infected macrophages was checked and it is founded that these cells were at least 10-fold less sensitive to compounds la and lb, as compared to wild-type promastigotes (Table 1). The efficacy of the two compounds is further tested on Sblll-resistant L. infantum parasites, namely RSb80 and RSM60 strains (see material and method section), and it is founded that these parasites are as sensitive as wild-type strain (Table 1).

Table 1

Comparison of survival of promastigote of L. infantum in presence of compounds lb, la and nicotinamide was also determined as described in materials and methods section. Growth curve experiments showed that compounds la and lb are 40 to 400 fold more active than nicotinamide, respectively (Figure 1).

The antiparasitic activity of compounds la and lb was then determined on a large panel of Leishmania species, responsible for various clinical symptoms, and on Trypanosoma brucei gambiense that causes Human African Trypanosomiasis. The IC₅₀ values of both compounds on promastigote (Leishmania) or epimastigote (Trypanosoma) forms are listed in Table 2. The results show some discrepancies of sensibility to compounds la and lb, depending on the species tested. L. braziliensis appears to be the most sensitive species, among the Leishmania strains tested. Interestingly, compounds la and lb showed similar and high efficacy against T. b. gambiense parasites.

Table 2

In conclusion, it is demonstrated that alpha-hydroxyacetophenone (compound la) and N- hydroxybenzamide (compound lb) are able to inhibit the in vitro proliferation of trypanosomatid parasites, such as Leishmania and Trypanosoma brucei species. The compounds exhibited micromolar inhibitory activities against promastigote and intracellular amastigote forms of Leishmania parasites with IC50 values ranging from 195.8 μΜ to 384.2 μΜ for compound la and from 19.6 μΜ to 174.1 μΜ for compound lb. In addition, these two compounds are not toxic on non-infected differentiated monocytes at antileishmanial doses. T. b. gambiense parasites are highly sensitive to both compounds with IC₅₀ values as low as 40.7 μΜ.

Claims

1. Compound of formula (1):

R₂-A-R,,

wherein:

- A represents a group chosen from a phenyl, a triazolyl, and a thienyl,

- Ri represents -CO-CH₂OH or -CO-NHOH,

- R₂ is chosen from H, triazolyl, methyltriazolyl, -CONHR₃, -CH₂-CONHR₃, - NHS0₂NHR₃, -CH₂-NHS0₂NHR₃, wherein R₃ represents H, a (C,-C₈) alkyl group, an aryl group, a (C₃-C ) cycloalkyl group, a heterocyclic group, or a heteroaryl group.

or a pharmaceutically acceptable salt thereof, for its use as a drug.

2. Compound according to claim 1, wherein:

- A represents a phenyl group,

- Ri represents -CO-CH₂OH or -CO-NHOH,

- R₂ in para-position of Ri is chosen from H, triazolyl, methyltriazolyl, -CONHR₃, -CH₂- CONHR₃, -NHS0₂NHR₃, -CH2-NHS0₂NHR₃, wherein R₃ represents H, or a (C,-C₈) alkyl group, an aryl group, a (C₃-C₈) cycloalkyl group, a heterocyclic group, or a heteroaryl group,

said compound corresponding to formula (l a) :

3. Compound according to claim 2, wherein:

- A represents a phenyl group,

- R₂ represents H,

- Ri represents -CO-CH₂OH or -CO-NHOH,

said compound corresponding to formula I

4. Compound according to claim 1 to 3, for its use as a drug for treating, inhibiting or preventing parasitic diseases, in particular protozoan parasitic diseases of a subject.

5. Compound according to claim 4, wherein the parasitic disease is caused by a protozoan parasite of the family of the Trypanosomatidae selected from the genus Trypanosoma or the genus Leishmania.

6. Compound according to claim 5, wherein the protozoan parasite of the genus Leishmania is selected from: Leishmania. infantum, Leishmania. tropica and Leishmania. Major.

7. Compound according to claim 5, wherein the protozoan parasite of the genus Trypanosoma is selected from Trypanosoma, brucei. gambiense.

8. Compound according to claim 4, wherein the parasitic diseases is a leishmaniasis, in particular cutaneous leishmaniasis, mucocutaneous leishmaniasis, or visceral leishmaniasis, or a trypanosomiasis.

9. Compound according to any one of claims 4 to 8, wherein the subject is a mammalian including human and dog.

10. Composition comprising:

- a compound of formula (1):

R₂-A-R_{l 5}

wherein:

- A represents a group chosen from a phenyl, a triazolyl, and a thienyl,

- R, represents -CO-CH₂OH or -CO-NHOH,

- R₂ is chosen from H, triazolyl, methyltriazolyl, -CONHR3, -CH₂-CONHR₃, - NHS0₂NHR₃, -CH₂-NHS0₂NHR₃, wherein R₃ represents H, a (C,-C₈) alkyl group, an aryl group, a (C₃-C₈) cycloalkyl group, a heterocyclic group, or a heteroaryl group,

or a pharmaceutically acceptable salt thereof, and

- at least one anti-parasitic compound, selected from the group comprising : miltefosin, antimony based drugs, like meglumine antimoniate or sodium stibogluconate, amphotericin B, benzimidazol, nifurtimox, paromomycin, pentamidin and its derivatives, arsenic derivatives, melarsoprol and difluoromethylornithin.

1 1. Method for reducing, suppressing or inhibiting a protozoan parasite of the family of the Trypanosomatidae in a target comprising administering to the target an effective amount of a compound of formula (1):

R₂-A-R,,

wherein:

- A represents a group chosen from a phenyl, a triazolyl, and a thienyl,

- R, represents -CO-CH₂OH or -CO-NHOH,

- R₂ is chosen from H, triazolyl, methyltriazolyl, -CONHR₃, -CH₂-CONHR₃, - NHS0₂NHR₃, -CH₂-NHS0₂NHR₃, wherein R₃ represents H, a (C_rC₈) alkyl group, an aryl group, a (C₃-C₈) cycloalkyl group, a heterocyclic group, or a heteroaryl group, or a pharmaceutically acceptable salt thereof.

12. Method according to claim 1 1, wherein the protozoan parasite of the family of the Trypanosomatidae is leishmania parasite, in particular Leishmania. infantum, Leishmania. tropica or Leishmania. Major, or trypanosoma parasite, in particular Trypanosoma, brucei. gambiense.