RESUMEN

The failures in the treatment of leishmaniasis is an increasing problem around the world, especially related to resistance. Thus, we describe the synthesis and in vivo anti-Leishmania activity of alkylphosphocholine and alkyltriazoles; besides, their likely action mechanisms stem from some eventual inhibition of parasite enzymes using computational tools. These compounds were tested in an in vivo hamster model infected with Leishmania Leishmania infantum chagasi. Fifty days after parasite inoculation, the two compounds 12-azidedodecylphosphocholine (3) and 3-(1-(12-fluorododecyl)-1H-1,2,3-triazol-1-yl)propano-1-ol (9), were separately administered once a day as oral suspensions (25 and 12.5 mg/kg/day, respectively) during ten days, and their efficacy was compared to the reference compound pentavalent antimonial Glucantime (GLU). Compound 3 significantly reduced the number of parasites in the spleen (4.93 × 102 amastigotes/g) and liver (4.52 × 103 amastigotes/g). Compound 9 reduced the number of amastigotes in the spleen to 1.30 × 104 and 1.36 × 103 amastigotes/g in the liver. GLU was the most effective overall treatment (7.50 × 101 and 2.28 × 102 amastigotes/g in the spleen and liver, respectively). The high activity levels of these compounds in vivo may stem from their high in vitro leishmanicidal activity and lipophilicity. The in silico absorption, distribution, metabolism, and excretion studies also showed some anti-Leishmania potential. Compound 9 had more lipophilic characteristics than those of compound 3. In silico studies of the nine enzymes of compounds 3 and 9 showed significant evidence of interactions with nicotimidase and tyrosine aminotransferase, demonstrating possible inhibition enzymes present in L. (L.) infantum chagasi. These compounds could be a promising template for developing a new class of leishmanicidal agents, by oral route, and deserve further investigation to explore different therapeutic regimens.

Asunto(s)

Antiprotozoarios/farmacología , Leishmania infantum/efectos de los fármacos , Leishmaniasis Visceral/tratamiento farmacológico , Fosforilcolina/farmacología , Triazoles/farmacología , Administración Oral , Animales , Antiprotozoarios/administración & dosificación , Antiprotozoarios/uso terapéutico , Cricetinae , ADN Complementario/biosíntesis , Femenino , Hígado/química , Mesocricetus , Simulación del Acoplamiento Molecular , Fosforilcolina/administración & dosificación , Fosforilcolina/química , Fosforilcolina/uso terapéutico , ARN/aislamiento & purificación , Bazo/química , Triazoles/administración & dosificación , Triazoles/química , Triazoles/uso terapéutico

RESUMEN

The new polymer inclusion membrane (PIM) with a 1-alkyltriazole matrix was used to separate palladium(II) ions from aqueous chloride solutions containing a mixture of Zn-Pd-Ni ions. The effective conditions for transport studies by PIMs were determined based on solvent extraction (SX) studies. Furthermore, the values of the stability constants and partition coefficients of M(II)-alkyltriazole complexes were determined. The values of both constants increase with the growing hydrophobicity of the 1-alkyltriazole molecule and have the highest values for the Pd(II) complexes. The initial fluxes, selectivity coefficients, and recovery factors values of for Pd, Zn and Ni were determined on the basis of membrane transport studies. The transport selectivity of PIMs were: Pd(II) > Zn(II) > Ni(II). The initial metal ion fluxes for all the cations increased with the elongation of the alkyl chain in the 1-alkyltriazole, but the selectivity coefficients decreased. The highest values of the initial fluxes at pH = 4.0 were found for Pd(II) ions. The best selectivity coefficients Pd(II)/Zn(II) and Pd(II)/Ni(II) equal to 4.0 and 13.4, respectively, were found for 1-pentyl-triazole. It was shown that the microstructure of the polymer membrane surface influences the kinetics of metal ion transport. Based on the conducted research, it was shown that the new PIMs with 1-alkyltriazole can be successfully used in an acidic medium to separate a mixture containing Pd(II), Zn(II) and Ni(II) ions.