Antileishmanial activity of sp super(2)-iminosugar derivatives

A series of sp super(2)-iminosugar-type glycomimetics bearing S-linked pseudoglycoside substituents (sulfide, sulfoxide and sulfone derivatives) has been synthesized and evaluated as new potential drugs against the protozoan parasite Leishmania, responsible of leishmaniasis, the second most relevant...

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Bibliographic Details
Published in:RSC advances 2015-02, Vol.5 (28), p.21812-21822
Main Authors: Sanchez-Fernandez, Elena M, Gomez-Perez, Veronica, Garcia-Hernandez, Raquel, Garcia Fernandez, Jose Manuel, Plata, Gabriela B, Padron, Jose M, Ortiz Mellet, Carmen, Castanys, Santiago, Gamarro, Francisco
Format: Article
Language:English
Subjects:
Bearing
Derivatives
Drugs
Leishmania donovani
Parasites
Parasitic diseases
Strategy
Sulfides
Toxicity
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Summary:A series of sp super(2)-iminosugar-type glycomimetics bearing S-linked pseudoglycoside substituents (sulfide, sulfoxide and sulfone derivatives) has been synthesized and evaluated as new potential drugs against the protozoan parasite Leishmania, responsible of leishmaniasis, the second most relevant parasitic disease after malaria. All the prepared compounds share a bicyclic 5N,6O-oxomethylidenenojirimycin glycone-like moiety bearing a substitution pattern of configurational complementarity with the natural alpha -glucosides and incorporate either an n-octyl or n-dodecyl aglycone-like substituent. Not surprisingly, they behaved as potent to moderate competitive inhibitors of alpha -glucosidase (inhibition constants, K sub(i), in the range 1.3 to 447 mu M). Evaluation of the antileishmanial activity indicated that the dodecyl pseudoglycosides present a significant antiparasitic activity in intracellular amastigotes of Leishmania donovani, the clinically relevant form of the parasite. The antileishmanial effect seems to be associated with the anticancer and proapoptotic activity of the glycomimetics, but not with the alpha -glucosidase inhibitory efficiency. The (S sub(S))-configured dodecylsulfoxide derivative 4, exhibiting the most favourable activity/toxicity profile, was further assayed in combination treatment with miltefosine, the first oral antileishmanial drug, using the fixed ratio isobologram method. The interaction between derivative 4 and 0.1, 0.2 and 0.3 mu M miltefosine was classified as synergistic, showing combination indices of 0.78, 0.76 and 0.80, respectively. Additionally, a miltefosine resistant Leishmanialine and the wild-type strain showed similar susceptibility to derivative 4. The results illustrate the potential of sp super(2)-iminosugar pseudoglycosides as promising prototypes for the development of new therapeutic strategies for leishmaniasis.
ISSN:2046-2069
DOI:10.1039/c5ra02627j