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than the D-lactate via (levels of excretion drastically decreased,
potentially inhibition at trypanothione reductase/glyoxilase levels)
[26]. Regarding to the compound P3py, both species were inhibited
in somehow in their glycosomal enzymatic clusters, so the subsis-
tence of the parasites is allowed by the energy obtained at mito-
chondrial level. The way to affect one of the most significant
metabolite excretion, succinate, was also shared by the two species,
decreasing its excretion to the medium with respect to control. On
the other hand, the end metabolites of anaerobic oxidation, such as
the D-lactate (in L. braziliensis) and ethanol (L. infantum) appeared
slightly increased in the culture medium, this suggests that despite
being available glucose in the medium compound P3Py interferes
with some step of tricarboxylic cycle (TCA) preventing the parasite
uses this fundamental way and having to resort to means of com-
pensation for energy production such as those used in absence of
glucose. Another mechanism of action could be postulated for this
compound is inhibition of transaminases, so that pyruvate cannot be
transformed into alanine in an amount sufficient for it to appear in
the culture medium [27].
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They also showed a wide range of ultrastructural alterations to
the promastigotes forms of Leishmania spp. treated with com-
pounds were found. These alterations, which mainly took place at
the mitochondrial and cytoplasmic levels, could be related to the
metabolic changes mentioned above concerning the production of
succinate and acetate, which might originate from a disturbance in
the enzymes involved in pyruvate metabolism inside the cells.
Thus, these in vitro results show that the synthetic aza-scorpiand
like macrocyclic derivatives are potentially promising agents for the
treatment of Leishmania infection. Further in vivo studies are war-
ranted to further evaluate this potential, actually a patent about this
family of compound has been already filled (P201132035).
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Nat. Rev. Drug Discov. 5 (2006) 941e955.
Acknowledgements
[20] M.E. Villagran, C. Marin, I. Rodriguez-González, J.A. de Diego, M. Sanchez-
Moreno, Use of an iron superoxide dismutase excreted by Trypanosoma cruzi
in the diagnosis of Chagas disease: seroprevalence in rural zones of the state
of Queretaro, Mexico, Am. J. Trop. Med. Hyg. 73 (2005) 510e516.
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adaptation to available carbon sources, Mol. Biochem. Parasitol. 149 (2006)
1e9.
[22] M. Ginger, Trypanosomatid biology and euglenozoan evolution: new insights
and shifting paradigms revealed through genome sequencing, Protist 156
(2005) 377e392.
[23] J.J. Cazzulo, Aerobic fermentation of glucose by trypanosomatids, FASEB J. 6
(1992) 3153e3161.
[24] P.A.M. Michels, F. Bringaud, M. Herman, V. Hannaert, Metabolic functions
of glycosomes in trypanosomatids, Biochem. Biophys. Acta 1763 (2006)
1463e1477.
Financial support by the Spanish Ministerio de Ciencia e Inno-
vación and FEDER funds of the E.U. (Projects CTQ2009-14288-CO4-
01 and CONSOLIDER INGENIO 2010 CSD2010-00065), Generalitat
Valenciana (PROMETEO 2011/008) is gratefully acknowledged.
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