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   Exp Parasitol 2000 Mar;94(3):198-200
   
Aminothiol multidentate chelators against Chagas disease.

    Deharo E, Loyevsky M, John C, Balanza E, Ruiz G, Munoz V, Gordeuk VR
    
   Institut de Recherche pour le Developpement (IRD), La Paz, CP 9214,
   Bolivia. plantibba@megalink.com
   
   Three compounds of an aminothiol family of iron chelators were
   examined for activity against trypomastigote (human) and epimastigote
   (vector) forms of Trypanosoma cruzi: tetraethyl and tetramethyl
   derivatives of ethane-1,2-bis (N-1-amino-3-ethyl butyl-3-thiol)
   (BAT-TE and BAT-TM) and N',N',N'-tris-(2-methyl-2-mercaptopriopyl)-
   1,4,7-triazacyclonane (TAT). BAT-TE at 270 microM completely arrested
   the growth of trypomastigote forms in mouse blood stored at 4 degrees
   C for 24 h (IC(50) 67.7+/-7 microM), while BAT-TM arrested growth at
   630 microM (IC(50) 158+/-17 microM) and TAT at concentrations >800
   microM (IC(50) 415+/-55 microM). In T. cruzi-infected mice, BAT-TE and
   BAT-TM had no anti-trypanosomal activity in doses up to 200 mg/kg,
   whether the route of administration was intraperitoneal or oral, and
   TAT was not tested due to insufficient quantity. TAT had an IC(50) of
   52+/-7 microM against the epimastigote forms while BAT-TM and BAT-TE
   were inhibitory only at concentrations >250 microM. The trypanocidal
   activity of BAT derivatives in blood stored at 4 degrees C makes these
   compounds potential candidates for the purpose of clearing donated
   blood of trypomastigotes. Copyright 2000 Academic Press.
   
   PMID: 10831386, UI: 20293541
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   J Inorg Biochem 1995 Dec;60(4):277-88
   
Chelating agent inhibition of Trypanosoma cruzi epimastigotes in vitro.

    Rodrigues RR, Lane JE, Carter CE, Bogitsh BJ, Singh PK, Zimmerman LJ,
    Molenda JJ, Jones MM
    
   Department of Biology, Vanderbilt University, Nashville, Tennessee
   37235, USA.
   
   A number of chelating agents and some of their derivatives are as
   effective as, or superior to, benznidazole, the compound currently in
   clinical use, in the suppression of the reproduction of epimastigotes
   of Trypanosoma cruzi, the protozoa that causes Chagas' disease. All
   compounds were examined at a culture concentration of 5 micrograms/mL.
   The most effective compounds included
   N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine, sodium
   diethylamine-N-carbodithioate, piperidine-N-carbodithioate and several
   of its analogs, a number of other carbodithioates with two nonpolar
   groups on the nitrogen, and tetraethylthiuram disulfide, a prodrug of
   sodium diethylamine-N-carbodithioate and widely used in the treatment
   of alcoholism. The introduction of additional ionic or nonionic polar
   groups on the chelating molecule generally results in a loss of
   tyrpanocidal activity. Common commercially available chelating agents
   which exhibited no activity included D-penicillamine,
   meso-2,3-dimercaptosuccinic acid, and triethylenetetramine
   tetrahydrochloride. Dose-response data on the culture indicated that
   some of these compounds exhibited inhibition of Trypanosoma cruzi
   epimastigotes at concentrations as low as 0.625 microgram/mL. It is
   proposed that the mechanism of action of these compounds is based on
   their ability to interfere with the essential metal metabolism at
   intracellular sites of the epimastigote involving iron, copper, or
   zinc. The results also indicate that a certain degree of
   hydrophobicity may be necessary for the groups attached to the literal
   metal-bonding structure if the compounds are to successfully inhibit
   the epimastigotes of Trypanosoma cruzi. The development of
   antiprotozoal drugs which are chelating agents specifically designed
   to selectively disrupt the essential metal metabolism of Trypanosoma
   cruzi should furnish a new generation of drugs which can be used in
   the treatment of Chagas' disease.
   
   PMID: 8530923, UI: 96081476
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   Comp Biochem Physiol Comp Physiol 1993 Dec;106(4):813-21
   
The effect of iron nutritional status on Trypanosoma cruzi infection in
germfree and conventional mice.

    Pedrosa ML, Nicoli JR, Silva ME, Silva ME, Silva ME, Vieira LQ, Bambirra
    EA, Vieira EC
    
   Departamento de Ciencias Biologicas, Universidade Federal de Ouro
   Preto, MG, Brazil.
   
   1. Conventional (CV) and gnotobiotic (GN) female CFW mice were
   infected with the Y strain of Trypanosoma cruzi. 2. After infection,
   both CV and GN groups received injections of iron-dextran or
   desferrioxamine. Non-injected mice served as controls. 3. The
   parasitemia was more intense in iron-dextran-treated mice. 4. The iron
   levels in serum, liver, and spleen were: (a) not decreased by
   desferrioxamine and (b) increased by iron-dextran treatments. 5. An
   increase in leukocyte numbers was observed in all GN and CV groups
   after infection. 6. There was no difference in total iron binding
   capacity (TIBC) and iron saturation transferrin (IST) between GN and
   CV mice before infection. 7. In CV groups, after infection, TIBC was
   decreased whereas the levels of IST were increased; in GN the opposite
   occurred. 8. Trypanosome-specific IgG and IgM antibody levels were
   raised in the GN group but not in the CV group.
   
   PMID: 7906641, UI: 94155566
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