Putrescine uptake inhibition by aromatic diamidines in leishmania infantum promastigotes

Reguera, Rosa M.; Fouce, Rafael Balaña; Cubría, J.C.; Bujidos, M.L.Alvarez; Ordóñez, David

doi:10.1016/0006-2952(94)90316-6

Cited by 35 publications

(10 citation statements)

References 20 publications

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“…This suggests that binding to DNA may not be the major mode of action. Other possible modes of action include inhibition of arginine transport into the Leishmania cells (Kandpal et al 1996), some toxic events in the mitochondria (Bray et al 2003;Cushion et al 2004) or inhibition of the biosynthesis or transport of polyamines in Leishmania (Reguera et al 1994;Calonge et al 1996;Basselin et al 1996Basselin et al , 1997Basselin et al , 2000. Pentamidine has been shown to inhibit the transport of putrescine and spermidine (Basselin et al 1996(Basselin et al , 2000 in Leishmania, thereby altering the balance between the extracellular and intracellular polyamine concentrations.…”

Section: Resultsmentioning

confidence: 99%

Anti-plasmodial and anti-leishmanial activity of conformationally restricted pentamidine congeners

Huang

Eynde

Mayence

et al. 2006

Journal of Pharmacy and Pharmacology

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A library of 52 pentamidine congeners in which the flexible pentyldioxy linker in pentamidine was replaced with various restricted linkers was tested for in-vitro activity against two Plasmodium falciparum strains and Leishmania donovani. The tested compounds were generally more effective against P. falciparum than L. donovani. The most active compounds against the chloroquine-sensitive (D6, Sierra Leone) and -resistant (W2, Indochina) strains of P. falciparum were bisbenzamidines linked with a 1,4-piperazinediyl or 1, 4-homopiperazinediyl moiety, with IC50 values (50% inhibitory concentration, inhibiting parasite growth by 50% in relation to drug-free control) as low as 7 nM based on the parasite lactate dehydrogenase assay. Seven piperazine-linked bisbenzamidines substituted at the amidinium nitrogens with a linear alkyl group of 3-6 carbons (22, 25, 27, 31) or cycloalkyl group of 4, 6 or 7 carbons (26, 32, 34) were more potent (IC50<40 nM) than chloroquine or pentamidine as anti-plasmodial agents. The most active anti-leishmanial agents were 4,4'-[1,4-phenylenebis(methyleneoxy)]bisbenzenecarboximidamide (2, IC50 approximately 0.290 microM) and 1,4-bis[4-(1H-benzimidazol-2-yl)phenyl] piperazine (44, IC50 approximately 0.410 microM), which were 10- and 7-fold more potent than pentamidine (IC50 approximately 2.90 microM). Several of the more active anti-plasmodial agents (e.g. 2, 31, 33, 36-38) were also potent anti-leishmanial agents, indicating broad antiprotozoal properties. However, a number of analogues that showed potent anti-plasmodial activity (1, 18, 21, 22, 25-28, 32, 43, 45) were not significantly active against the Leishmania parasite. This indicates differential modes of anti-plasmodial and anti-leishmanial actions for this class of compounds. These compounds provide important structure-activity relationship data for the design of improved chemotherapeutic agents against parasitic infections.

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Section: Resultsmentioning

confidence: 99%

Anti-plasmodial and anti-leishmanial activity of conformationally restricted pentamidine congeners

Huang

Eynde

Mayence

et al. 2006

Journal of Pharmacy and Pharmacology

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“…The P2 adenosine transporter of Trypanosoma brucei (23) appears to play some part in the transport of this drug, although the situation is complex (24,47), with at least two additional transporters also capable of carrying the drug (29). In Leishmania donovani, pentamidine was found to be a competitive inhibitor of arginine transport (40,41) and a noncompetitive inhibitor of putrescine and spermidine transport in Leishmania infantum (51), L. donovani, and L. mexicana (12). With the exception of the P2 nucleoside transporter in T. brucei, the physiological roles of the carrier proteins which accumulate pentamidine have yet to be identified.…”

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confidence: 99%

Resistance to Pentamidine in Leishmania mexicana Involves Exclusion of the Drug from the Mitochondrion

Basselin

Denise

Coombs

et al. 2002

Antimicrob Agents Chemother

136

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The uptake of [3 H]pentamidine into wild-type and drug-resistant strains of Leishmania mexicana was compared. Uptake was carrier mediated. Pentamidine-resistant parasites showed cross-resistance to other toxic diamidine derivatives. A substantial decrease in accumulation of the drug accompanied the resistance phenotype, although the apparent affinity for pentamidine by its carrier was not altered when initial uptake velocity was measured. The apparent V max , however, was reduced. An efflux of pentamidine could be measured in both wild-type and resistant cells. Only a relatively small proportion of the total accumulated pentamidine was available for efflux in wild-type cells, while in resistant cells the majority of loaded pentamidine was available for release. Pharmacological reagents which diminish the mitochondrial membrane potential reduced pentamidine uptake in wild-type parasites, and the mitochondrial membrane potential was shown to be reduced in resistant cells. A fluorescent analogue of pentamidine, 4,6-diamidino-2-phenylindole, accumulated in the kinetoplast of wild-type but not resistant parasites. These data together indicate that diamidine drugs accumulate in the Leishmania mitochondrion and that the development of the resistance phenotype is accompanied by lack of mitochondrial accumulation of the drug and its exclusion from the parasites.

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“…The most important result is that this relationship is conserved using the results on Leishmania infantum promastigotes (Panel A, Figure 3) obtained by Balana-Fouce et a/. (1989), Reguera et a/. (1994) and by Calonge ef a/.…”

Section: Resultsmentioning

confidence: 67%

Structural Determinants of Putrescine Uptake Inhibition Produced by Cationic Diamidines in the Model of TrypanosomatidCrithidia fasciculata

Navas

García-Fernández²,

Reguera³

et al. 1996

Biological Chemistry Hoppe-Seyler

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The effect of a heterologous series of cationic diamidines has been tested on cell growth and polyamine uptake on the model of insect Trypanosomatid Crithidia fasciculata. The maximum inhibitory effect on both parameters was found for pentamidine and dibromopropamidine, which exhibit a longer distance between amino and imino substituents. A minimum inhibitory effect was found with amicarbalide. A good relationship was obtained when the distance between amino moieties was plotted versus the inhibitory effect on putrescine uptake, suggesting a role of this structural property on polyamine transport in Crithidia fasciculata. In addition, a similar correlation was obtained for another Trypanosomatid parasite, Leishmania infantum.

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Putrescine uptake inhibition by aromatic diamidines in leishmania infantum promastigotes

Cited by 35 publications

References 20 publications

Anti-plasmodial and anti-leishmanial activity of conformationally restricted pentamidine congeners

Anti-plasmodial and anti-leishmanial activity of conformationally restricted pentamidine congeners

Resistance to Pentamidine in Leishmania mexicana Involves Exclusion of the Drug from the Mitochondrion

Structural Determinants of Putrescine Uptake Inhibition Produced by Cationic Diamidines in the Model of TrypanosomatidCrithidia fasciculata

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