Chemosensitizers in Drug Transport Mechanisms Involved in Protozoan Resistance

Pradines, Bruno; Pages, Jean-Marie; Barbe, Jacques

doi:10.2174/156800505774912875

Cited by 21 publications

(14 citation statements)

References 255 publications

(383 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The position of the N 2 in the alkyl chain should affect the pK of the compounds, with TDR 58846 expected to be more basic by approximately 1.5 pK units. Since the initial observation on the CQ-reversing potential of VER and DES (5,26), more than 40 compounds that enhance the activity of CQ have been identified (42,52). We examined the classical series of CQ reversal drugs in combination with TDR 58845 and TDR 58846.…”

Section: Discussionmentioning

confidence: 99%

Novel 4-Aminoquinoline Analogs Highly Active against the Blood and Sexual Stages of Plasmodium In Vivo and In Vitro

Saénz

Mutka

Udenze

et al. 2012

Antimicrob Agents Chemother

View full text Add to dashboard Cite

New drugs to treat malaria must act rapidly and be highly potent against asexual blood stages, well tolerated, and affordable to residents of regions of endemicity. This was the case with chloroquine (CQ), a 4-aminoquinoline drug used for the prevention and treatment of malaria. However, since the 1960s, Plasmodium falciparum resistance to this drug has spread globally, and more recently, emerging resistance to CQ by Plasmodium vivax threatens the health of 70 to 320 million people annually. Despite the emergence of CQ resistance, synthetic quinoline derivatives remain validated leads for new drug discovery, especially if they are effective against CQ-resistant strains of malaria. In this study, we investigated the activities of two novel 4-aminoquinoline derivatives, TDR 58845, N 1 -(7-chloro-quinolin-4-yl)-2-methyl-propane-1,2-diamine, and TDR 58846, N 1 -(7-chloro-quinolin-4-yl)-2,N 2 ,N 2 -trimethylpropane-1,2-diamine and found them to be active against P. falciparum in vitro and Plasmodium berghei in vivo. The P. falciparum clones and isolates tested were susceptible to TDR 58845 and TDR 58846 (50% inhibitory concentrations [IC 50 s] ranging from 5.52 to 89.8 nM), including the CQ-resistant reference clone W2 and two multidrug-resistant parasites recently isolated from Thailand and Cambodia. Moreover, these 4-aminoquinolines were active against early and late P. falciparum gametocyte stages and cured BALB/c mice infected with P. berghei. TDR 58845 and TDR 58846 at 40 mg/kg were sufficient to cure mice, and total doses of 480 mg/kg of body weight were well tolerated. Our findings suggest these novel 4-aminoquinolines should be considered for development as potent antimalarials that can be used in combination to treat multidrug-resistant P. falciparum and P. vivax.

show abstract

Section: Discussionmentioning

confidence: 99%

Novel 4-Aminoquinoline Analogs Highly Active against the Blood and Sexual Stages of Plasmodium In Vivo and In Vitro

Saénz

Mutka

Udenze

et al. 2012

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Various ABC transporters in Leishmania have been implicated in mediating drug resistance (38). These include Ldmdr1 in L. donovani (23), Lamdr1 and Lamdr2 in L. amazonensis (21,29), LtpgpA in L. tarentolae (20,22,33), Ltmdr1 in L. tropica (19), Lemdr1 in L. enriettii (11), LmepgpA in L. mexicana (13), LmpgpA in L. major (7), and PEN r in L. major (12).…”

Section: Discussionmentioning

confidence: 99%

“…Hydrolysis of ATP is tightly coupled to drug efflux. Recent evidence has shown that some P-gp (9,11,21,23) and MRP (34,35) transporters are involved in drug resistance in the protozoan parasite Leishmania (38). Resistance to pentavalent antimonials such as sodium stibogluconate (SSG) in Leishmania tarentolae is due to an MRP member (LtPGPA).…”

mentioning

confidence: 99%

Flavonoid Dimers as Bivalent Modulators for Pentamidine and Sodium StiboglucanateResistance in Leishmania

Wong

Chan

Burkett

et al. 2007

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Drug resistance by overexpression of ATP-binding cassette (ABC) transporters is an impediment in the treatment of leishmaniasis. Flavonoids are known to reverse multidrug resistance (MDR) in Leishmania and mammalian cancers by inhibiting ABC transporters. Here, we found that synthetic flavonoid dimers with three (compound 9c) or four (compound 9d) ethylene glycol units exhibited a significantly higher reversing activity than other shorter or longer ethylene glycol-ligated dimers, with ϳ3-fold sensitization of pentamidine and sodium stibogluconate (SSG) resistance in Leishmania, respectively. This modulatory effect was dosage dependent and not observed in apigenin monomers with the linker, suggesting that the modulatory effect is due to its bivalent nature. The mechanism of reversal activity was due to increased intracellular accumulation of pentamidine and total antimony in Leishmania. Compared to other MDR modulators such as verapamil, reserpine, quinine, quinacrine, and quinidine, compounds 9c and 9d were the only agents that can reverse SSG resistance. In terms of reversing pentamidine resistance, 9c and 9d have activities comparable to those of reserpine and quinacrine. Modulators 9c and 9d exhibited reversal activity on pentamidine resistance among LeMDR1 ؊/؊ , LeMDR1 ؉/؉ , and LeMDR1-overexpressed mutants, suggesting that these modulators are specific to a non-LeMDR1 pentamidine transporter. The LeMDR1 copy number is inversely related to pentamidine resistance, suggesting that it might be involved in importing pentamidine into the mitochondria. In summary, bivalency could be a useful strategy for the development of more potent ABC transporter modulators and flavonoid dimers represent a promising reversal agent for overcoming pentamidine and SSG resistance in parasite Leishmania.

show abstract

“…Multi-drug resistance (MDR)-like proteins are involved in quinoline resistance in P. falciparum [23-25]. PfMRP is involved in QN resistance [26,27].…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin as a potential anti-malarial drug: in vitro synergy in combinational therapy with quinine against Plasmodium falciparum

Parquet

Henry

Wurtz

et al. 2010

Malar J

Self Cite

View full text Add to dashboard Cite

BackgroundQuinine (QN) remains the first line anti-malarial drug for the treatment of complicated malaria in Europe and Africa. The emergence of QN resistance has been documented. QN resistance is not yet a significant problem, but there is an urgent need to discover partners for use in combination with QN. The aim of the study was to assess the in vitro potentiating effects of atorvastatin (AVA), a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, in combination with QN against Plasmodium falciparum and to evaluate whether the effects of AVA could be associated with gene copy number or mutations in genes involved in QN resistance, such as pfcrt, pfmdr1, pfmrp and pfnhe.MethodsThe susceptibilities to combination of AVA with QN were assessed against 21 parasite strains using the in vitro isotopic microtest. Genotypes and gene copy number were assessed for pfcrt, pfmdr1, pfmdr2, pfmrp genes. In addition, the number of DNNND, DDNHNDNHNN repeats in pfnhe-1 ms4760 and the ms4760 profile were determined for each strains of P. falciparum.ResultsAVA demonstrated synergistic effects in combination with QN against 21 P. falciparum strains. The QN IC50 was reduced by 5% (0% to 15%; 95%CI: 1%-8%), 10% (3% to 23%; 95%CI: 7%-14%) and 22% (14% to 40%; 95%CI: 19%-25%) in presence of AVA at concentrations of 0.1, 0.5 and 1.0 μM, respectively. These reductions were all significant (p < 0.009). The reduction in the QN IC50 in presence of AVA was not significantly correlated with the QN IC50 (r = 0.22, P = 0.3288) or the AVA IC50 (r = 0.03, P = 0.8946). The synergistic effect of AVA in combination with QN was not significantly associated with polymorphisms in the pfcrt, pfmdr1, pfmrp, and pfnhe-1 genes that could be involved in QN resistance. The synergistic effect of AVA on QN responses was not significantly associated with pfmdr1 copy number (P = 0.0428).ConclusionThe synergistic effect of AVA in combination with QN was found to be unrelated to mutations occurring in transport protein genes involved in QN drug resistance. The different mechanisms of drug uptake and/or mode of action for AVA compared to the other anti-malarial drugs, as well as the AVA-mediated synergy of the anti-malarial effect of QN, suggests that AVA will be a good candidate for combinatorial malaria treatment. All of these observations support calls for both an in vivo evaluation with pharmacokinetic component and clinical trials of AVA as an anti-malarial therapy.

show abstract

Chemosensitizers in Drug Transport Mechanisms Involved in Protozoan Resistance

Cited by 21 publications

References 255 publications

Novel 4-Aminoquinoline Analogs Highly Active against the Blood and Sexual Stages of Plasmodium In Vivo and In Vitro

Novel 4-Aminoquinoline Analogs Highly Active against the Blood and Sexual Stages of Plasmodium In Vivo and In Vitro

Flavonoid Dimers as Bivalent Modulators for Pentamidine and Sodium StiboglucanateResistance in Leishmania

Atorvastatin as a potential anti-malarial drug: in vitro synergy in combinational therapy with quinine against Plasmodium falciparum

Contact Info

Product

Resources

About