Antimalarial polyamine analogs

Edwards, M. L.; Stemerick, David M.; Bitonti, Alan J.; Dumont, Jennifer; McCann, PP; Bey, Philippe; Sjoerdsma, Albert

doi:10.1021/jm00106a015

Cited by 46 publications

(39 citation statements)

References 2 publications

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“…In consequence, the antimalarial activity of the compounds may be related to their lipophilicity and the selective uptake by infected RBC. A similar pattern was observed previously by Edwards et al (22) for a series of ␣,-dibenzyltetraamine analogues of MDL27695 (Fig. 1), the activity of which correlated with selective uptake by RBC.…”

supporting

confidence: 90%

“…1). These molecules were anticipated to display antiprotozoal activity because they are structurally related to the known antitrypanosomal alkylpolyamines MDL27695 (7,22), CHE-3-7-3 (5), and BW-1 (43) and particularly to the 4-aminopiperidine-based antimalarial agents described recently by Ellman and coworkers (8,9). To test this hypothesis, 44 1-phenethyl-4-aminopiperidine derivatives were tested in vitro against four protozoan parasites responsible for HAT (T. brucei rhodesiense), Chagas' disease (Trypanosoma cruzi), visceral leishmaniasis (Leishmania donovani), and malaria (P. falciparum).…”

mentioning

confidence: 99%

“…1), the activity of which correlated with selective uptake by RBC. The authors postulated that accumulation in RBC may be related to the lipophilicity of the compounds (22). On the other hand, Calas and colleagues have shown a positive relationship between the abilities of long-methylene-chain mono-and bisquaternary ammonium salts to inhibit P. falciparum growth in vitro and their inhibition of phosphatidylcholine biosynthesis (1,2).…”

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confidence: 99%

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Antiprotozoal Activity of 1-Phenethyl-4-Aminopiperidine Derivatives

Dardonville

Fernandez-Fernandez

Gibbons

et al. 2009

Antimicrob Agents Chemother

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A series of 44 4-aminopiperidine derivatives was screened in vitro against four protozoan parasites (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum). This screening identified 29 molecules selectively active against bloodstream-form T. b. rhodesiense trypomastigotes, with 50% inhibitory concentrations (IC 50 ) ranging from 0.12 to 10 M, and 33 compounds active against the chloroquine-and pyrimethamine-resistant K1 strain of P. falciparum (IC 50 range, 0.17 to 5 M). In addition, seven compounds displayed activity against intracellular T. cruzi amastigotes in the same range as the reference drug benznidazole (IC 50 , 1.97 M) but were also cytotoxic to L-6 cells, showing little selectivity for T. cruzi. None of the molecules tested showed interesting antileishmanial activity against axenic amastigotes of L. donovani. To our knowledge, this is the first report of the antitrypanosomal activity of molecules bearing the 4-aminopiperidine skeleton.Tropical diseases due to parasitic protozoa cause great mortality and disability in the less developed world. Malaria and kinetoplastid diseases such as human African trypanosomiasis (HAT, or sleeping sickness), Chagas' disease, and leishmaniases are among the main neglected parasitic diseases, affecting hundreds of millions of people worldwide (http://www.dndi.org /index.php/diseases.html?idsϭ2). However, the low income of the affected populations does not make it financially attractive for pharmaceutical companies to invest in the development of new drugs against these diseases. The number of antiprotozoal drugs available is limited, and they are old, toxic, and losing efficacy due to the emergence of resistant parasites. New drugs are thus urgently needed (37).The landscape of drug discovery and development for new antiparasitic drugs has changed in the past few years thanks to financial backing from not-for-profit organizations and the involvement of public-private partnerships. The collaboration of various pharmaceutical companies with the Special Programme for Research and Training in Tropical Diseases (TDR), giving access to their compound libraries to help scientists search for new antiparasitic drugs, is a good example of the pragmatic approach required for the development of new medicaments for those neglected diseases (15,32,40). The screening of compound libraries to discover new hit and lead compounds against protozoan parasites has been used very efficiently by our group for the past few years. Very potent antiprotozoal compounds, active in vitro and in vivo against Trypanosoma brucei rhodesiense and Plasmodium falciparum, were identified by our group (16,17,38). These lead compounds were discovered by screening against T. brucei and P. falciparum a small library (Ͻ100 molecules) of dicationic compounds structurally related to known antiparasitic drugs (e.g., pentamidine, diminazene) but primarily synthesized by us for different medicinal targets.Following this successful approach, we have now selected from our i...

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confidence: 99%

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Antiprotozoal Activity of 1-Phenethyl-4-Aminopiperidine Derivatives

Dardonville

Fernandez-Fernandez

Gibbons

et al. 2009

Antimicrob Agents Chemother

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“…Putrescine influx in P. knowlesi-infected erythrocytes was inhibited by BCBD in a dose-dependent manner, and the cytocidal concentration of growth of intraerythrocytic parasite (IC 50 value of 7.64 Ϯ 0.94 ng/ml) was found to be many-fold lower than other known polyamine analogues or biosynthetic inhibitors (47)(48)(49). The novelty of this approach is that inhibitory effect of BCBD on the parasite growth and multiplication in the culture medium is cytocidal as addition of exogenous polyamines fails to reverse the effect of BCBD.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Simian Malarial Parasite (Plasmodium knowlesi)-induced Putrescine Transport in Rhesus Monkey Erythrocytes

Singh

Puri

Singh

et al. 1997

Journal of Biological Chemistry

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A stage-dependent increase in the level of putrescine, spermidine, and spermine during intraerythrocytic growth of Plasmodium knowlesi in rhesus monkey erythrocytes was observed. Further, intraerythrocytic P. knowlesi-induced putrescine influx was found in trophozoite stage-infected erythrocytes and process was time-and temperature-dependent and showed saturable kinetics. Characteristics of induced putrescine influx appears in infected erythrocytes to be close to the normal erythrocytes in terms of affinity of putrescine to the putrescine transporter (K m 34.6 ؎ 3.8 M as normal erythrocytes and K m 37.2 ؎ 5.2 M in infected erythrocytes). However, the difference involves the significant increase in the putrescine influx rate after infection (V max ‫؍‬ 4.21 nmol/min/10 10 normal erythrocytes, compared with 11.6 nmol/min/10 10 infected erythrocytes). Energy dependence, involvement of -SH group, and noninterference by amino acid, spermidine, and spermine in the putrescine influx process clearly demonstrate the presence of a distinct transporter for putrescine in infected erythrocytes. A putrescine conjugate N 1 ,N 4 -bis-(7-chloroquinoline-4-yl)butane-1,4-diamine (BCBD) was synthesized, which inhibits the putrescine influx in the P. knowlesi infected erythrocytes (K i of 43.2 M) as well as in vitro growth of P. knowlesi (IC 50 value, 7.64 ؎ 0.97 ng/ml BCBD, 10.8 ؎ 0.45 ng/ml chloroquine). Addition of exogenous polyamines failed to reverse the inhibitory effect of BCBD in vitro. Administration of BCBD (24 mg/kg body weight, intraperitoneal, twice a day for 4 days) cured the Swiss mice infected with multidrugresistant infection of Plasmodium yoelii. Therefore, inhibition of putrescine transport in malaria-infected erythrocytes offers a lead in the search of a new class of chemotherapeutic molecules against malaria.

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“…[87] It has been shown that certain PA analogues can act, for example, as antiparasitic [88] and antimalarial [89] agents, and as antidiarrhoeals. [90] Thus, DEHSPM is already under clinical evaluation to control chronic diarrhoea, in particular associated with AIDS patients, whereas a new class of metabolically unstable, to avoid accumulation of cytotoxic metabolites, PA antidiarrhoeals (e.g.…”

Section: Polyamine Analogues Involved In Other Cellular Functionsmentioning

confidence: 99%

Structure, Biological Activity and Synthesis of Polyamine Analogues and Conjugates

Karigiannis

Papaioannou²

2000

Eur. J. Org. Chem.

119

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The structure and the biological significance of naturally occurring and synthetic polyamine analogues and conjugates are presented and the available methodologies for their synthesis are described. These methodologies involve either the selective functionalization of the amino functions, using suitable protecting groups or acylating agents, or fragment synthesis protocols. The latter employ suitable amino components and simple reactions, like Michael addition to α,β‐unsaturated nitriles, alkylation of amines and sulfonamides, reductive alkylation and acylation followed by reduction of the thus‐obtained amides, as key‐reactions, or azides as key‐intermediates, for the assembly of the polyamine skeleton. Syntheses performed in solution as well as in the solid phase are discussed.

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Antimalarial polyamine analogs

Cited by 46 publications

References 2 publications

Antiprotozoal Activity of 1-Phenethyl-4-Aminopiperidine Derivatives

Antiprotozoal Activity of 1-Phenethyl-4-Aminopiperidine Derivatives

Characterization of Simian Malarial Parasite (Plasmodium knowlesi)-induced Putrescine Transport in Rhesus Monkey Erythrocytes

Structure, Biological Activity and Synthesis of Polyamine Analogues and Conjugates

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