Phenoxypropoxybiguanides, Prodrugs of DHFR−Inhibiting Diaminotriazine Antimalarials

Jensen, N. P.; Ager, Arba L.; Bliss, Robert A.; Canfield, Craig J.; Kotecka, Barbara; Rieckmann, Karl H.; Terpinski, Jacek; Jacobus, David P.

doi:10.1021/jm010089z

Cited by 89 publications

(67 citation statements)

References 21 publications

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“…Importantly, the methods employed in our study cannot distinguish between folic acid and PUR-1 competition for uptake through the PSAC channel on the outer membrane of the infected cell vs. competition for uptake across a carrier protein located on the parasite plasma membrane. However, taken together with the findings of Nzila et al (Nzila, et al, 2003) and Wang et al (Wang, et al, 1999) it seems reasonable to believe that a selective inhibitor of the NPP will block uptake of exogenous folic acid from the bloodstream and function synergistically with selective inhibitors of parasite dihydrofolate reductase, such as WR99210 (Canfield, et al, 1993,Kinyanjui, et al, 1999 and "biguanide" prodrugs of the Jacobus series (Jensen, et al, 2001). …”

Section: Inhibition Of Pur-1 Staining By Furosemidementioning

confidence: 97%

Selective killing of the human malaria parasite Plasmodium falciparum by a benzylthiazolium dye

Kelly

Winter

Braun³

et al. 2007

Experimental Parasitology

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Malaria is an infectious disease caused by protozoan parasites of the genus Plasmodium. The most virulent form of the disease is caused by P. falciparum which infects hundreds of millions of people and is responsible for the deaths of 1 to 2 million individuals each year. An essential part of the parasitic process is the remodeling of the red blood cell membrane and its protein constituents to permit a higher flux of nutrients and waste products into or away from the intracellular parasite. Much of this increased permeability is due to a single type of broad specificity channel variously called the new permeation pathway (NPP), the nutrient channel, and the Plasmodial surface anion channel (PSAC). This channel is permeable to a range of low molecular weight solutes both charged and uncharged, with a strong preference for anions. Drugs such as furosemide that are known to block anion-selective channels inhibit PSAC. In this study we have investigated a dye known as benzothiocarboxypurine, BCP, which had been studied as a possible diagnostic aid given its selective uptake by P. falciparum infected red cells. We found that the dye enters parasitized red cells via the furosemide-inhibitable PSAC, forms a brightly fluorescent complex with parasite nucleic acids, and is selectively toxic to infected cells. Our study describes an antimalarial agent that exploits the altered permeability of Plasmodium-infected red cells as a means to killing the parasite and highlights a chemical reagent that may prove useful in high throughput screening of compounds for inhibitors of the channel.

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Section: Inhibition Of Pur-1 Staining By Furosemidementioning

confidence: 97%

Selective killing of the human malaria parasite Plasmodium falciparum by a benzylthiazolium dye

Kelly

Winter

Braun³

et al. 2007

Experimental Parasitology

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“…In an effort to circumvent these problems PS-15 ( Fig. 5), the phenoxypropoxybiguanide precursor for WR99210, was synthesized [68]. However, further assessment of PS-15 was suspended because of regulatory restrictions in the use of the starting material, i.e.…”

Section: Artemisinin and Its Derivatesmentioning

confidence: 99%

New Chemotherapeutic Strategies Against Malaria, Leishmaniasis and Trypanosomiases

Zucca

Scutera²,

Savoia³

2013

CMC

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Due to the persistent lack of suitable vaccines, chemotherapy remains the only option for the treatment of patients infected by protozoan parasites. However, most available antiparasitic drugs have serious disadvantages, ranging from high cost and poor compliance to high toxicity and rapid induction of resistance. In recent decades basic research laboratories identified a considerable number of promising new molecules, but their development has not been pursued in depth by pharmaceutical firms because of poor prospects of economic return. The establishment of adequately funded public-private partnerships is currently reversing the trend. This review deals with new drugs against Plasmodium, Leishmania and Trypanosoma parasites, focusing on the molecules that are in the most advanced stage of development. The purpose of this article is to provide the reader with a panoramic view of the updated literature on the challenges and strategies of contemporary antiprotozoal drug research, paying the due attention to the already published reviews.Keywords: Antibiotics, antiprotozoal chemotherapy, Leishmania, natural products, Plasmodium, Trypanosoma. 4 INTRODUCTIONInfections caused by parasitic protozoa take an enormous toll on human health. Their prevalence is higher in tropical and equatorial countries, where the major number of deaths is due to malaria, leishmaniasis, and African and American trypanosomiasis. High mortality rates are associated to poor sanitary conditions, high percentages of untreated HIV-infected individuals, and lack of efficient prophylactic measures [1]. In the developed countries the situation is not so tragic, but nonetheless it has its drawbacks. If it is true that in these countries most HIV-infected patients are treated, the number of chronically immuno-deficient carriers of transplanted organs is set to grow. In these patients latent parasitic infections, such as leishmaniasis and toxoplasmosis, can reappear as opportunistic infections. Moreover, the climate changes linked to global warming in temperate countries are extending the insect vector habitats, as is the case of the northward spread of leishmania-transmitting sandflies, assessed by epidemiological surveys of canine leishmaniasis in Italy [2][3][4]. Some additional cases of parasitic infections have also been registered due to "transplant tourism", i.e. travel with the intent of receiving or donating an organ, a practice that is rapidly increasing [5]. A further danger for industrialized countries comes from massive migration of infected subjects from endemic countries: a typical example is the presence of thousands of Trypanosoma cruzi-infected people in North America and Spain [6].In the absence of prophylactic or curative vaccines the only available choice is chemotherapy. However, this relies on drugs which are tens of years old, afflicted with serious disadvantages, such as heavy side-effects, selection of resistant strains, or high production costs. Unfortunately, this situation is not likely to improve in the short t...

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“…Hastings and Sibley in particular look at many more mutants in their analysis. The drugs under comparison in Table 1 are limited to (i) pyrimethamine, a 2,4-diaminopyrimidine that is the most widely used antimalarial DHFR inhibitor and is a key component of the drug sulfadoxinepyrimethamine, (ii) chlorcycloguanil, a triazine DHFR inhibitor and the active metabolite of chlorproguanil, which is a key component of a fixed dose combination of chlorproguanil-dapsone (or Lapdap), which has undergone phase-three studies in a partnership involving GlaxoSmithKline and WHO͞TDR and is about to be submitted for regulatory approval (15), and (iii) WR99210, a phenoxypropoxydiaminotriazine, a member of a family of DHFR inhibitors that are generated as metabolites from the corresponding biguanide, some of which are being considered for development (16).…”

Section: Comparison Of Hastings and Sibley's Work (7) With Other Recementioning

confidence: 99%

Chemotherapeutic hope on the horizon for Plasmodium vivax malaria?

Ridley

2002

Proc. Natl. Acad. Sci. U.S.A.

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Phenoxypropoxybiguanides, Prodrugs of DHFR−Inhibiting Diaminotriazine Antimalarials

Cited by 89 publications

References 21 publications

Selective killing of the human malaria parasite Plasmodium falciparum by a benzylthiazolium dye

Selective killing of the human malaria parasite Plasmodium falciparum by a benzylthiazolium dye

New Chemotherapeutic Strategies Against Malaria, Leishmaniasis and Trypanosomiases

Chemotherapeutic hope on the horizon for Plasmodium vivax malaria?

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