Microwave-Assisted Ring Opening of Epoxides:  A General Route to the Synthesis of 1-Aminopropan-2-ols with Anti Malaria Parasite Activities

Robin, Aélig; Brown, Fraser; Bahamontes-Rosa, Noemi; Wu, Binghua; Beitz, Eric; Kun, Jürgen F. J.; Flitsch, Sabine L.

doi:10.1021/jm070553l

Cited by 57 publications

(36 citation statements)

References 23 publications

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“…Given the recently disclosed antimalarial properties of aminopropanols [7,8,9], and taking structure-activity relationship studies with regard to chloroquine into account [40], the elaboration of a 1,2,3-triaminopropane unit substituted with an aryl group, a N,Ndiethylamino moiety and an azaheteroaromatic nucleus was envisaged as a potential novel antimalarial pharmacophore. From a retrosynthetic point of view, 2-(aminomethyl)aziridines can be regarded as suitable precursors for the preparation of 1,2,3-triaminopropanes through ring opening by amines.…”

Section: Results and Discussion -Synthesismentioning

confidence: 99%

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Synthesis of 2-(aminomethyl)aziridines and their microwave-assisted ring opening to 1,2,3-triaminopropanes as novel antimalarial pharmacophores

D’hooghe

Kenis

Vervisch

et al. 2011

European Journal of Medicinal Chemistry

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A variety of 2-(aminomethyl)aziridines was prepared and converted into the corresponding 1,2,3-triaminopropanes through a novel, microwave-assisted and regioselective ring opening by diethylamine in acetonitrile. Antiplasmodial assays revealed antimalarial activity for 2-[(1,2,4-triazol-1-yl)methyl]aziridines and 2-(N,N-diethylaminomethyl)aziridines, as well as for the corresponding 1-(diethylamino)propanes obtained through ring opening, pointing to the relevance of both the 2-(aminomethyl)aziridine and the 1,2,3-triaminopropane unit as novel antimalarial pharmacophores.

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Section: Results and Discussion -Synthesismentioning

confidence: 99%

“…Recently, the β-amino alcohol moiety has been introduced as a promising antimalarial pharmacophore, and the synthesis of a number of novel aminopropanols with significant antimalarial activity has revealed the medicinal importance of this class of glycerol analogues [7,8,9]. Their aza-derivatives, i.e.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 2-(aminomethyl)aziridines and their microwave-assisted ring opening to 1,2,3-triaminopropanes as novel antimalarial pharmacophores

D’hooghe

Kenis

Vervisch

et al. 2011

European Journal of Medicinal Chemistry

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“…By way of example here we mention β-lactams, which besides their antibacterial activity acquired a prominent place in organic chemistry as synthetic building blocks (synthons) for further elaboration [118]. Following the initial observation that 1-aminopropan-2-ols are active against P. falciparum in the micromolar range [119], a library of gamma-aminoalchools was produced through the ring opening of cis-3-alkoxy-4-aryl-β-lactams [120]. These compounds also showed antimalarial activity in vitro.…”

Section: Natural Productsmentioning

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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“…Compounds used for testing were a series of 1-aminopropan-2-ols [14] and various quarternery ammonium salts dissolved in water, acetonitrile or dimethyl sulphoxide, respectively. Other chemicals were purchased from SigmaAldrich and Merck.…”

Section: Chemical Librarymentioning

confidence: 99%

A yeast-based phenotypic screen for aquaporin inhibitors

Altmann

Barzel

et al. 2007

Pflugers Arch - Eur J Physiol

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Aquaporins mediate transport of water or small, uncharged solutes across cellular membranes according to the prevailing osmotic and chemical gradients. Because of their implication in human diseases and pathophysiological states, aquaporins are considered as potential drug targets. Yet, specific aquaporin inhibitors for in vivo studies are not available. Common functional aquaporin assays that monitor biophysical parameters related to volume changes, such as light scattering or fluorescence quenching, are time consuming and require costly equipment. Hence, they are not well geared for screening large numbers of compounds. In this paper, we describe a less demanding phenotypic yeast-based assay on 96-well microplates. The assay uses a methylamine-sensitive yeast strain in which a methylamine-permeable test aquaporin is expressed to rescue proliferation on selection plates. Specific inhibition of the aquaporin directly correlates to reduced cell proliferation.

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Microwave-Assisted Ring Opening of Epoxides: A General Route to the Synthesis of 1-Aminopropan-2-ols with Anti Malaria Parasite Activities

Cited by 57 publications

References 23 publications

Synthesis of 2-(aminomethyl)aziridines and their microwave-assisted ring opening to 1,2,3-triaminopropanes as novel antimalarial pharmacophores

Synthesis of 2-(aminomethyl)aziridines and their microwave-assisted ring opening to 1,2,3-triaminopropanes as novel antimalarial pharmacophores

New Chemotherapeutic Strategies Against Malaria, Leishmaniasis and Trypanosomiases

A yeast-based phenotypic screen for aquaporin inhibitors

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