Synthesis of Novel 2-Alkoxy-3-amino-3-arylpropan-1-ols and 5-Alkoxy-4-aryl-1,3-oxazinanes with Antimalarial Activity

D’hooghe, Matthias; Dekeukeleire, S.; Mollet, Karen; Lategan, Carmen; Smith, Peter J.; Chibale, Kelly; Kimpe, Norbert De

doi:10.1021/jm9002632

Cited by 47 publications

(24 citation statements)

References 51 publications

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“…The catalyst was filtered, the solvent was removed under vacuum and the product was purified by flash column chromatography over silica gel (eluent: hexane : ethyl acetate gradient) to afford the amine product. control cells (no added compound) was set to 100 % cell viability and from this graphs of absorbance versus cell density per well were prepared to assess cell viability using GraphPad Prism software 48 .…”

Section: Deprotection Of the Cbz Protected Azetidinones (General Methmentioning

confidence: 99%

Synthesis and Evaluation of Azetidinone Analogues of Combretastatin A-4 as Tubulin Targeting Agents

et al. 2010

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Section: Deprotection Of the Cbz Protected Azetidinones (General Methmentioning

confidence: 99%

Synthesis and Evaluation of Azetidinone Analogues of Combretastatin A-4 as Tubulin Targeting Agents

et al. 2010

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“…The absorbance value of control cells (no added compound) was set to 100% cell viability and from this graphs of absorbance versus cell density per well were prepared to assess cell viability using GraphPad Prism software. 59 .…”

Section: Mtt Assay Proceduresmentioning

confidence: 99%

Synthesis, evaluation and structural studies of antiproliferative tubulin-targeting azetidin-2-ones

O’Boyle

Greene

Bergin

et al. 2011

Bioorganic & Medicinal Chemistry

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A series of azetidin-2-ones substituted at positions 1, 3 and 4 of the azetidinone ring scaffold were synthesised and evaluated for antiproliferative, cytotoxic and tubulin-binding activity. In these compounds, the cis double bond of the vascular targeting agent combretastatin A-4 is replaced with the azetidinone ring in order to enhance the antiproliferative effects displayed by combretastatin A-4 and prevent the cis/trans isomerisation that is associated with inactivation of combretastatin A-4. The series of azetidinones was synthetically accessible via the Staudinger and Reformatsky reactions. Of a diverse range of heterocyclic derivatives, 3-(2-thienyl) analogue 28 and 3-(3-thienyl) analogue 29 displayed the highest potency in human MCF-7 breast cancer cells with IC(50) values of 7 nM and 10nM, respectively, comparable to combretastatin A-4. Compounds from this series also exhibited potent activity in MDA-MB-231 breast cancer cells and in the NCI60 cell line panel. No significant toxicity was observed in normal murine breast epithelial cells. The presence of larger, bulkier groups at the 3-position, for example, 3-naphthyl derivative 21 and 3-benzothienyl derivative 26, resulted in relatively lower antiproliferative activity in the micromolar range. Tubulin-binding studies of 28 (IC(50)=1.37 μM) confirmed that the molecular target of this series of compounds is tubulin. These novel 3-(thienyl) β-lactam antiproliferative agents are useful scaffolds for the development of tubulin-targeting drugs.

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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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Synthesis of Novel 2-Alkoxy-3-amino-3-arylpropan-1-ols and 5-Alkoxy-4-aryl-1,3-oxazinanes with Antimalarial Activity

Cited by 47 publications

References 51 publications

Synthesis and Evaluation of Azetidinone Analogues of Combretastatin A-4 as Tubulin Targeting Agents

Synthesis and Evaluation of Azetidinone Analogues of Combretastatin A-4 as Tubulin Targeting Agents

Synthesis, evaluation and structural studies of antiproliferative tubulin-targeting azetidin-2-ones

New Chemotherapeutic Strategies Against Malaria, Leishmaniasis and Trypanosomiases

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