RESUMO
Functionalized 3-trifluoromethyl-2-isoxazolines and 3-trifluoromethylisoxazoles were easily prepared from trifluoromethyl aldoxime 2 under mild conditions by using DIB as oxidant. Theoretical studies of the reactivity of trifluoroacetonitrile oxide 4 toward olefins and alkynes were carried out. The 3-trifluoromethyl-2-isoxazolines were ring-opened with NaBH4 and NiCl2 to yield the corresponding trifluoromethylated γ-amino alcohols.
RESUMO
The halogen-bonded adduct between DABCO and two molecules of perfluorooctyl iodide (DABCO·(C(8)F(17)I)(2)) acts as a recyclable organocatalyst for the Morita-Baylis-Hillman reaction. This "supramolecular fluorous catalyst" is readily accessible and can be recovered by simple precipitation/filtration.
Assuntos
Flúor/química , Fluorocarbonos/química , Halogênios/química , Catálise , EstereoisomerismoRESUMO
The insertion reaction of diazocarbonyls to acids could be performed smoothly in fluorinated alcohols in the absence of metal catalyst. This new procedure allowed the chemoselective preparation of various functionalized compounds such as acyloxyesters, depsipeptides, and sulfonate, phosphonate, or boronate derivatives.
Assuntos
Álcoois/química , Compostos de Diazônio/química , Cetonas/química , Alcanossulfonatos/síntese química , Alcanossulfonatos/química , Ácidos Borônicos/síntese química , Ácidos Borônicos/química , Catálise , Técnicas de Química Combinatória , Halogenação , Estrutura Molecular , Organofosfatos/síntese química , Organofosfatos/químicaRESUMO
The influence of substituents on the properties of tri- and hexafluorinated alcohols derived from 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) was examined. Measurements of specific solvent-solute interactions revealed that H-bond donation (HBD) of fluorinated alcohols is sensitive to the steric hindrance of the OH group, whereas their Brønsted acidity is dependent only on the number of fluorine atoms. For hexafluorinated alcohols (HFAs), their association with amines characterized by X-ray diffraction showed that the balance between HBD and acidity is influenced by their structure. Moreover, the ability of HFAs to donate H-bonds is exerted in synclinal (sc), synperiplanar (sp), and also antiperiplanar (ap) conformations along the C-O bond. Comparison of the effects of fluorinated alcohols as promoting solvents in three reactions is reported. The positive correlation between rate constants and H-bonding donation ability for sulfide oxidation and imino Diels-Alder reaction brings to light the role of this property, while acidity might have a minor influence. In the third reaction, epoxide opening by piperidine, none of these properties can clearly be put forward at this stage.
Assuntos
Ácidos/química , Álcoois/química , Propanóis/química , Trifluoretanol/química , Ligação de Hidrogênio , Conformação Molecular , Prótons , Solventes , Difração de Raios XRESUMO
The synthesis of 8-aminoquinolines and 1,10-phenanthrolines with substituents in α of the nitrogen has been performed through an inverse-demanding aza-Diels-Alder (Povarov reaction) in the fluoroalcohols TFE or HFIP. This path involves simple starting materials: 1,2-phenylenediamines, enol ethers and aldehydes.
Assuntos
Aminoquinolinas/síntese química , Fenantrolinas/síntese química , Estrutura MolecularRESUMO
Trifluoromethyl nitrones were obtained in high yields by condensation of various hydroxylamines with trifluoroacetaldehyde hydrate. The nucleophilic diastereoselective additions of organometallic reagents to these nitrones afforded the corresponding optically active trifluoroethyl hydroxylamines in good yields.
Assuntos
Acetaldeído/análogos & derivados , Clorofluorcarbonetos de Metano/química , Hidroxilamina/química , Óxidos de Nitrogênio/química , Fenômenos Ópticos , Acetaldeído/química , EstereoisomerismoRESUMO
Novel fluorinated analogues of goniothalamin 1 and howiinol A 2 have been prepared from trifluorocrotonate derivatives. Trifluoromethyl goniothalamin (R/S) 4 showed a slightly lower activity than 1, while the trifluoromethyl howiinol A 16 exhibited similar activities on several cell lines in the micromolar range. Unlike (R) goniothalamin and howiinol A, trifluoromethyl parent compounds remained unchanged when submitted to biomimetic oxidative systems.
Assuntos
Flúor/química , Goniothalamus/química , Lactonas/química , Pironas/química , Pironas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Oxirredução , Pironas/síntese química , Relação Estrutura-AtividadeAssuntos
Catálise , Flúor/química , Química Verde/métodos , Acilação , Esterificação , Sais/química , Relação Estrutura-AtividadeRESUMO
1,4-Addition of anilines onto Michael acceptors proceeds easily in specific polar protic solvents, without any promoting agent. According to the solvent and to the electrophile, the selectivity of the reaction can be finely tuned. With methyl acrylate as electrophile, only monoaddition takes place in water, while the diadduct is yielded in hexafluoroisopropyl alcohol (HFIP). The use of methyl vinyl ketone as a partner affords the monoadduct in water, the diadduct in trifluoroethanol (TFE), and the quinoline in HFIP.
Assuntos
Aminas/química , Compostos Aza/química , Solventes/química , Acrilatos/química , Alquilação , Butanonas/químicaRESUMO
The ring opening of epoxides by various amino acid esters is described in refluxing trifluoroethanol without any catalyst. Under these simple conditions the corresponding beta-amino alcohols are obtained in good to excellent yields in relatively short reaction times compared to previously reported methods.
Assuntos
Aminoácidos/química , Amino Álcoois/síntese química , Catálise , Compostos de Epóxi/química , Ésteres/química , Estrutura Molecular , Trifluoretanol/químicaRESUMO
We have designed novel small inhibitors of rabbit 20S proteasome using a trifluoromethyl-beta-hydrazino acid scaffold. Structural variations influenced their inhibition of the three types of active sites. Proteasome inhibition at the micromolar level was selective, calpain I and cathepsin B were not inhibited.
Assuntos
Mimetismo Molecular , Peptídeos/química , Inibidores de Proteases/síntese química , Inibidores de Proteassoma , Animais , Domínio Catalítico , Flúor , Glicina/análogos & derivados , Inibidores de Proteases/farmacologia , Coelhos , Relação Estrutura-AtividadeRESUMO
Gold nanoparticles (AuNPs) coated with hexafluoroisopropanol moieties were prepared, and their surface was changed through simple hydrogen bond association with various amines, which allow orientation of the solubility of these AuNPs in determined organic solvents.
Assuntos
Ouro/química , Nanopartículas Metálicas/química , Aminas/química , Ligação de Hidrogênio , Propanóis/química , SolubilidadeRESUMO
The antileishmanial activity of 19 fluoro-artemisinin derivatives was evaluated in vitro against the promastigote forms of Leishmania donovani. The most active compound BB 201, an amino derivative, exhibited an IC50 at about 1microM and no cross-resistance was found on miltefosine-resistant and sitamaquine-resistant lines. Despite these promising data, no activity was observed on intramacrophage amastigote stage. Although the membranes that have to be crossed by the compounds and pH conditions between intraerythrocyte Plasmodium and intramacrophage Leishmania have similarities, the targets affected by artemisinin derivatives in promastigotes could be differentially expressed in amastigotes.
Assuntos
Antiparasitários/farmacologia , Artemisininas/farmacologia , Leishmania donovani/efeitos dos fármacos , Aminoquinolinas/farmacologia , Animais , Antiparasitários/síntese química , Antiparasitários/química , Artemisininas/química , Resistência a Medicamentos , Eritrócitos/parasitologia , Indicadores e Reagentes , Leishmania donovani/crescimento & desenvolvimento , Macrófagos/parasitologia , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologiaRESUMO
Artemisinin and its derivatives represent an important class of antimalarials. In order to obtain new derivatives with a longer half-life and better bioavailability, the development of fluorinated analogues has received increasing attention. The purpose of this study was to investigate the permeation of artemisinin and of two fluoroalkyl derivatives of dihydroartemisinin (DHA), namely 10beta-(trifluoropropyloxy)dihydroartemisinin (F(1)-DHA) and 10-trifluoromethyl-16-[2-(hydroxyethyl)piperazine] (F(2)-DHA), across rat intestine using Ussing diffusion chambers. Further, the saturation solubility and partition coefficient of the compounds were determined in order to determine whether the substitution of hydrogen atoms by fluorine can induce great changes in these molecular properties. Artemisinin and F(2)-DHA permeability coefficients of 27.5 +/- 1.6 and 23.2 +/- 1.2 (x 10(-6), cm s(-1)), respectively, are predictive of good oral absorption. This indicates that the introduction of a fluoroalkyl group in a compound such as artemisinin in order to prolong its half-life does not constitute an obstacle for its absorption after oral administration. Moreover, the introduction of a polar substituent into the DHA structural scaffold increased the aqueous solubility of F(2)-DHA relative to artemisinin. F(1)-DHA permeability measurements showed low transepithelial diffusion across the intestinal mucosa. This indicates that the introduction of a fluorinated substituent at the alpha-methylene carbon of DHA ethers in order to provide protection against oxidative processes constitutes an obstacle for the absorption after oral administration.
Assuntos
Antimaláricos/farmacocinética , Artemisininas/farmacocinética , Absorção Intestinal , Piperazinas/farmacocinética , Administração Oral , Animais , Transporte Biológico , Difusão , Meia-Vida , Técnicas In Vitro , Masculino , Permeabilidade , Ratos , Ratos Sprague-Dawley , Solubilidade , Relação Estrutura-AtividadeRESUMO
This report is an overview on the design, preparation, and evaluation of metabolically stable artemisinins, using fluorine substitution. The chemical challenges encountered for the incorporation of fluorine-containing elements and the preparation of a large range of 10-trifluoromethyl artemisinin derivatives are detailed. Impact of the fluorine substitution on the antimalarial activity is also highlighted. Preclinical data of lead compounds, and evidence for their strong and prolonged antimalarial activity are presented.
Assuntos
Antimaláricos/farmacocinética , Artemisininas/farmacocinética , Flúor/química , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Artemisininas/química , Artemisininas/farmacologia , Éteres , Meia-Vida , Camundongos , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , RatosRESUMO
The oxidative system H2O2/fluorinated alcohol (TFE, HFIP) was used for direct acid- and MeReO3-catalyzed synthesis of 1,2,4,5-tetraoxanes from cyclic (C6, C7, and C12) and acyclic ketones. The influence of ring size and alkyl chain length were studied and antimalarial activities of synthetic 3,3,6,6-tetraalkyl-1,2,4,5-tetraoxanes were determined. Variations in their antimalarial activities were significant, although they share similar electrochemical properties of the peroxide bond.
Assuntos
Antimaláricos/síntese química , Tetraoxanos/farmacologia , Antimaláricos/farmacologia , Catálise , Peróxido de Hidrogênio , Cetonas/química , Oxirredução , Relação Estrutura-Atividade , Tetraoxanos/síntese químicaRESUMO
In this paper, we report a simple route to accede to a new family of C-10 fluorinated derivatives of artemisinin 7. We demonstrated that nucleophilic substitution of the allylic bromide 6 with alcohols can occur at carbon 10 (compounds 7) under solvolytic conditions (S(N)'/S(N) ratio, 87:13). Furthermore, using the particular properties of hexafluoroisopropanol (HFIP), we are able to increase the selectivity of the substitution. Primary alcohols are completely selective for allylic substitution. With amines as nucleophiles, selectivity of substitution is dependent on their nucleophilicity, but attack at carbon 16 was always favored. However, the S(N)'/S(N) ratio could be slightly increased by adding HFIP, which is able to modulate their nucleophilicity through hydrogen bonding. In preliminary in vitro assessments, these new compounds, 7, exhibited a satisfying activity against malaria.
Assuntos
Artemisininas/química , Flúor/química , Sesquiterpenos/química , Aminas/química , Artemisininas/síntese química , Estrutura Molecular , Sesquiterpenos/síntese químicaRESUMO
[reaction: see text] New artemisinin-derived dimers, fluorinated or not, have been prepared by a self-cross metathesis reaction in the presence of first- or second-generation ruthenium catalysts without degradation of the endoperoxide bridge and with a good E/Z selectivity (up to 100:0).
Assuntos
Antineoplásicos Fitogênicos/síntese química , Artemisininas/síntese química , Sesquiterpenos/síntese química , Antineoplásicos Fitogênicos/química , Artemisininas/química , Catálise , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Sesquiterpenos/química , EstereoisomerismoRESUMO
Trifluoromethylated nitrogen-containing molecules have been shown to have important biological effects and their synthesis is in the focus of the pharmaceutical industry. In the last few years, simple nitrogen derivatives of fluoral, i.e. imines, acetals and oxazolidines, have emerged as powerful building blocks to synthesize these target molecules and relevant precursors. This review summarizes the chemistry of these "N-derivatives of fluoral", with special highlight on the syntheses of peptidomimetic units (amino alcohols, amino acids...) and heterocycles (piperidines, beta-lactams...).