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1.
RSC Adv ; 13(49): 34391-34399, 2023 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-38024964

RESUMO

Heterocycles are a cornerstone of fragment-based drug discovery (FBDD) due to their prevalence in biologically active compounds. However, novel heterocyclic fragments are only valuable if they can be suitably elaborated to compliment a chosen target protein. Here we describe the synthesis of 5-halo-1H-pyrazolo[3,4-c]pyridine scaffolds and demonstrate how these compounds can be selectively elaborated along multiple growth-vectors. Specifically, N-1 and N-2 are accessed through protection-group and N-alkylation reactions; C-3 through tandem borylation and Suzuki-Miyaura cross-coupling reactions; C-5 through Pd-catalysed Buchwald-Hartwig amination; and C-7 through selective metalation with TMPMgCl.LiCl followed by reaction with electrophiles or transmetalation to ZnCl2 and Negishi cross-coupling. Linking multiple functionalisation strategies emulates a hit-to-lead pathway and demonstrates the utility of pyrazolo[3,4-c]pyridines to FBDD.

2.
Molecules ; 27(15)2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35897943

RESUMO

SiO2-SO3H, with a surface area of 115 m2/g and pore volume of 0.38 cm3g-1, and 1.32 mmol H+/g was used as a 20% w/w catalyst for the preparation of methyl salicylate (wintergreen oil or MS) from acetylsalicylic acid (ASA). A 94% conversion was achieved in a microwave reactor over 40 min at 120 °C in MeOH. The resulting crude product was purified by flash chromatography. The catalyst could be reused three times.


Assuntos
Micro-Ondas , Dióxido de Silício , Aspirina , Biocombustíveis , Catálise , Esterificação , Óleos Voláteis , Extratos Vegetais , Óleos de Plantas/química , Salicilatos
3.
Molecules ; 27(3)2022 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-35164218

RESUMO

SiO2-SO3H, with a surface area of 115 m2·g-1, pore volumes of 0.38 cm3·g-1 and 1.32 mmol H+/g, was used as a transesterification catalyst. Triglycerides of waste cooking oil reacted with methanol in refluxing toluene to yield mixtures of diglycerides, monoglycerides and fatty acid methyl esters (FAMEs) in the presence of 20% (w/w) catalyst/oil using the hydrophilic sulfonated silica (SiO2-SO3H) catalyst alone or with the addition of 10% (w/w) co-catalyst/oil [(Bun4N)(BF4) or Aliquat 336]. The addition of the ammonium salts to the catalyst lead to a decrease in the amounts of diglycerides in the products, but the concentrations of monoglycerides increased. Mixtures of (Bun4N)(BF4)/catalyst were superior to catalyst alone or Aliquat 336/catalyst for promoting the production of mixtures with high concentrations of FAMEs. The same experiments were repeated using DMSO as the solvent. The use of the more polar solvent resulted in excellent conversion of the triglycerides to FAME esters with all three-catalyst media. A simplified mechanism is presented to account for the experimental results.


Assuntos
Biocombustíveis/análise , Dimetil Sulfóxido/química , Compostos de Amônio Quaternário/química , Dióxido de Silício/química , Sulfatos/química , Tolueno/química , Triglicerídeos/química , Catálise , Esterificação
4.
J Org Chem ; 86(19): 13402-13419, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34553940

RESUMO

We have prepared a library of functionalized quinolines through the magnesiation of 7-chloroquinolines under mild conditions, employing both batch and continuous flow conditions. The preparation involved the generation of mixed lithium-magnesium intermediates, which were reacted with different electrophiles. Mixed lithium-zinc reagents allowed the synthesis of halogenated and arylated derivatives. Some of the synthesized 4-carbinol quinolines have shown interesting antiproliferative properties, their hydroxyl group being a suitable amino group bioisostere. We also report a two-step approach for optically active derivatives.


Assuntos
Magnésio , Quinolinas , Indicadores e Reagentes , Lítio , Zinco
5.
Org Lett ; 23(19): 7396-7400, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34499518

RESUMO

We have accomplished regioselective deprotometalation of aromatic and heteroaromatic nitriles via (TMP)2Zn·2MgCl2·2LiCl and TMPMgCl·LiCl (TMP = 2,2,6,6-tetramethylpiperidyl) with the exploration of new and scarcely investigated metalation positions. Regioselectivity was rationalized by DFT calculations. The quenching of the generated organozinc and organomagnesium intermediates with various electrophiles gave access to 47 highly functionalized nitriles with yields up to 95%. Additionally, we report a difunctionalization strategy and the use of functionalized nitriles as building blocks to construct relevant heterocycles.

6.
J Org Chem ; 86(1): 1204-1215, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33296214

RESUMO

We have prepared novel highly functionalized benzene derivatives by regioselective metalation of ester-, amide-, carbamate-, and carbonate-substituted 2-phenyl-2-oxazolines with mixed lithium-magnesium amides followed by reaction with different electrophiles. While a complementary metalation site can be accessed by using different bases, steric and electronic effects promoted by the aromatic ring substituents also play an important role in reaction regioselectivity. Computational calculations of the aromatic hydrogen pKa values have helped us to rationalize the metalation preference by the complex-induced proximity effect concept.

7.
Beilstein J Org Chem ; 17: 2968-2975, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35003373

RESUMO

Microwave-mediated N-arylation of 4-chloroquinazolines in THF/H2O rapidly and efficiently afforded a library of novel 6-halo-2-phenyl-substituted 4-anilinoquinazolines. The methodology was compatible with numerous ortho-, meta-, and para-substituted N-methylanilines as well as substituted anilines and furnished the corresponding 4-anilinoquinazolines in good yields. Preliminary screening of the synthesized compounds against tumor cells (HCT-116 and T98G) showed promising antiproliferative properties.

8.
J Nanosci Nanotechnol ; 19(6): 3663-3668, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30744803

RESUMO

A SiO2-SO3H amorphous catalyst containing a small surface area of 115.0 m²g-1 and 1.32 mmol H+/g was prepared from fine construction sand and sodium carbonate and sulfonated with H2SO4. In a 10% (w/w) basis, it is very efficient for catalyzing the esterification of carboxylic acids with phenol. The reaction processes were performed using conventional heating and under microwave irradiation. The yields were higher in the microwave-irradiated esterification. The catalyst could be used for three esterification sequences in both processes.

9.
Heliyon ; 4(3): e00571, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29862338

RESUMO

Two solvent free methods of a one-to-one alcohol/acid mol ratio synthesis of benzyl esters of the formic, acetic, benzoic, salicylic, nicotinic, and oxalic acids are described. The stoichiometric reactions used 1.5 mol ratio solid NbCl5 as the reagent and required from two to three hours for completion at room temperature; for the catalytic processes, NbCl5 was grafted directly, at room temperature, onto a silica gel of specific area of 507 m2g-1, produced from construction sand and sodium carbonate, forming a 5.4% Nb w/w SiO2-Nb gel with a specific area of 412 m2g-1. At 10% w/w catalyst/alcohol ratio, this SiO2-Nb catalyst gave similarly very good yields but required from 6 to 9 hours at the reflux temperature of the slurry. The catalyst could be re-used three times.

10.
J Org Chem ; 83(2): 871-880, 2018 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-29240427

RESUMO

We prepared a number of di- and trifunctionalized quinolines by selective metalation of chloro-substituted quinolines with metal amides followed by reaction with different electrophiles. Metalation of the C-3 position of the quinolinic ring with lithium diisopropylamide at -70 °C is easy to achieve, whereas reaction with lithium-magnesium and lithium-zinc amides affords C-2 or C-8 functionalized derivatives in a regioselective fashion. These complementary methods could be rationalized by DFT calculations and are convenient strategies toward the synthesis of bioactive quinoline derivatives such as chloroquine analogues.

11.
Org Lett ; 17(2): 238-41, 2015 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-25541908

RESUMO

A variety of C-2 and C-5 difunctionalized indolizines have been prepared through the reaction of 1-ester-substituted indolizines with organometallic bases followed by a reaction with different electrophiles. Metalation takes place under mild conditions allowing the isolation of a number of difunctionalized indolizines in good yields. The regioselectivity of the reaction appears to be governed by the nature of the base and electrophile.


Assuntos
Indolizinas/química , Indolizinas/síntese química , Compostos Organometálicos/química , Paládio/química , Catálise , Ésteres , Estrutura Molecular , Estereoisomerismo
12.
Sci Rep ; 4: 7449, 2014 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-25502598

RESUMO

In most species of social insect the queen signals her presence to her workers via pheromones. Worker responses to queen pheromones include retinue formation around the queen, inhibition of queen cell production and suppression of worker ovary activation. Here we show that the queen signal of the Brazilian stingless bee Friesella schrottkyi is a mixture of cuticular hydrocarbons. Stingless bees are therefore similar to ants, wasps and bumble bees, but differ from honey bees in which the queen's signal mostly comprises volatile compounds originating from the mandibular glands. This shows that cuticular hydrocarbons have independently evolved as the queen's signal across multiple taxa, and that the honey bees are exceptional. We also report the distribution of four active queen-signal compounds by Matrix-assisted laser desorption/ionization (MALDI) imaging. The results indicate a relationship between the behavior of workers towards the queen and the likely site of secretion of the queen's pheromones.


Assuntos
Abelhas/fisiologia , Hormônios de Inseto/fisiologia , Ovário/fisiologia , Comunicação Animal , Animais , Feminino , Comportamento Social
13.
Br J Pharmacol ; 171(15): 3666-79, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24712707

RESUMO

BACKGROUND AND PURPOSE: The antipyretic and hypothermic prodrug dipyrone prevents PGE2 -dependent and -independent fever induced by LPS from Escherichia coli and Tityus serrulatus venom (Tsv) respectively. We aimed to identify the dipyrone metabolites responsible for the antipyretic and hypothermic effects. EXPERIMENTAL APPROACH: Male Wistar rats were treated i.p. with indomethacin (2 mg·kg(-1) ), dipyrone, 4-methylaminoantipyrine (4-MAA), 4-aminoantipyrine (4-AA) (60-360 mg·kg(-1) ), 4-formylaminoantipyrine, 4-acethylaminoantipyrine (120-360 mg·kg(-1) ) or vehicle 30 min before i.p. injection of LPS (50 µg·kg(-1) ), Tsv (150 µg·kg(-1) ) or saline. Rectal temperatures were measured by tele-thermometry and dipyrone metabolite concentrations determined in the plasma, CSF and hypothalamus by LC-MS/MS. PGE2 concentrations were determined in the CSF and hypothalamus by elisa. KEY RESULTS: In contrast to LPS, Tsv-induced fever was not followed by increased PGE2 in the CSF or hypothalamus. The antipyretic time-course of 4-MAA and 4-AA on LPS-induced fever overlapped with the period of the highest concentrations of 4-MAA and 4-AA in the hypothalamus, CSF and plasma. These metabolites reduced LPS-induced fever and the PGE2 increase in the plasma, CSF and hypothalamus. Only 4-MAA inhibited Tsv-induced fever. The higher doses of dipyrone and 4-MAA also induced hypothermia. CONCLUSIONS AND IMPLICATIONS: The presence of 4-MAA and 4-AA in the CSF and hypothalamus was associated with PGE2 synthesis inhibition and a decrease in LPS-induced fever. 4-MAA was also shown to be an antipyretic metabolite for PGE2 -independent fever induced by Tsv suggesting that it is responsible for the additional antipyretic mechanism of dipyrone. Moreover, 4-MAA is the hypothermic metabolite of dipyrone.


Assuntos
Ampirona/farmacologia , Dinoprostona/metabolismo , Dipirona/análogos & derivados , Febre/tratamento farmacológico , Ampirona/sangue , Ampirona/líquido cefalorraquidiano , Ampirona/metabolismo , Animais , Antipiréticos/sangue , Antipiréticos/líquido cefalorraquidiano , Antipiréticos/farmacocinética , Antipiréticos/farmacologia , Temperatura Corporal/efeitos dos fármacos , Dinoprostona/líquido cefalorraquidiano , Dipirona/sangue , Dipirona/líquido cefalorraquidiano , Dipirona/metabolismo , Dipirona/farmacocinética , Dipirona/farmacologia , Febre/induzido quimicamente , Febre/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Hipotermia/induzido quimicamente , Hipotermia/metabolismo , Indometacina/farmacologia , Lipopolissacarídeos , Masculino , Pró-Fármacos/farmacocinética , Ratos Wistar , Venenos de Escorpião
14.
Bioanalysis ; 5(21): 2631-45, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24180504

RESUMO

BACKGROUND: After oral administration dipyrone is rapidly hydrolyzed to 4-methylaminoantipyrine, which is absorbed and further metabolized to 4-formylaminoantipyrine and to 4-aminoantipyrine, which is acetylated by a polymorphic N-acetyltransferase system to 4-acetylaminoantipyrine. To evaluate the presence of dipyrone metabolites in different rat matrices after intraperitoneal administration, an analytical method was developed and validated. METHODOLOGY: The four main dipyrone metabolites were extracted from plasma, cerebrospinal fluid and hypothalamus samples by LLE prior to LC-MS/MS. RESULTS: Standard calibration graphs for all metabolites were linear (r > 0.99). The intra- and inter-day precision and accuracy values were both inferior to 15%. CONCLUSION: This method is simple and specific for studying dipyrone metabolites after intraperitoneal administration.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Dipirona/análise , Hipotálamo/química , Espectrometria de Massas em Tandem/métodos , Animais , Dipirona/sangue , Dipirona/líquido cefalorraquidiano , Dipirona/metabolismo , Hipotálamo/metabolismo , Masculino , Ratos , Ratos Wistar
15.
Chemistry ; 15(2): 457-68, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19035380

RESUMO

A wide range of polyfunctional aryl and heteroaryl zinc reagents were efficiently prepared in THF by using (TMP)(2)Mg2 LiCl (TMP=2,2,6,6-tetramethylpiperamidyl) in the presence of ZnCl(2). The possible pathways of this metalation procedure as well as possible reactive intermediates are discussed. This experimental protocol expands the tolerance of functional groups and allows an efficient zincation of sensitive heterocycles such as quinoxaline or pyrazine. The zincated arenes and heteroarenes react with various electrophiles providing the expected products in 60-95 % yield.


Assuntos
Cloretos/química , Compostos Heterocíclicos/química , Magnésio/química , Compostos Organometálicos/química , Compostos de Zinco/química , Zinco/química , Piperazina , Piperazinas/química , Prótons
18.
Org Lett ; 7(21): 4561-4, 2005 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-16209479

RESUMO

[structure: see text] New conjunctive reagents E-2 and Z-3 can be used, after transmetalation, in Negishi couplings with vinyl and aryl iodides. The subsequently unmasked terminal alkynes can be further manipulated to arrive at retinoid-like products.


Assuntos
Reagentes de Ligações Cruzadas/química , Compostos Organometálicos/química , Polienos/química , Retinoides/química , Acilação , Estrutura Molecular
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