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1.
Parasitol Res ; 119(10): 3503-3515, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32772176

RESUMO

Malaria, babesiosis, trypanosomosis, and leishmaniasis are some of the most life-threatening parasites, but the range of drugs to treat them is limited. An effective, safe, and low-cost drug with a large activity spectrum is urgently needed. For this purpose, an aryl amino alcohol derivative called Alsinol was resynthesized, screened in silico, and tested against Plasmodium, Babesia, Trypanosoma, and Leishmania. In silico Alsinol follows the Lipinski and Ghose rules. In vitro it had schizontocidal activity against Plasmodium falciparum and was able to inhibit gametocytogenesis; it was particularly active against late gametocytes. In malaria-infected mice, it showed a dose-dependent activity similar to chloroquine. It demonstrated a similar level of activity to reference compounds against Babesia divergens, and against promastigotes, and amastigotes stages of Leishmania in vitro. It inhibited the in vitro growth of two African animal strains of Trypanosoma but was ineffective in vivo in our experimental conditions. It showed moderate toxicity in J774A1 and Vero cell models. The study demonstrated that Alsinol has a large spectrum of activity and is potentially affordable to produce. Nevertheless, challenges remain in the process of scaling up synthesis, creating a suitable clinical formulation, and determining the safety margin in preclinical models.


Assuntos
Amino Álcoois/farmacologia , Antiprotozoários/farmacologia , Amino Álcoois/síntese química , Amino Álcoois/química , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Babesia/efeitos dos fármacos , Babesia/crescimento & desenvolvimento , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Modelos Animais de Doenças , Leishmania/efeitos dos fármacos , Leishmania/crescimento & desenvolvimento , Estágios do Ciclo de Vida/efeitos dos fármacos , Camundongos , Plasmodium/efeitos dos fármacos , Plasmodium/crescimento & desenvolvimento , Infecções por Protozoários/tratamento farmacológico , Infecções por Protozoários/parasitologia , Resultado do Tratamento , Trypanosoma/efeitos dos fármacos , Trypanosoma/crescimento & desenvolvimento , Células Vero
2.
Med Chem ; 16(3): 385-391, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30727909

RESUMO

BACKGROUND: Numerous synthetic bile acid derivatives have been recognized for their various biological activities. Among these, bile acid amides have emerged as an attractive antibacterial agent. We herein illustrate the synthesis and antibacterial evaluation of deoxycholic acidamino alcohols conjugates. OBJECTIVE: Design and Synthesis of novel deoxycholic acid-amino alcohol conjugates to investigate their antibacterial activity against E. coli and S. aureus. METHODS: Novel deoxycholic acid-amino alcohol conjugates were synthesized, from conjugation of deoxycholic acid-NHS ester with amino alcohols. Various amino alcohols moieties were appended to the C24 position of deoxycholic acid to yield deoxycholic acid-amino alcohol conjugates. All the synthesized compounds were characterized by 1H NMR, 13C NMR, IR and massspectroscopy. The entire synthesized deoxycholic acid-amino alcohol conjugates were evaluated for their antibacterial activity against E. coli and S. aureus using the broth dilution method. RESULTS: The outcome illustrated that some of the novel deoxycholic acid-amino alcohol conjugates exhibited enhanced anti-bacterial activities. Amongst them, deoxycholic acid-amino alcohol conjugate containing (-R)-2-aminocyclohexanol (1) demonstrated promising efficacy against both strains S. aureus ATCC 25923 (MIC 15 µg/mL) and E. coli ATCC 25922 (MIC 45 µg/mL) and was identified as a lead molecule. CONCLUSION: Numbers of novel deoxycholic acid-amino alcohol conjugates were synthesized and their antimicrobial activities provided useful information that the potency was strongly depending on the structures of deoxycholic acid-amino alcohol conjugates.


Assuntos
Amino Álcoois/farmacologia , Antibacterianos/farmacologia , Ácido Desoxicólico/análogos & derivados , Ácido Desoxicólico/farmacologia , Amino Álcoois/síntese química , Antibacterianos/síntese química , Desenho de Fármacos , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade
3.
Molecules ; 25(1)2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31861609

RESUMO

A library of 1,2-aminoalcohol derivatives with a neoisopulegol-based octahydrobenzofuran core was developed and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. The allylic chlorination of (+)-neoisopulegol, derived from natural (-)-isopulegol followed by cyclization, gave the key methyleneoctahydrobenzofuran intermediate. The stereoselective epoxidation of the key intermediate and subsequent oxirane ring opening with primary amines afforded the required 1,2-aminoalcohols. The ring closure of the secondary amine analogues with formaldehyde provided spiro-oxazolidine ring systems. The dihydroxylation of the methylenetetrahydrofuran moiety with OsO4/NMO (4-methylmorpholine N-oxide) resulted in the formation of a neoisopulegol-based diol in a highly stereoselective reaction. The antimicrobial activity of both the aminoalcohol derivatives and the diol was also explored.


Assuntos
Amino Álcoois/síntese química , Anti-Infecciosos/síntese química , Benzofuranos/química , Monoterpenos Cicloexânicos/química , Amino Álcoois/química , Amino Álcoois/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Benzaldeídos/química , Catálise , Ciclização , Fungos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos Organometálicos/química
4.
Org Lett ; 21(21): 8736-8739, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31625750

RESUMO

Asymmetric synthesis of γ-amino alcohols from unprotected allylic alcohols by a copper-catalyzed hydroamination strategy has been developed. Using easily accessible starting materials, a range of chiral 1,3-amino alcohols were prepared with excellent regio- and enantioselectivity. Further, this protocol provided an efficient one-step method for the enantioselective synthesis of γ-amino alcohols in an intermolecular manner.


Assuntos
Amino Álcoois/química , Amino Álcoois/síntese química , Cobre/química , Aminação , Catálise , Técnicas de Química Sintética
5.
Int J Mol Sci ; 20(16)2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31430981

RESUMO

A library of isopulegol-based bi-, tri- and tetrafunctional chiral ligands has been developed from commercially available (-)-isopulegol and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. Michael addition of primary amines towards α-methylene-γ-butyrolactone, followed by reduction, was accomplished to provide aminodiols in highly stereoselective transformations. Stereoselective epoxidation of (+)-neoisopulegol, derived from natural (-)-isopulegol, and subsequent oxirane ring opening with primary amines afforded aminodiols. The regioselective ring closure of N-substituted aminodiols with formaldehyde was also investigated. Hydroxylation of (+)-neoisopulegol resulted in diol, which was then transformed into aminotriols by aminolysis of its epoxides. Dihydroxylation of (+)-neoisopulegol or derivatives with OsO4/NMO gave neoisopulegol-based di-, tri- and tetraols in highly stereoselective reactions. The antimicrobial activity of aminodiol and aminotriol derivatives as well as di-, tri- and tetraols was also explored. In addition, structure-activity relationships were examined by assessing substituent effects on the aminodiol and aminotriol systems.


Assuntos
Monoterpenos Cicloexânicos/síntese química , 4-Butirolactona/síntese química , 4-Butirolactona/química , Aminação , Amino Álcoois/síntese química , Amino Álcoois/química , Benzaldeídos/síntese química , Benzaldeídos/química , Catálise , Técnicas de Química Sintética , Monoterpenos Cicloexânicos/química , Ligantes , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Estereoisomerismo
6.
Org Biomol Chem ; 17(33): 7655-7659, 2019 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-31360984

RESUMO

Acyclic (l)-threoninol nucleic acids ((l)-aTNA) containing poly-cytosines are prepared and investigated at various pH values, revealing the formation of a highly stable structure at lower pH that have the characteristics of an i-motif. Depending on the sequence, the aTNA forms inter-, bi- and intra-molecular i-motif structures. Pyrene was conjugated to aTNA sequences and both monomeric and excimer fluorescence were efficiently quenched by the i-motif structures and thus demonstrated that the aTNA i-motif can serve as a pH switch.


Assuntos
Amino Álcoois/síntese química , Butileno Glicóis/síntese química , Ácidos Nucleicos/síntese química , Amino Álcoois/química , Butileno Glicóis/química , Concentração de Íons de Hidrogênio , Conformação Molecular , Ácidos Nucleicos/química , Poli C/química
7.
Eur J Med Chem ; 177: 374-385, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158751

RESUMO

To discover broad spectrum antifungal agents, two strategies were applied, and a novel class of l-amino alcohol derivatives were designed and synthesized. 3-F substituted compounds 14i, 14n, 14s and 14v exhibited excellent antifungal activities with broad antifungal spectra against C. albicans and C. tropicalis, with MIC values in the range of 0.03-0.06 µg/mL, and against A. fumigatus and C. neoformans, with MIC values in the range of 1-2 µg/mL. Notably, Compounds 14i, 14n, 14s and 14v also displayed moderate activities against fluconazole-resistance strains 17# and CaR that were isolated from AIDS patients. Moreover, only compounds in the S-configuration showed antifungal activity. Preliminary mechanistic studies showed that the potent antifungal activity of compound 14v stemmed from inhibition of C. albicans CYP51. Compounds 14n and 14v were almost nontoxic to mammalian A549 cells, and their stability in human plasma was excellent.


Assuntos
Amino Álcoois/farmacologia , Antifúngicos/farmacologia , Células A549 , Amino Álcoois/síntese química , Amino Álcoois/metabolismo , Amino Álcoois/toxicidade , Antifúngicos/síntese química , Antifúngicos/metabolismo , Antifúngicos/toxicidade , Aspergillus fumigatus/efeitos dos fármacos , Aspergillus fumigatus/enzimologia , Candida albicans/efeitos dos fármacos , Candida tropicalis/efeitos dos fármacos , Domínio Catalítico , Cryptococcus neoformans/efeitos dos fármacos , Desenho de Fármacos , Estabilidade de Medicamentos , Ergosterol/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Ligação Proteica , Estereoisomerismo , Esterol 14-Desmetilase/química , Esterol 14-Desmetilase/metabolismo , Relação Estrutura-Atividade
8.
J Am Chem Soc ; 141(20): 8104-8109, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31046256

RESUMO

Due to the great value of amino alcohols, new methods for their synthesis are in high demand. Abundant aliphatic alcohols represent the ideal feedstock for the method development toward this important motif. To date, transition-metal-catalyzed approaches for the directed remote amination of alcohols have been well established. Yet, they have certain disadvantages such as the use of expensive catalysts and limited scope. Very recently, transition-metal-free visible-light-induced radical approaches have emerged as new powerful tools for directed remote amination of alcohols. Relying on 1,5-HAT reactivity, these methods are limited to ß - or δ-amination only. Herein, we report a novel transition-metal- and visible-light-free room-temperature radical approach for remote ß -, γ-, and δ-C(sp3)-N bond formation in aliphatic alcohols using mild basic conditions and readily available diazonium salt reagents.


Assuntos
Álcoois/química , Amino Álcoois/síntese química , Carbono/química , Ciclização , Radicais Livres/química , Hidrogênio/química , Cetonas/síntese química
9.
J Am Chem Soc ; 141(24): 9468-9473, 2019 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-31140795

RESUMO

We report the development of a Pd(II)/(±)-MeO-SOX/2,5-dimethylbenzoquinone system that enables unprecedented access to anti-1,3 amino alcohol motifs in good yields (33 substrates, avg. 66% isolated yield, >20:1 dr) and high selectivities (avg. 10:1 dr). Switching ligands to (±)-CF3-SOX with the use of a less bulky quinone oxidant, the kinetic syn-1,3 amino alcohol motif can be accessed in comparable yields and selectivities. Advantages of the stereodivergent nature of this reaction are seen in the synthesis of anti- and syn-1,3 amino alcohol vitamin D3 analogue intermediates in half the steps and higher overall yield relative to previous routes. Additionally, all eight possible stereoisomers of a chiral diamino alcohol core are generated from two amino acids. Mechanistic studies reveal that the anti-isomer is furnished through concurrent Pd(II)(SOX) catalyzed C-H amination and Pd(0)(SOX) catalyzed isomerization cycles.


Assuntos
Compostos Organoplatínicos/química , Oxazinas/síntese química , Sulfóxidos/química , Alcenos/química , Amino Álcoois/síntese química , Benzoquinonas/química , Catálise , Estereoisomerismo
10.
Acta Pharmacol Sin ; 40(6): 746-754, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30315249

RESUMO

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a critical role in controlling pacemaker activity in both heart and nervous system. Developing HCN channel inhibitors has been proposed to be an important strategy for the treatment of pain, heart failure, arrhythmias, and epilepsy. One HCN channel inhibitor, ivabradine, has been clinically approved for the treatment of angina pectoris and heart failure. In this study, we designed and synthesized eight alkanol amine derivatives, and assessed their effects on HCN channels expressed in COS7 cells using a whole-cell patch clamp method. Among them, compound 4e displayed the most potent inhibitory activity with an IC50 of 2.9 ± 1.2 µM at - 120 mV on HCN2 channel expressed in COS7 cells. Further analysis revealed that application of compound 4e (10 µM) caused a slowing of activation and a hyperpolarizing shift (ΔV1/2 = - 30.2 ± 2.9 mV, n = 5) in the voltage dependence of HCN2 channel activation. The inhibitory effect of compound 4e on HCN1 and HCN4 channel expressed in COS7 cells was less potent with IC50 of 17.2 ± 1.3 and 7.3 ± 1.2 µM, respectively. Besides, we showed that application of compound 4e (10 µM) inhibited Ih and action potential firing in acutely dissociated mouse small dorsal root ganglion neurons. Our study provides a new strategy for the design and development of potent HCN channel inhibitors.


Assuntos
Amino Álcoois/farmacologia , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/antagonistas & inibidores , Moduladores de Transporte de Membrana/farmacologia , Potenciais de Ação/efeitos dos fármacos , Amino Álcoois/síntese química , Amino Álcoois/química , Animais , Células COS , Chlorocebus aethiops , Humanos , Masculino , Moduladores de Transporte de Membrana/síntese química , Moduladores de Transporte de Membrana/química , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Canais de Potássio
11.
J Am Chem Soc ; 140(51): 18032-18038, 2018 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-30354144

RESUMO

The functionalization of unactivated C(sp3)-H bonds of aliphatic amines catalyzed by transition-metal complexes is important because amine-based functionality is present in a majority of biologically active molecules and commercial pharmaceuticals. However, such reactions are underdeveloped and challenging to achieve in general because the basicity and reducing properties of alkylamines tends to interfere with potential reagents and catalysts. The functionalization of C-H bonds ß to the nitrogen of aliphatic amines to form prevalent 1,2-amino functionalized structures is particularly challenging because the C-H bond ß to nitrogen is stronger than the C-H bond α to nitrogen, and the nitrogen in the amine or its derivatives usually directs a catalyst to react at more distal γ- and δ-C-H bonds to form 5- or 6-membered metallacyclic intermediate. The enantioselective functionalization of a C-H bond at any position in amines also has been vexing and is currently limited to reactions of specific, sterically hindered, cyclic structures. We report iridium-catalyzed, ß-selective silylations of unactivated C(sp3)-H bonds of aliphatic amines to form silapyrrolidines that are both silicon-containing analogs of common saturated nitrogen heterocycles and precursors to 1,2-amino alcohols by Tamao-Fleming oxidation. These silylations of amines are accomplished by introducing a simple methylene linker between the heteroatom and silicon that has not been used previously for the silylation of C-H bonds. The reactions occur with high enantioselectivity when catalyzed by complexes of new chiral, pyridyl imidazoline ligands, and the rates of reactions with catalysts of these highly basic ligands are particularly fast, occuring in some cases at or even below room temperature.


Assuntos
Aminas/química , Amino Álcoois/síntese química , Complexos de Coordenação/química , Irídio/química , Compostos de Organossilício/síntese química , Pirrolidinas/síntese química , Catálise , Oxirredução , Estereoisomerismo
12.
Chembiochem ; 19(21): 2293-2299, 2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30136342

RESUMO

A chiral amino alcohol based ligand was found to promote the highly enantioselective addition of terminal conjugated diynes to aromatic and aliphatic aldehydes. The combination of easily available C2 -symmetric (R)- and (S)-BINOL with Ti(OiPr)4 , Zn powder, and EtI was also found to catalyze the asymmetric addition of 1,3-diynes to aldehydes under mild reaction conditions, and thus, both enantiomers of the chiral conjugated diynols could be prepared with high enantioselectivities. The resulting optically active conjugated diynols were found to have potential anticancer activities with significant differences against HepG2 and HeLa cancer cells, and remarkable enantioselective cytotoxicity was observed for the first time.


Assuntos
Aldeídos/química , Amino Álcoois/química , Antineoplásicos/química , Di-Inos/química , Aldeídos/síntese química , Aldeídos/farmacologia , Amino Álcoois/síntese química , Amino Álcoois/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Catálise , Di-Inos/síntese química , Di-Inos/farmacologia , Células HeLa , Células Hep G2 , Humanos , Ligantes , Naftóis/síntese química , Naftóis/química , Naftóis/farmacologia , Neoplasias/tratamento farmacológico , Estereoisomerismo , Titânio/química , Zinco/química
13.
J Am Chem Soc ; 140(29): 9087-9090, 2018 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-29989803

RESUMO

In the presence of a neutral dppf-modified iridium catalyst and Cs2CO3, linear allylic acetates react with primary amines to form products of hydroamination with complete 1,3-regioselectivity. The collective data, including deuterium labeling studies, corroborate a catalytic mechanism involving rapid, reversible acetate-directed aminoiridation with inner-sphere/outer-sphere crossover followed by turnover-limiting proto-demetalation mediated by amine.


Assuntos
Acetatos/química , Compostos Alílicos/química , Aminas/química , Amino Álcoois/síntese química , Irídio/química , Compostos Alílicos/síntese química , Catálise , Modelos Químicos , Estereoisomerismo
14.
J Org Chem ; 83(17): 10487-10500, 2018 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-30039699

RESUMO

Chiral 1,2-amino alcohols are privileged scaffolds with important applications as drug candidates and chiral ligands. Although various methods for the preparation of this structural motif have been reported, these methods are limited because of the use of precious metals and ligands. Here, we report a practical and high yielding synthesis of chiral 1,2-amino alcohols using arylglyoxals and pseudoephedrine auxiliary. This reaction is catalyzed by a Brønsted acid and provides morpholinone products in high yields and selectivities. The morpholine ring was converted into 1,2-amino alcohols in a two-step protocol.


Assuntos
Amino Álcoois/química , Amino Álcoois/síntese química , Glioxal/química , Morfolinas/química , Morfolinas/síntese química , Técnicas de Química Sintética , Estereoisomerismo
15.
Bioorg Chem ; 78: 298-306, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29625269

RESUMO

A series of pterostilbene ß-amino alcohol derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). In vitro assays demonstrated that most of the derivatives were selective acetylacholinesterase (AChE) inhibitors with moderate multifunctional properties. Among them, compound 5f exhibited the best inhibitory activity for EeAChE (IC50 = 24.04 µM), that was better than pterostilbene under our experimental condition. In addition, compound 5f displayed reasonable antioxidant activity and could confer significant neuroprotective effect against H2O2-induced PC-12 cell injury. Moreover, 5f also showed self-induced Aß1-42 aggregation inhibitory potency and displayed high BBB permeability in vitro. These multifunctional properties highlight 5f as a promising candidate for further studies directed to the development of novel drugs against AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Amino Álcoois/farmacologia , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Fármacos Neuroprotetores/farmacologia , Estilbenos/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Amino Álcoois/síntese química , Amino Álcoois/química , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Modelos Moleculares , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Células PC12 , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos , Ratos , Estilbenos/síntese química , Estilbenos/química , Relação Estrutura-Atividade
16.
J Vis Exp ; (132)2018 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-29553559

RESUMO

Amino alcohols are versatile compounds with a wide range of applications. For instance, they have been used as chiral scaffolds in organic synthesis. Their synthesis by conventional organic chemistry often requires tedious multi-step synthesis processes, with difficult control of the stereochemical outcome. We present a protocol to enzymatically synthetize amino alcohols starting from the readily available L-lysine in 48 h. This protocol combines two chemical reactions that are very difficult to conduct by conventional organic synthesis. In the first step, the regio- and diastereoselective oxidation of an unactivated C-H bond of the lysine side-chain is catalyzed by a dioxygenase; a second regio- and diastereoselective oxidation catalyzed by a regiodivergent dioxygenase can lead to the formation of the 1,2-diols. In the last step, the carboxylic group of the alpha amino acid is cleaved by a pyridoxal-phosphate (PLP) decarboxylase (DC). This decarboxylative step only affects the alpha carbon of the amino acid, retaining the hydroxy-substituted stereogenic center in a beta/gamma position. The resulting amino alcohols are therefore optically enriched. The protocol was successfully applied to the semipreparative-scale synthesis of four amino alcohols. Monitoring of the reactions was conducted by high performance liquid chromatography (HPLC) after derivatization by 1-fluoro-2,4-dinitrobenzene. Straightforward purification by solid-phase extraction (SPE) afforded the amino alcohols with excellent yields (93% to >95%).


Assuntos
Amino Álcoois/síntese química , Dioxigenases/química , Lisina/química , Amino Álcoois/química , Catálise , Dioxigenases/metabolismo , Estereoisomerismo
17.
Nat Commun ; 9(1): 410, 2018 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-29379007

RESUMO

Enantiopure vicinal amino alcohols and derivatives are essential structural motifs in natural products and pharmaceutically active molecules, and serve as main chiral sources in asymmetric synthesis. Currently known asymmetric catalytic protocols for this class of compounds are still rare and often suffer from limited scope of substrates, relatively low regio- or stereoselectivities, thus prompting the development of more effective methodologies. Herein we report a dual catalytic strategy for the convergent enantioselective synthesis of vicinal amino alcohols. The method features a radical-type Zimmerman-Traxler transition state formed from a rare earth metal with a nitrone and an aromatic ketyl radical in the presence of chiral N,N'-dioxide ligands. In addition to high level of enantio- and diastereoselectivities, our synthetic protocol affords advantages of simple operation, mild conditions, high-yielding, and a broad scope of substrates. Furthermore, this protocol has been successfully applied to the concise synthesis of pharmaceutically valuable compounds (e.g., ephedrine and selegiline).


Assuntos
Aldeídos/química , Amino Álcoois/síntese química , Técnicas de Química Sintética , Ácidos de Lewis/química , Óxidos de Nitrogênio/química , Catálise , Luz , Oxirredução , Processos Fotoquímicos , Estereoisomerismo
18.
Med Chem ; 14(3): 293-303, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28745231

RESUMO

BACKGROUND: We prepared a novel series of enantiopure mefloquine analogues with pyrrolo[ 1,2-a]quinoxaline core in order to fight Plasmodium falciparum resistant strain. OBJECTIVES: To observe the influence of pyrrolo[1,2-a]quinoxaline core versus quinoline core on the antimalarial activity. METHOD: Four enantiopure aminoalcoholpyrrolo[1,2-a]quinoxalines 2 were synthetized via Sharpless asymmetric dihydroxylation reaction in eight steps. Their antimalarial activity was evaluated on two Plasmodium falciparum strains 3D7 and W2 with a SYBR Green I fluorescence-based method and their cytotoxicity was measured on four cell lines HepG2, THP-1, CHO and HFF. RESULTS: IC50 values of the four compounds 2 were close to the micromolar against the two P. falciparum strains. They were more active against P. falciparum strain W2 vs. P. falciparum strain 3D7. (R)- enantiomers were always more active than their (S)-counterpart whatever the strain. Selectivity indexes of compounds 2 were lower than 100. CONCLUSION: A novel series of enantiopure aminoalcohols with pyrrolo[1,2-a]quinoxaline core were synthesized in eight steps. They displayed IC50 values close to the micromolar against two P. falciparum strains 3D7 and W2. Although, In this series, 2,8-bistrifluoromethylquinoline was a best core than pyrrolo[1,2-a]quinoxaline for an optimal antimalarial activity, the pyrroloquinoxaline 2b showed an interesting antimalarial activity.


Assuntos
Amino Álcoois/farmacologia , Antimaláricos/farmacologia , Mefloquina/análogos & derivados , Mefloquina/farmacologia , Pirróis/farmacologia , Quinoxalinas/farmacologia , Amino Álcoois/síntese química , Amino Álcoois/química , Amino Álcoois/toxicidade , Animais , Antimaláricos/síntese química , Antimaláricos/química , Antimaláricos/toxicidade , Células CHO , Linhagem Celular Tumoral , Cloroquina/farmacologia , Cricetulus , Humanos , Mefloquina/química , Mefloquina/toxicidade , Plasmodium falciparum/efeitos dos fármacos , Pirróis/síntese química , Pirróis/química , Pirróis/toxicidade , Quinoxalinas/síntese química , Quinoxalinas/química , Quinoxalinas/toxicidade , Estereoisomerismo
19.
Chirality ; 30(1): 74-84, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29080267

RESUMO

We recently reported a new C3-symmetric (R)-phenylglycinol N-1,3,5-benzenetricarboxylic acid-derived chiral high-performance liquid chromatography (HPLC) stationary phase (CSP 1) that demonstrated better results as compared to a previously described N-3,5-dintrobenzoyl (DNB) (R)-phenylglycinol-derived CSP. Over a decade ago, (S)-leucinol, (R)-phenylglycine, and (S)-leucine derivatives were used as the starting materials of 3,5-DNB-based Pirkle-type CSPs for chiral separation. In this study, three new C3-symmetric CSPs (CSP 2, 3, and 4) were prepared by combining the ideas and results mentioned above. Here we describe the synthetic procedures and applications of the new C3-symmetric CSPs (CSP 2-CSP 4).


Assuntos
Aminoácidos/síntese química , Amino Álcoois/síntese química , Etanolaminas/química , Aminoácidos/química , Amino Álcoois/química , Cromatografia Líquida de Alta Pressão , Estereoisomerismo
20.
Eur J Med Chem ; 143: 780-791, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29220798

RESUMO

Excess adiposity is a hallmark of obesity, which is caused due to an imbalance between energy intake and energy consumed. Obesity is often associated with several metabolic disorders like dyslipidemia, cardiovascular diseases and type 2 diabetes. Earlier, our group had reported natural product Aegeline (amino-alcohol) isolated from the plant Aegle marmelos as an anti-diabetic and anti-dyslipidemic compound. With this background, we synthesized a series of novel amino alcohol and thiazolidinedione hybrid molecules and studied their antiadipogenic activity. As a result, we have identified a potent hybrid compound 12c as an inhibitor of adipocyte differentiation. The compound 12c inhibits lipid accumulation and adipogenesis in 3T3-L1 preadipocyte cell line. Exposure of compound 12c blocks mitotic clonal expansion and arrests cells in S-phase of cell cycle. Detailed analysis showed that compound 12c decreases expression of two major transcription factors that are involved in adipocyte differentiation, PPARγ, C/EBPα, and other adipogenesis associated genes like aP2 and FAS. Thus, we concluded that compound 12c shows potential ability to inhibit adipocyte differentiation which can be used therapeutically for the treatment of obesity and its associated metabolic disorders.


Assuntos
Adipogenia/efeitos dos fármacos , Amidas/farmacologia , Amino Álcoois/farmacologia , Tiazolidinedionas/farmacologia , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Amidas/química , Amino Álcoois/síntese química , Amino Álcoois/química , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Tiazolidinedionas/síntese química , Tiazolidinedionas/química
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