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1.
Chem Commun (Camb) ; 56(6): 956-959, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31858094

RESUMO

On-resin intramolecular native chemical ligation (NCL) assisted by N-ethylcysteine using Fmoc/SPPS to obtain cyclic peptides is described. N-terminal cysteine-containing peptides were subjected to NCL conditions leading to cyclization-cleavage reactions and consecutive S → N shift, rendering cyclic peptides in good yields and purities. The compounds were evaluated against P. falciparum 3D7.


Assuntos
Peptídeos Cíclicos/síntese química , Compostos de Sulfidrila/química , Cisteína/análogos & derivados , Cisteína/química , Estrutura Molecular , Peptídeos Cíclicos/química , Resinas Sintéticas/química
2.
ACS Med Chem Lett ; 10(1): 137-141, 2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30655961

RESUMO

Malaria is a major tropical disease where important needs are to mitigate symptoms and to prevent the establishment of infection. Cyclopeptides containing N-methyl amino acids with in vitro activity against erythrocytic forms as well as liver stage are presented. The synthesis, parasitological characterization, physicochemical properties, in vivo evaluation, and mice pharmacokinetics are described.

3.
ACS Comb Sci ; 20(4): 212-219, 2018 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-29446619

RESUMO

The results from the synthesis of peptides by Fmoc/SPPS on a 2-CTC resin and then lactamization in solution or solid phase for the preparation of cyclopeptides are presented. Both procedures allow the synthesis of the desired compounds in good to very good yield and with high cyclization efficiency for on-resin macrocyclization. In addition, the activities of the corresponding cyclopeptides against the chloroquine-resistant K1 strain of Plasmodium falciparum were evaluated. Cyclo-Cys(Trt)-Gly-Thr( tBu)-Gly-Cys(Trt)-Gly showed potent in vitro and selective activity against this parasite, EC50 = 28 nM.


Assuntos
Antimaláricos/síntese química , Malária/tratamento farmacológico , Peptídeos Cíclicos/síntese química , Antimaláricos/farmacologia , Ciclização , Resistência a Medicamentos , Biblioteca de Peptídeos , Peptídeos Cíclicos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Técnicas de Síntese em Fase Sólida , Relação Estrutura-Atividade
4.
Eur J Med Chem ; 126: 776-788, 2017 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-27951486

RESUMO

Distamycin, a natural polyamide containing three heterocycle rings with a polar end, has inspired several groups to prepare synthetic analogues, which proved to have anti-trypanosomal and anti-tumoral activity. We describe the synthesis of bi and tri thiazoles amides that harbor different substitutions at their ends and the evaluation of their anti-Trypanosoma brucei activity. The most active compound 10b showed better biological activity (EC50 310 nM and selectivity index 16) than the control drug nifurtimox (EC50 15 µM and selectivity index 10). Studies on the mode of action show that the parasiticidal activity of 10b originates from disruption of lysosomal homeostasis, which is followed by release of redox active iron, an increase in oxidizing species and collapse of cell membrane integrity. In this respect, our study suggests that non-charged lipophylic distamycins destabilize cell membranes.


Assuntos
Distamicinas/farmacologia , Tripanossomicidas/química , Trypanosoma/efeitos dos fármacos , África , Antineoplásicos/química , Antineoplásicos/farmacologia , Membrana Celular/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Tiazóis/síntese química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos
5.
ACS Comb Sci ; 18(5): 225-9, 2016 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-27073985

RESUMO

A versatile palladium-catalyzed tandem synthetic sequence to afford E-stilbenes libraries has been developed. Excellent regio- and stereocontrol have been achieved by means of the sequence of Hiyama and Heck cross-couplings. Undesirable homocoupling byproducts were avoided employing immobilized substrates.


Assuntos
Paládio/química , Bibliotecas de Moléculas Pequenas/síntese química , Estilbenos/síntese química , Catálise
6.
Future Med Chem ; 7(3): 355-82, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25650721

RESUMO

Macrocycles possess desirable properties that make them promising candidates for the discovery of novel drugs. They present structural features to favor bioactive conformations, selectivity to the receptors, cell permeability and metabolic stability. More effective and nontoxic drugs to cure human African trypanosomiasis, Leishmaniasis and Chagas disease are needed, especially because resistance has been detected. Therefore, major efforts should be made for investigation in new bioactive compounds exhibiting different mechanisms of action. Macrocycles might fulfill the expectations for the development of new drugs to treat those diseases. In the current review, we focus on macrocycles exhibiting biological activities as antitrypanosomal and/or antileishmanial. The isolation, synthetic and biological studies of this class of compounds published from 2005 to 2014 are summarized.


Assuntos
Antiprotozoários/uso terapêutico , Compostos Macrocíclicos/uso terapêutico , Doenças Negligenciadas/tratamento farmacológico , Tripanossomicidas/uso terapêutico , Antiprotozoários/química , Descoberta de Drogas , Humanos , Compostos Macrocíclicos/química , Conformação Molecular , Tripanossomicidas/química
7.
Bioorg Med Chem Lett ; 22(15): 4994-7, 2012 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-22765903

RESUMO

The synthesis of a Microcystis aeruginosa predicted metabolite analog of aerucyclamide B was performed. This hexacyclopeptide was obtained from three heterocyclic building blocks by a convergent macrocycle-assembly methodology. The compound exhibited good in vitro antiplasmodial activity (IC(50): 0.18 µM, K1, cholorquine resistant strain).


Assuntos
Antimaláricos/síntese química , Microcystis/metabolismo , Peptídeos Cíclicos/metabolismo , Antimaláricos/metabolismo , Antimaláricos/farmacologia , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Oxazóis/química , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Tiazóis/química
8.
Mar Drugs ; 8(11): 2755-80, 2010 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-21139843

RESUMO

Thiazoles, oxazole and their corresponding reduced derivatives, thiazolines and oxazolines, are found in marine sources exhibiting significant biological activities. The isolation, synthetic, and biological studies of these natural products, covering literature from January 2007 to June 2010, are summarized.


Assuntos
Alcaloides , Oxazóis , Tiazóis , Alcaloides/síntese química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Animais , Produtos Biológicos/síntese química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Desenho de Fármacos , Descoberta de Drogas/métodos , Humanos , Oxazóis/síntese química , Oxazóis/isolamento & purificação , Oxazóis/farmacologia , Tiazóis/síntese química , Tiazóis/isolamento & purificação , Tiazóis/farmacologia
9.
Tetrahedron Lett ; 48(10): 1827-1830, 2007 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-18320006

RESUMO

The synthesis of the C(1)-N(15) fragment of the marine natural product Scleritodermin A has been accomplished through a short and stereocontrolled sequence. Highlights of this route include the synthesis of the novel ACT fragment and the formation of the alpha-keto amide linkage by the use of a highly activated alpha, beta-ketonitrile.

10.
Rev Esp Salud Publica ; 80(4): 335-47, 2006.
Artigo em Espanhol | MEDLINE | ID: mdl-16913609

RESUMO

BACKGROUND: To know the geographic distribution of the prevalence of psychological distress is important for mental health services planning. This study is aimed at identifying the individual factors and those related to the area of residence which may explain the geographic variability of psychological distress (by healthcare districts) in Catalonia. METHODS: The data was taken from the 1994 Catalonian Health Survey and from the 1996 Catalonia population statistics. The prevalence of psychological distress is estimated by age and sex and by healthcare district. In a two-level logic regression model, a study is made of the relationship between the individual variables (first level: health survey n = 12,455) and those of the area of residence (second level: the healthcare district, n = 46) to the geographic distribution of the prevalence of psychological distress. RESULTS: The significant variables at individual level are in men: age (45-64 years OR: 0.63 y > 64 years OR: 0.22), working status (no work OR: 1.60), number of chronic diseases (CD) (CD = 1 OR: 1.75 CD = 2 OR: 2.06 CD = 3-5 OR: 3.36 and CD > 5 OR: 8.9). In women: age (25-44 years OR: 0.63 45-64 years OR: 0.45 and > 64 years OR: 0.32), working status (no work OR: 1.30), number of chronic diseases (CD = 1 OR: 1.75 CD = 2 OR: 2.44 CD = 3-5 OR: 4.09 and CD > 5 OR: 11.14), and also the kind of parental household in women (single-parental OR: 1.42). The variables at the level of the area of residence are in migration (men OR: 1.55 and women OR: 1.68) and unemployment (men OR: 1.07 and women OR: 1.06). CONCLUSIONS: The individual factors do not suffice to explain the geographical variability of the prevalence of psychological distress, but the characteristics of the area of residence are also important.


Assuntos
Estresse Psicológico/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Meio Ambiente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Espanha/epidemiologia
11.
Rev. esp. salud pública ; 80(4): 335-347, jun.-jul. 2006. mapas, tab
Artigo em Espanhol | IBECS | ID: ibc-050484

RESUMO

Fundamento: Para planificar las necesidades de servicios sanitarioses fundamental conocer la distribución de la morbilidad portrastornos psicológicos en el territorio así como los factores que ladeterminan. El objetivo es identificar los factores que pueden explicarla variabilidad geográfica de estos trastornos en Cataluña.Métodos: Los datos proceden de la Encuesta de Salud de l994 yde la estadística de población de l996 para Cataluña. Se estima la prevalenciade trastornos psicológicos por edad y sexo y por sector sanitario.En un modelo de regresión logística a dos niveles se estudia laasociación entre las variables individuales (primer nivel: Encuestade Salud n=12.455) y las de la zona de residencia (segundo nivel: elsector sanitario, n= 46) con la prevalencia de trastornos psicológicos.Resultados: Las variables individuales que influyen en las diferenciasentre sectores son: la edad (45-64 años OR:0,63 y >64 años:OR:0,22), la situación laboral (no trabaja OR:1,60) y el número detrastornos crónicos (TC) (TC=1 OR: 1,75 TC=2 OR: 2,06 TC=3-5OR:3,36 y TC>5 OR: 8,9) en hombres. En las mujeres, además deestas variables (edad 25-44 años OR: 0,63 45-64 años OR:0,45 y >64años OR: 0,32 la situación laboral no trabaja OR:1,30 y el número detrastornos crónicos (TC) TC=1 OR: 1,75 TC=2 OR: 2,44 TC=3-5OR:4,09 y TC>5 OR: 11,14), influye el tipo de hogar (monoparentalOR: 1,42). Las variables a nivel de la zona de residencia son la proporciónde inmigración (hombres OR:1,55 y mujeres OR:1,68) y dedesempleo (hombres OR:1,07 y mujeres OR:1,06).Conclusiones: Los factores individuales no son suficientes paraexplicar la variabilidad geográfica de la prevalencia de los trastornospsicológicos, ya que también influyen las características de la zonade residencia


Background: To know the geographic distribution of the prevalenceof psychological distress is important for mental healthservices planning. This study is aimed at identifying the individualfactors and those related to the area of residence which may explainthe geographic variability of psychological distress (by healthcaredistricts) in Catalonia.Methods: The data was taken from the 1994 Catalonian HealthSurvey and from the 1996 Catalonia population statistics. The prevalenceof psychological distress is estimated by age and sex and byhealthcare district. In a two-level logic regression model, a study ismade of the relationship between the individual variables (first level:health survey n=12,455) and those of the area of residence (secondlevel: the healthcare district, n=46) to the geographic distribution ofthe prevalence of psychological distress.Results: The significant variables at individual level are in men:age (45-64 years OR:0,63 y >64 years OR: 0,22), working status (nowork OR:1,60) , number of chronic diseases (CD) (CD=1 OR: 1,75CD=2 OR: 2,06 CD=3-5 OR:3,36 and CD>5 OR: 8,9). In women:age (25-44 years OR: 0,63 45-64 years OR:0,45 and >64 years OR:0,32), working status (no work OR:1,30), number of chronic diseases(CD=1 OR: 1,75 CD=2 OR: 2,44 CD=3-5 OR:4,09 and CD>5OR: 11,14), and also the kind of parental household in women (single-parental OR: 1,42). The variables at the level of the area of residenceare inmigration (men OR:1,55 and women OR:1,68) andunemployment (men OR:1,07 and women OR:1,06).Conclusions: The individual factors do not suffice to explain thegeographical variability of the prevalence of psychological distress,but the characteristics of the area of residence are also important


Assuntos
Humanos , Transtornos Mentais/epidemiologia , Unidade Hospitalar de Psiquiatria/organização & administração , Comparação Transcultural , Fatores Sexuais , Fatores Etários , Morbidade , Fatores Socioeconômicos , Condições Sociais
12.
Bioorg Med Chem Lett ; 16(5): 1309-11, 2006 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-16384701

RESUMO

Thiazoline and oxazoline analogues of the natural product mycothiazole were synthesized from a common intermediate and evaluated in vitro against HCT-15 colon cancer cells and L(4) larvae of nematode Nippostrongylus brasiliensis. The nature of the heterocyclic moiety seems to modulate the cytotoxic or anthelmintic activity.


Assuntos
Anti-Helmínticos/síntese química , Anti-Helmínticos/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Animais , Anti-Helmínticos/química , Anti-Helmínticos/toxicidade , Linhagem Celular Tumoral , Larva/efeitos dos fármacos , Estrutura Molecular , Nippostrongylus/efeitos dos fármacos , Oxazolona/análogos & derivados , Oxazolona/síntese química , Oxazolona/química , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/toxicidade
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