RESUMO
Therapies for human African trypanosomiasis and Chagas disease, caused by Trypanosoma brucei and Trypanosoma cruzi, respectively, are limited, providing minimal therapeutic options for the millions of individuals living in very poor communities. Here the effects of 10 novel quinolines are evaluated in silico and by phenotypic studies using in vitro and in vivo models. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties revealed that most molecules did not infringe on Lipinski's rules, which is a prediction of good oral absorption. These quinolines showed high probabilities of Caco2 permeability and human intestinal absorption and low probabilities of mutagenicity and of hERG1 inhibition. In vitro screens against bloodstream forms of T. cruzi demonstrated that all quinolines were more active than the reference drug (benznidazole [Bz]), except for DB2171 and DB2192, with five (DB2187, DB2131, DB2186, DB2191, and DB2217) displaying 50% effective concentrations (EC50s) of <3 µM (4-fold lower than that of Bz). Nine quinolines were more effective than Bz (2.7 µM) against amastigotes, showing EC50s ranging from 0.6 to 0.1 µM. All quinolines were also highly active in vitro against African trypanosomes, showing EC50s of ≤0.25 µM. The most potent and highly selective candidates for each parasite species were tested in in vivo models. Results for DB2186 were promising in mice with T. cruzi and T. brucei infections, reaching a 70% reduction of the parasitemia load for T. cruzi, and it cured 2 out of 4 mice infected with T. brucei DB2217 was also active in vivo and cured all 4 mice (100% cure rate) with T. brucei infection.
Assuntos
Doença de Chagas/tratamento farmacológico , Quinolinas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Animais , Células CACO-2 , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Mamíferos , Camundongos , Parasitemia/tratamento farmacológico , RatosRESUMO
Infections with protozoan parasites are a major cause of disease and mortality in many tropical countries of the world. Diseases caused by species of the genera Trypanosoma (Human African Trypanosomiasis and Chagas Disease) and Leishmania (various forms of Leishmaniasis) are among the seventeen "Neglected Tropical Diseases" (NTDs) defined as such by WHO due to the neglect of financial investment into research and development of new drugs by a large part of pharmaceutical industry and neglect of public awareness in high income countries. Another major tropical protozoan disease is malaria (caused by various Plasmodium species), which -although not mentioned currently by the WHO as a neglected disease- still represents a major problem, especially to people living under poor circumstances in tropical countries. Malaria causes by far the highest number of deaths of all protozoan infections and is often (as in this review) included in the NTDs. The mentioned diseases threaten many millions of lives world-wide and they are mostly associated with poor socioeconomic and hygienic environment. Existing therapies suffer from various shortcomings, namely, a high degree of toxicity and unwanted effects, lack of availability and/or problematic application under the life conditions of affected populations. Development of new, safe and affordable drugs is therefore an urgent need. Nature has provided an innumerable number of drugs for the treatment of many serious diseases. Among the natural sources for new bioactive chemicals, plants are still predominant. Their secondary metabolism yields an immeasurable wealth of chemical structures which has been and will continue to be a source of new drugs, directly in their native form and after optimization by synthetic medicinal chemistry. The current review, published in two parts, attempts to give an overview on the potential of such plant-derived natural products as antiprotozoal leads and/or drugs in the fight against NTDs.
Assuntos
Plantas Medicinais/metabolismo , Plantas Medicinais/química , Infecções por Protozoários/tratamento farmacológico , Produtos Biológicos/metabolismo , Produtos Biológicos/uso terapêutico , Produtos Biológicos/química , Humanos , Extratos Vegetais/metabolismo , Extratos Vegetais/uso terapêutico , Extratos Vegetais/química , Animais , Fitoterapia , Antiprotozoários/metabolismo , Antiprotozoários/uso terapêutico , Antiprotozoários/químicaRESUMO
A series of thirteen new megazol derivatives, designed exploring the molecular hybridization approach between megazol (3) and heterocombretastatins (2), was synthesized. These new compounds were tested for in vitro antiparasitic activity upon axenic amastigotes of Leishmania donovani. Biological results led us to identify a new potent megazol derivative (4g), which presents an IC(50) = 0.081microg/mL, more active tham the reference drug miltefosine (IC(50) = 0.131microg/mL).
Assuntos
Antiprotozoários/química , Antiprotozoários/farmacologia , Leishmania/efeitos dos fármacos , Tiadiazóis/química , Tiadiazóis/farmacologia , Animais , Antiprotozoários/síntese química , Antiprotozoários/toxicidade , Bibenzilas/química , Linhagem Celular , Desenho de Fármacos , Concentração Inibidora 50 , Ratos , Sulfonas/química , Tiadiazóis/síntese química , Tiadiazóis/toxicidadeRESUMO
Lanaroflavone (1), a biflavonoid isolated from the methanol extract of the aerial part of Campnosperma panamense by bioguided fractionation, has been assessed for in vitro antiprotozoal activity. Lanaroflavone showed both antimalarial and leishmanicidal activities, but was inactive against Chagas disease vector, Trypanosoma cruzi.
Assuntos
Anacardiaceae , Antiprotozoários/farmacologia , Fitoterapia , Extratos Vegetais/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antimaláricos/administração & dosagem , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Antiprotozoários/administração & dosagem , Antiprotozoários/uso terapêutico , Doença de Chagas/tratamento farmacológico , Flavonoides/administração & dosagem , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Humanos , Testes de Sensibilidade Parasitária , Componentes Aéreos da Planta , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêutico , Folhas de Planta , Tripanossomicidas/administração & dosagem , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêuticoRESUMO
Three derivatives of N-(3,4-dimethyl-5-isoxazolyl)-1,2-naphthoquinone-4-amino (1), a compound which exhibits significant activity against Trypanosoma cruzi and Plasmodium falciparum but with cytotoxicity toward murine L-6 cells, were synthesized with the aim of ameliorating its cytotoxicity. The in vitro antiprotozoal and cytotoxic activities of the synthesized compounds were evaluated against T. cruzi, Trypanosoma brucei rhodesiense, P. falciparum and murine L-6 cells. The hydroxymethyl (2) and the oxime (3) derivatives were active against T. cruzi, with IC50 values in a range comparable to those of 1 (IC50: 0.65 microg/ml) and benznidazole (IC50: 0.56 microg/ml) while the carboxymethyloxime (4) was inactive. Compounds 2 and 3 were cytotoxic toward L-6 cells, with IC50 values identical to that of 1 (IC50: 0.50 microg/ml). The results did not support the suggestion that 2 and 3 may be used as prodrugs of 1.
Assuntos
Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Isoxazóis/síntese química , Isoxazóis/farmacologia , Naftoquinonas/síntese química , Naftoquinonas/farmacologia , Animais , Antiprotozoários/uso terapêutico , Linhagem Celular , Química Farmacêutica/métodos , Química Farmacêutica/tendências , Avaliação Pré-Clínica de Medicamentos/métodos , Isoxazóis/uso terapêutico , Estrutura Molecular , Naftoquinonas/uso terapêutico , Plasmodium falciparum/efeitos dos fármacos , Ratos , Suíça , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacosRESUMO
Subsequent to the National Epidemiologic Surveillance Program developed in 1997 by the National AIDS Program, anti-HTLV-I/II antibodies among blood donors in Santa Fe Province started to be detected. On the basis of this initial finding, it was regarded of interest to evaluate the true HTLV-I/II seroprevalence in this population during a four-year survey. Thus, from 1997 up to 2002, 9425 samples were studied from 17 out of the 19 provincial departments. Out of the total sampling, 38 proved reactive by agglutination techniques, 18 of which were confirmed by western blot (WB). Out of the latter, 10 were HTLV-I/II seropositive with a final prevalence of 0.1% (10/9425), whereas 7 were indeterminate and 1 negative. Among these 10 confirmed sera, 2 (0.02%) were HTLV, 3 (0.03%) HTLV-I and 5 (0.05%) HTLV-II. It should be highlighted that the presence of HTLV-I/II infection in blood donors in Santa Fe Province was demonstrated for the first time, with a prevalence greater than that reported for blood donors in non-endemic Argentine areas. Such findings confirm the need of corresponding systematic screening through regulatory blood bank norms in Santa Fe Province.
Subsecuentemente a que en 1997 el Programa Nacional de SIDA implementó un Programa de Vigilancia Epidemiológica a escala nacional, se comenzaron a detectar anticuerpos anti-HTLV-I/II en donantes de sangre de la Provincia de Santa Fe. En base a ese hallazgo inicial, se consideró pertinenteestimar la seroprevalencia de HTLV-I/II en donantes santafecinos en el curso de los 4 años siguientes. Así,desde 1997 hasta 2002, se estudiaron 9425 muestras provenientes de 17 de los 19 departamentos de laProvincia. Del total de muestras, 38 resultaron reactivas por técnicas de tamizaje, y de ellas 18 fueron confirmadas por western blot (WB). De esas muestras, 10 fueron HTLV-I/II seropositivas con una prevalencia finalde 0.1% (10/9425), en tanto que 7 resultaron indeterminadas y 1 negativa. De las seropositivas, 2 (0.02 %)eran HTLV, 3 (0.03 %) HTLV-I, y 5 (0.05 %) HTLV-II. Cabe destacar que por primera vez se constató lapresencia de infección por HTLV-I/II en donantes de sangre de Santa Fe, y con una prevalencia mayor a lasreferidas para donantes de sangre de áreas no endémicas de Argentina. Estos datos fundamentan la necesidadde un screening sistemático para la infección por HTLV-I/II mediante normas regulatorias en bancos desangre de esta provincia..
Assuntos
Humanos , Doadores de Sangue/estatística & dados numéricos , Infecções por HTLV-I/epidemiologia , Argentina/epidemiologia , Infecções por HTLV-I/diagnóstico , Infecções por HTLV-II/diagnóstico , Infecções por HTLV-II/epidemiologia , Programas de Rastreamento , Prevalência , Estudos Retrospectivos , Estudos SoroepidemiológicosRESUMO
Subsequent to the National Epidemiologic Surveillance Program developed in 1997 by the National AIDS Program, anti-HTLV-I/II antibodies among blood donors in Santa Fe Province started to be detected. On the basis of this initial finding, it was regarded of interest to evaluate the true HTLV-I/II seroprevalence in this population during a four-year survey. Thus, from 1997 up to 2002, 9425 samples were studied from 17 out of the 19 provincial departments. Out of the total sampling, 38 proved reactive by agglutination techniques, 18 of which were confirmed by western blot (WB). Out of the latter, 10 were HTLV-I/II seropositive with a final prevalence of 0.1% (10/9425), whereas 7 were indeterminate and 1 negative. Among these 10 confirmed sera, 2 (0.02%) were HTLV, 3 (0.03%) HTLV-I and 5 (0.05%) HTLV-II. It should be highlighted that the presence of HTLV-I/II infection in blood donors in Santa Fe Province was demonstrated for the first time, with a prevalence greater than that reported for blood donors in non-endemic Argentine areas. Such findings confirm the need of corresponding systematic screening through regulatory blood bank norms in Santa Fe Province.(AU)
Subsecuentemente a que en 1997 el Programa Nacional de SIDA implementó un Programa de Vigilancia Epidemiológica a escala nacional, se comenzaron a detectar anticuerpos anti-HTLV-I/II en donantes de sangre de la Provincia de Santa Fe. En base a ese hallazgo inicial, se consideró pertinenteestimar la seroprevalencia de HTLV-I/II en donantes santafecinos en el curso de los 4 años siguientes. Así,desde 1997 hasta 2002, se estudiaron 9425 muestras provenientes de 17 de los 19 departamentos de laProvincia. Del total de muestras, 38 resultaron reactivas por técnicas de tamizaje, y de ellas 18 fueron confirmadas por western blot (WB). De esas muestras, 10 fueron HTLV-I/II seropositivas con una prevalencia finalde 0.1% (10/9425), en tanto que 7 resultaron indeterminadas y 1 negativa. De las seropositivas, 2 (0.02 %)eran HTLV, 3 (0.03 %) HTLV-I, y 5 (0.05 %) HTLV-II. Cabe destacar que por primera vez se constató lapresencia de infección por HTLV-I/II en donantes de sangre de Santa Fe, y con una prevalencia mayor a lasreferidas para donantes de sangre de áreas no endémicas de Argentina. Estos datos fundamentan la necesidadde un screening sistemático para la infección por HTLV-I/II mediante normas regulatorias en bancos desangre de esta provincia..(AU)
Assuntos
Humanos , Doadores de Sangue/estatística & dados numéricos , Infecções por HTLV-I/epidemiologia , Argentina/epidemiologia , Infecções por HTLV-I/diagnóstico , Infecções por HTLV-II/diagnóstico , Infecções por HTLV-II/epidemiologia , Programas de Rastreamento , Prevalência , Estudos Retrospectivos , Estudos SoroepidemiológicosRESUMO
Prospective anterolateral neural fold was grafted from normal axolotls into the posterior neural fold region (statocyst area) of eyeless mutant hosts. These unilateral anteroposterior grafts stimulated bilateral eye formation in the eyeless mutant at a rate of 79%. Replacing the statocyst area of mutants with the statocyst area from normals stimulated bilateral eye formation in 49% of the cases. Grafting of prospective anterolateral neural fold between normals and mutants or excising the statocyst region of mutants, had no effect. The results are interpreted on the basis of a hypothetical anteroposterior morphogenetic system that might be out of balance in the mutant.
Assuntos
Anoftalmia/genética , Ambystoma mexicanum , Animais , Anoftalmia/embriologia , Olho/embriologia , Genes Recessivos , Morfogênese , MutaçãoRESUMO
In studies of amphibian neurulation, the terms "neural ridge," "neural fold," and "neural crest" are sometimes used as synonyms. This has occasionally led to the misconception that grafting of the neural crest is equivalent to grafting of the neural fold. The neural fold, however, is composed of three parts: the neural crest, prospective neural tube tissue, and epidermis. In order to investigate how these neural fold components move during neurulation, time-lapse photography, electron microscopy, and grafting were performed. Ambystoma mexicanum embryos were photographed during neurulation at regular intervals. The photographs were analyzed to find the position of those cells at beginning of neurulation that end up on the line of fusion as the neural folds close. Posteriorly, these cells are already on the emerging neural fold. In the anterior neural folds, however, these cells are located in the lateral epidermis. Electron microscopy of the neural folds confirms the presence of epidermis. To follow the movement of the cells differentiating into melanophores (neural crest), neural fold parts were grafted into albino hosts. The crest cells differentiating into melanophores following ectopic grafting are located in the flank of the neural fold that is in contact with the neural plate. In grafts from the outside (distal) flank, no melanophores developed. Semithin sections show that the third part of the neural fold consists of apically constricted cells known to differentiate into neural tissue. Because the neural folds consist of epidermis, neural tissue, and neural crest, neural fold and neural crest cannot be used as synonyms.
Assuntos
Ambystoma/embriologia , Sistema Nervoso/embriologia , Crista Neural/citologia , Animais , Movimento Celular , Melanóforos/citologia , Sistema Nervoso/citologiaRESUMO
We analysed the neurulation movements in the Mexican salamander Ambystoma mexicanum. Embryos were exposed to colchicine or nocodazole prior to neural fold formation. Exposure to these drugs prevented the anterior neural folds from closing. Neurulation however proceeded normally in the posterior regions of the embryo. We were unable to find apically constricted cells in the neural plate of colchicine-blocked neurulae. Only rounded-up neural plate cells were present (semithin sections). This situation was typical in embryos exposed to colchicine prior to neural fold formation. Concentrations of colchicine up to 2.5 x 10(-3) were not capable of blocking neurulation once the neural folds were formed. The wedge-shaped cells were present in similar numbers to those found in controls. We quantified the cell shape changes in the neural plate and in the epidermis in both controls and drug-arrested embryos. The comparison of these to classes of data shows that epidermal spreading is prevented by colchicine but only slightly affected by nocodazole. Embryos blocked in late neurulation by exposure to these drugs can resume neurulation following neural plate excision in nocodazole but not in colchicine. We conclude from this observation that the epidermis contributes to raising and closing of the neural folds. The presence of neural folds in absence of wedge-shaped cells in the neural plate is also taken as evidence that neurulation is not exclusively driven by forces generated in or acting on the neural plate. Our view on the concerted interplay of various embryonic components is illustrated in a summarizing diagram (Fig. 11).