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1.
Chem Biol Interact ; 394: 110954, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38518852

RESUMEN

The literature reports that thiazole and isatin nuclei present a range of biological activities, with an emphasis on anticancer activity. Therefore, our proposal was to make a series of compounds using the molecular hybridization strategy, which has been used by our research group, producing hybrid molecules containing the thiazole and isatin nuclei. After structural planning and synthesis, the compounds were characterized and evaluated in vitro against breast cancer cell lines (T-47D, MCF-7 and MDA-MB-231) and against normal cells (PBMC). The activity profile on membrane proteins involved in chemoresistance and tumorigenic signaling proteins was also evaluated. Among the compounds tested, the compounds 4c and 4a stood out with IC50 values of 1.23 and 1.39 µM, respectively, against the MDA-MB-231 cell line. Both compounds exhibited IC50 values of 0.45 µM for the MCF-7 cell line. Compounds 4a and 4c significantly decreased P-gp mRNA expression levels in MCF-7, 4 and 2 folds respectively. Regarding the impact on tumorigenic signaling proteins, compound 4a inhibited Akt2 in MDA-MB-231 and compound 4c inhibited the mRNA expression of VIM in MCF-7.


Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Isatina , Proteínas Proto-Oncogénicas c-akt , ARN Mensajero , Tiazoles , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Isatina/farmacología , Isatina/química , Isatina/síntesis química , Línea Celular Tumoral , ARN Mensajero/metabolismo , ARN Mensajero/genética , Tiazoles/farmacología , Tiazoles/química , Femenino , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Simulación del Acoplamiento Molecular , Células MCF-7 , Ensayos de Selección de Medicamentos Antitumorales , Relación Estructura-Actividad
2.
Eur J Med Chem ; 267: 116163, 2024 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-38290351

RESUMEN

The World Health Organization (WHO) estimated that there were 247 million malaria cases in 2021 worldwide, representing an increase in 2 million cases compared to 2020. The urgent need for the development of new antimalarials is underscored by specific criteria, including the requirement of new modes of action that avoid cross-drug resistance, the ability to provide single-dose cures, and efficacy against both assexual and sexual blood stages. Motivated by the promising results obtained from our research group with [1,2,4]triazolo[1,5-a]pyrimidine and pyrazolo[1,5-a]pyrimidine derivatives, we selected these molecular scaffolds as the foundation for designing two new series of piperaquine analogs as potential antimalarial candidates. The initial series of hybrids was designed by substituting one quinolinic ring of piperaquine with the 1,2,4-triazolo[1,5-a]pyrimidine or pyrazolo[1,5-a]pyrimidine nucleus. To connect the heterocyclic systems, spacers with 3, 4, or 7 methylene carbons were introduced at the 4 position of the quinoline. In the second series, we used piperazine as a spacer to link the 1,2,4-triazolo[1,5-a]pyrimidine or pyrazolo[1,5-a]pyrimidine group to the quinoline core, effectively merging both pharmacophoric groups via a rigid spacer. Our research efforts yielded promising compounds characterized by low cytotoxicity and selectivity indices exceeding 1570. These compounds displayed potent in vitro inhibitory activity in the low nanomolar range against the erythrocytic form of the parasite, encompassing both susceptible and resistant strains. Notably, these compounds did not show cross-resistance with either chloroquine or established P. falciparum inhibitors. Even though they share a pyrazolo- or triazolo-pyrimidine core, enzymatic inhibition assays revealed that these compounds had minimal inhibitory effects on PfDHODH, indicating a distinct mode of action unrelated to targeting this enzyme. We further assessed the compounds' potential to interfere with gametocyte and ookinete infectivity using mature P. falciparum gametocytes cultured in vitro. Four compounds demonstrated significant gametocyte inhibition ranging from 58 % to 86 %, suggesting potential transmission blocking activity. Finally, we evaluated the druggability of these new compounds using in silico methods, and the results indicated that these analogs had favorable physicochemical and ADME (absorption, distribution, metabolism, and excretion) properties. In summary, our research has successfully identified and characterized new piperaquine analogs based on [1,2,4]triazolo[1,5-a]pyrimidine and pyrazolo[1,5-a]pyrimidine scaffolds and has demonstrated their potential as promising candidates for the development of antimalarial drugs with distinct mechanisms of action, considerable selectivity, and P. falciparum transmission blocking activity.


Asunto(s)
Antimaláricos , Malaria Falciparum , Piperazinas , Quinolinas , Humanos , Antimaláricos/farmacología , Antimaláricos/química , Plasmodium falciparum , Quinolinas/química , Malaria Falciparum/tratamiento farmacológico , Pirimidinas/química
3.
An Acad Bras Cienc ; 95(suppl 2): e20230566, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38055446

RESUMEN

In this work, an in silico study and evaluation of the cytotoxicity of 4-(4-chlorophenyl)thiazole compounds against mouse splenocytes and the chloroquine-sensitive Plasmodium falciparum 3D7 strain are reported. The in silico results showed that the compounds have important pharmacokinetic properties for compounds with potential drug candidates. Regarding cytotoxicity assays against splenocytes, the compounds have low cytotoxicity. In addition, they were able to promote activation of these cells by increasing nitric oxide production without promoting cell death. Finally, they were able to promote cell proliferation. Regarding the in vitro anti-P. falciparum activity assays, it was observed that the compounds were able to inhibit the parasite's growth, presenting IC50 values ​​ranging from 0.79 to greater than 10 µM. These results are promising when compared to chloroquine. Therefore, this study showed that 4-(4-chlorophenyl)thiazole compounds are promising candidates for antimalarials.


Asunto(s)
Antimaláricos , Antagonistas del Ácido Fólico , Animales , Ratones , Antimaláricos/farmacología , Tiazoles , Bazo , Cloroquina/farmacología , Plasmodium falciparum
4.
3 Biotech ; 13(12): 391, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37953832

RESUMEN

Clarisia racemosa Ruiz & Pav is a neotropical species found in humid forests from southern Mexico to southern Brazil. There are few studies related to the ethnopharmacological use of C. racemosa. Our objective was to evaluate the hydroalcoholic extract of C. racemosa as a potential antiparasitic agent. For this, we performed in vitro assays against strains of Leishmania amazonensis, Trypanosoma cruzi, Plasmodium falciparum, and Schistosoma mansoni. At the same time, immunomodulatory activity tests were carried out. The results demonstrated that the extract was able to stimulate and activate immune cells. In preliminary antiparasitic tests, structural modifications were observed in the promastigote form of L. amazonensis and in adult worms of S. mansoni. The extract was able to inhibit the growth of trypomastigote form of T. cruzi and finally showed low antiparasitic activity against strains of P. falciparum. It is pioneering work and these results demonstrate that C. racemosa extract is a promising alternative and contributes to the arsenal of possible forms of treatment to combat parasites. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03799-2.

5.
ChemMedChem ; 18(17): e202300264, 2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-37392377

RESUMEN

A multistep and diversity-oriented synthetic route aiming at the A3 coupling/domino cyclization of o-ethynyl anilines, aldehydes and s-amines is described. The preparation of the corresponding precursors included a series of transformations, such as haloperoxidation and Sonogashira cross-coupling reactions, amine protection, desilylation and amine reduction. Some products of the multicomponent reaction underwent further detosylation and Suzuki coupling. The resulting library of structurally diverse compounds was evaluated against blood and liver stage malaria parasites, which revealed a promising lead with sub-micromolar activity against intra-erythrocytic forms of Plasmodium falciparum. The results from this hit-to-lead optimization are hereby reported for the first time.


Asunto(s)
Antimaláricos , Antimaláricos/farmacología , Indoles , Aldehídos , Aminas , Compuestos de Anilina , Ciclización , Catálisis
6.
Malar J ; 22(1): 160, 2023 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-37208708

RESUMEN

BACKGROUND: Malaria remains one of the most serious public health problems in sub-Saharan Africa and Mozambique is the world's fourth largest contributor, with 4.7% of disease cases and 3.6% of total deaths due to malaria. Its control relies on the fight against the vector and treatment of confirmed cases with anti-malarial drugs. Molecular surveillance is an important tool for monitoring the spread of anti-malarial drug resistance. METHODS: A cross-sectional study recruited 450 participants with malaria infection detected by Rapid Diagnostic Tests, from three different study sites (Niassa, Manica and Maputo) between April and August 2021. Correspondent blood samples were collected on filter paper (Whatman® FTA® cards), parasite DNA extracted and pfk13 gene sequenced using Sanger method. SIFT software (Sorting Intolerant From Tolerant) was used, predict whether an amino acid substitution affects protein function. RESULTS: No pfkelch13-mediated artemisinin resistance gene mutation was detected in this study settings. However, non-synonymous mutations were detected at prevalence of 10.2%, 6% and 5% in Niassa, Manica and Maputo, respectively. Most (56.3%) of the reported non-synonymous mutations were due to substitution at the first base of the codon, 25% at the second base and 18.8% at the third base. Additionally, 50% of non-synonymous mutations showed a SIFTscore bellow cut off value of 0.05, therefore, they were predicted to be deleterious. CONCLUSION: These results do not show an emergence of artemisinin resistance cases in Mozambique. However, the increased number of novel non-synonymous mutations highlights the relevance of increasing the number of studies focused on the molecular surveillance of artemisinin resistance markers, for its early detection.


Asunto(s)
Antimaláricos , Artemisininas , Malaria Falciparum , Humanos , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Mozambique/epidemiología , Estudios Transversales , Malaria Falciparum/parasitología , Artemisininas/uso terapéutico , Mutación , Resistencia a Medicamentos/genética , Proteínas Protozoarias/metabolismo
7.
Int J Biol Macromol ; 242(Pt 2): 124745, 2023 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-37150376

RESUMEN

Malaria, leishmaniasis and Chagas disease are vector-borne protozoal infections with a disproportionately high impact on the most fragile societies in the world, and despite malaria-focused research gained momentum in the past two decades, both trypanosomiases and leishmaniases remain neglected tropical diseases. Affordable effective drugs remain the mainstay of tackling this burden, but toxicicty, inneficiency against later stage disease, and drug resistance issues are serious shortcomings. One strategy to overcome these hurdles is to get new therapeutics or inspiration in nature. Indeed, snake venoms have been recognized as valuable sources of biomacromolecules, like peptides and proteins, with antiprotozoal activity. This review highlights major snake venom components active against at least one of the three aforementioned diseases, which include phospholipases A2, metalloproteases, L-amino acid oxidases, lectins, and oligopeptides. The relevance of this repertoire of biomacromolecules and the bottlenecks in their clinical translation are discussed considering approaches that should increase the success rate in this arduous task. Overall, this review underlines how venom-derived biomacromolecules could lead to pioneering antiprotozoal treatments and how the drug landscape for neglected diseases may be revolutionized by a closer look at venoms. Further investigations on poorly studied venoms is needed and could add new therapeutics to the pipeline.


Asunto(s)
Enfermedad de Chagas , Leishmaniasis , Malaria , Humanos , Venenos de Serpiente/química , Péptidos/farmacología , Enfermedad de Chagas/tratamiento farmacológico , Leishmaniasis/tratamiento farmacológico
8.
Exp Parasitol ; 248: 108498, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-36907541

RESUMEN

In this work, 13 thiosemicarbazones (1a - m) and 16 thiazoles (2a - p) were obtained, which were properly characterized by spectroscopic and spectrometric techniques. The pharmacokinetic properties obtained in silico revealed that the derivatives are in accordance with the parameters established by lipinski and veber, showing that such compounds have good bioavailability or permeability when administered orally. In assays of antioxidant activity, thiosemicarbazones showed moderate to high antioxidant potential when compared to thiazoles. In addition, they were able to interact with albumin and DNA. Screening assays to assess the toxicity of compounds to mammalian cells revealed that thiosemicarbazones were less toxic when compared to thiazoles. In relation to in vitro antiparasitic activity, thiosemicarbazones and thiazoles showed cytotoxic potential against the parasites Leishmania amazonensis and Trypanosoma cruzi. Among the compounds, 1b, 1j and 2l stood out, showing inhibition potential for the amastigote forms of the two parasites. As for the in vitro antimalarial activity, thiosemicarbazones did not inhibit Plasmodium falciparum growth. In contrast, thiazoles promoted growth inhibition. This study shows in a preliminary way that the synthesized compounds have antiparasitic potential in vitro.


Asunto(s)
Tiosemicarbazonas , Trypanosoma cruzi , Animales , Antioxidantes/farmacología , Antiparasitarios/toxicidad , Relación Estructura-Actividad , Tiazoles/farmacología , Tiazoles/química , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/química , Mamíferos
9.
Int J Biol Macromol ; 231: 123339, 2023 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-36682648

RESUMEN

The Amazon rainforest is considered the largest tropical timber reserve in the world. The management of native forests in the Amazon is one of the most sensitive geopolitical issues today, given its national and international dimension. In this work, we obtained and characterized physicochemical lignins extracted from branches and leaves of Protium puncticulatum and Scleronema micranthum. In addition, we evaluated in vitro its potential as an antioxidant, cytotoxic agent against animal cells and antiparasitic against promastigotes of Leishmania amazonensis, trypomastigotes of T. cruzi and against Plasmodium falciparum parasites sensitive and resistant to chloroquine. The results showed that the lignins obtained are of the GSH type and have higher levels of guaiacyl units. However, they show structural differences as shown by spectroscopic analysis and radar charts. As for biological activities, they showed antioxidant potential and low cytotoxicity against animal cells. Antileishmanial/trypanocidal assays have shown that lignins can inhibit the growth of promastigotes and trypomastigotes in vitro. The lignins in this study showed low anti-Plasmodium falciparum activity against susceptible strains of Plasmodium falciparum and were able to inhibit the growth of the chloroquine-resistant strain. And were not able to inhibit the growth of Schistosoma mansoni parasites. Finally, lignins proved to be promising excipients in the release of benznidazole. These findings show the potential of these lignins not yet studied to promote different biological activities.


Asunto(s)
Enfermedad de Chagas , Trypanosoma cruzi , Animales , Antiparasitarios/uso terapéutico , Lignina/uso terapéutico , Excipientes , Antioxidantes/uso terapéutico , Enfermedad de Chagas/tratamiento farmacológico , Cloroquina
11.
Cell Metab ; 34(8): 1183-1200.e12, 2022 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-35841892

RESUMEN

Hypoglycemia is a clinical hallmark of severe malaria, the often-lethal outcome of Plasmodium falciparum infection. Here, we report that malaria-associated hypoglycemia emerges from a non-canonical resistance mechanism, whereby the infected host reduces glycemia to starve Plasmodium. This hypometabolic response is elicited by labile heme, a byproduct of hemolysis that induces illness-induced anorexia and represses hepatic glucose production. While transient repression of hepatic glucose production prevents unfettered immune-mediated inflammation, organ damage, and anemia, when sustained over time it leads to hypoglycemia, compromising host energy expenditure and adaptive thermoregulation. The latter arrests the development of asexual stages of Plasmodium via a mechanism associated with parasite mitochondrial dysfunction. In response, Plasmodium activates a transcriptional program associated with the reduction of virulence and sexual differentiation toward the generation of transmissible gametocytes. In conclusion, malaria-associated hypoglycemia represents a trade-off of a hypometabolic-based defense strategy that balances parasite virulence versus transmission.


Asunto(s)
Hipoglucemia , Malaria Falciparum , Malaria , Glucosa , Humanos , Malaria Falciparum/parasitología , Plasmodium falciparum
12.
ACS Med Chem Lett ; 13(2): 225-235, 2022 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-35178179

RESUMEN

Malaria, leishmaniasis, and sleeping sickness are potentially fatal diseases that represent a real health risk for more than 3,5 billion people. New antiparasitic compounds are urgent leading to a constant search for novel scaffolds. Herein, pyrazino[2,1-b]quinazoline-3,6-diones containing indole alkaloids were explored for their antiparasitic potential against Plasmodium falciparum, Trypanosoma brucei, and Leishmania infantum. The synthetic libraries furnished promising hit compounds that are species specific (7, 12) or with broad antiparasitic activity (8). Structure-activity relationships were more evident for Plasmodium with anti-isomers (1S,4R) possessing excellent antimalarial activity, while the presence of a substituent on the anthranilic acid moiety had a negative effect on the activity. Hit compounds against malaria did not inhibit ß-hematin, and in silico studies predicted these molecules as possible inhibitors for prolyl-tRNA synthetase both from Plasmodium and Leishmania. These results disclosed a potential new chemotype for further optimization toward novel and affordable antiparasitic drugs.

13.
Nutr Cancer ; 74(4): 1188-1202, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34739306

RESUMEN

In the past few years flavonoids have been gaining more attention regarding their (still un) exploited anticancer properties. Flavonoids are natural compounds present in fruits, vegetables, and seeds, meaning that they are already present in the daily life of every person, with a described broad-spectrum of pharmacological activities, including anticancer, anti-inflammatory and antioxidant. In the present review we discuss the anticancer activity of three important flavonoids - myricetin (MYR) (flavanol group), hesperetin (HESP) and naringenin (NAR) (flavanone group). Although some mechanisms underlying their activities remain still unclear, they can act as potential inhibitors of key tumorigenic signaling pathways, such as PI3K/Akt/mTOR, p38 MAPK and NF-κB. Simultaneously, they can reset the levels of pro-apoptotic proteins that belong to the Bcl-2 and caspase family and decrease the intracellular levels of ROS and pro-inflammatory cytokines, such as TNF-α, IL-1ß and IL-6. Together with their synergetic effect they have the potential to become key elements in the prevention and/or treatment of several types of cancer, with the major improvement to the patient life quality, due to their non-existent toxicity.


Asunto(s)
Neoplasias , Fosfatidilinositol 3-Quinasas , Carcinogénesis , Flavanonas , Flavonoides/farmacología , Hesperidina , Humanos , FN-kappa B/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/prevención & control , Fosfatidilinositol 3-Quinasas/metabolismo
14.
ChemMedChem ; 17(5): e202100650, 2022 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-34882979

RESUMEN

Inspired by previous disclosure of room-temperature ionic liquids derived from primaquine and cinnamic acids, which displayed slightly enhanced blood-stage activity compared to the parent drug, we have now combined this emblematic antimalarial with natural fatty acids. This affords surface-active ionic liquids whose liver-stage antiplasmodial activity is either retained or slightly enhanced, while revealing blood-stage antiplasmodial activity at least one order of magnitude higher than that of the parent compound. These findings open new perspectives towards the cost-effective recycling of classical drugs that are either shelved or in decline, and which is not limited to antimalarial agents.


Asunto(s)
Antimaláricos , Antagonistas del Ácido Fólico , Líquidos Iónicos , Antimaláricos/farmacología , Análisis Costo-Beneficio , Antagonistas del Ácido Fólico/farmacología , Líquidos Iónicos/farmacología , Plasmodium falciparum , Primaquina/farmacología
15.
Value Health Reg Issues ; 26: 66-74, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34119775

RESUMEN

OBJECTIVES: In 2015, a dam collapsed at Samarco iron ore mine in the municipality of Mariana, Brazil, and contaminated more than 600 km of watercourses and destroyed almost 1600 acres of vegetation. Nineteen people died and more than 600 families lost their homes. This study aimed to estimate health-related quality of life (HRQoL) losses owing to this disaster. METHODS: We collected data from a probabilistic sample of 459 individuals aged 15 years or older. Household face-to-face interviews were conducted in December 2018. Pre-event data were not available for this population, so respondents were asked to evaluate at present and in retrospect their health status using EQ-5D-3L. The Minas Gerais societal value sets for EQ-5D-3L health preferences, estimated in 2011, were used to calculate utility losses. The health loss estimation from EQ-5D will form the basis for the calculation of compensation payments for the victims. RESULTS: Approximately 74% of the study population suffered some HRQoL loss. On average, EQ-5D index values decreased from 0.95 to 0.76. The greatest effects were observed for the anxiety/depression dimension, followed by pain/discomfort. Before the tragedy, the proportion of individuals with severe anxiety/depression and pain/discomfort was equal to 1% rising to 23% and 11%, respectively. CONCLUSIONS: Catastrophic losses owing to the Samarco disaster were found. The EQ-5D-3L instrument showed feasibility and sensitiveness to measure HRQoL losses owing to a negative health shock in a low-income Brazilian population.


Asunto(s)
Desastres , Calidad de Vida , Brasil , Estudios Transversales , Estado de Salud , Humanos
16.
ChemMedChem ; 15(22): 2164-2175, 2020 11 18.
Artículo en Inglés | MEDLINE | ID: mdl-32813331

RESUMEN

Chagas disease and malaria are two neglected tropical diseases (NTDs) that prevail in tropical and subtropical regions in 149 countries. Chagas is also present in Europe, the US and Australia due to immigration of asymptomatic infected individuals. In the absence of an effective vaccine, the control of both diseases relies on chemotherapy. However, the emergence of parasite drug resistance is rendering currently available drugs obsolete. Hence, it is crucial to develop new molecules. Phthalimides, thiosemicarbazones, and 1,3-thiazoles have been used as scaffolds to obtain antiplasmodial and anti-Trypanosoma cruzi agents. Herein we present the synthesis of 24 phthalimido-thiosemicarbazones (3 a-x) and 14 phthalimido-thiazoles (4 a-n) and the corresponding biological activity against T. cruzi, Plasmodium falciparum, and cytotoxicity against mammalian cell lines. Some of these compounds showed potent inhibition of T. cruzi at low cytotoxic concentrations in RAW 264.7 cells. The most active compounds, 3 t (IC50 =3.60 µM), 3 h (IC50 =3.75 µM), and 4 j (IC50 =4.48 µM), were more active than the control drug benznidazole (IC50 =14.6 µM). Overall, the phthalimido-thiosemicarbazone derivatives were more potent than phthalimido-thiazole derivatives against T. cruzi. Flow cytometry assay data showed that compound 4 j was able to induce necrosis and apoptosis in trypomastigotes. Analysis by scanning electron microscopy showed that T. cruzi trypomastigote cells treated with compounds 3 h, 3 t, and 4 j at IC50 concentrations promoted changes in the shape, flagella, and surface of the parasite body similar to those observed in benznidazole-treated cells. The compounds with the highest antimalarial activity were the phthalimido-thiazoles 4 l (IC50 =1.2 µM), 4 m (IC50 =1.7 µM), and 4 n (IC50 =2.4 µM). Together, these data revealed that phthalimido derivatives possess a dual antiparasitic profile with potential effects against T. cruzi and lead-like characteristics.


Asunto(s)
Ftalimidas/farmacología , Plasmodium falciparum/efectos de los fármacos , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Ftalimidas/síntesis química , Ftalimidas/química , Relación Estructura-Actividad , Tripanocidas/síntesis química , Tripanocidas/química
17.
Chem Biol Interact ; 315: 108899, 2020 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-31738906

RESUMEN

Parasitic diseases still represent serious public health problems, since the high and steady emergence of resistant strains is evident. Because parasitic infections are distributed predominantly in developing countries, less toxic, more efficient, safer and more accessible drugs have become desirable in the treatment of the infected population. This is the case of leishmaniasis, an infectious disease caused by a protozoan of the genus Leishmania sp., responsible for triggering pathological processes from the simplest to the most severe forms leading to high rates of morbidity and mortality throughout the world. In the search for new leishmanicidal drugs, the thiosemicarbazones and the indole fragments have been identified as promising structures for leishmanicidal activity. The present study proposes the synthesis and structural characterization of new indole-thiosemicarbazone derivatives (2a-j), in addition to performing in vitro evaluations through cytotoxicity assays using macrophages (J774) activity against forms of Leishmania infantum and Leishmania amazonensis promastigote as well as ultrastructural analyzes in promastigotes of L. infantum. Results show that the indole-thiosemicarbazone derivatives were obtained with yield values varying from 32.09 to 94.64%. In the evaluation of cytotoxicity, the indole-thiosemicarbazone compounds presented CC50 values between 53.23 and 357.97 µM. Concerning the evaluation against L. amazonensis promastigote forms, IC50 values ranged between 12.31 and  > 481.52 µM, while the activity against L. infantum promastigotes obtained IC50 values between 4.36 and 23.35 µM. The compounds 2d and 2i tested against L. infantum were the most promising in the series, as they showed the lowest IC50 values: 5.60 and 4.36 respectively. The parasites treated with the compounds 2d and 2i showed several structural alterations, such as shrinkage of the cell body, shortening and loss of the flagellum, intense mitochondrial swelling and vacuolization of the cytoplasm leading the parasite to cellular unviability. Therefore, the indole-thiosemicarbazone compounds are promising because they yield considerable synthesis, have low cytotoxicity to mammalian cells and act as leishmanicidal agents.


Asunto(s)
Antiprotozoarios/farmacología , Indoles/farmacología , Leishmania infantum/efectos de los fármacos , Leishmaniasis/tratamiento farmacológico , Tiosemicarbazonas/farmacología , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Leishmaniasis/parasitología , Macrófagos/efectos de los fármacos , Mitocondrias/efectos de los fármacos
19.
Cad Saude Publica ; 34(5): e00003217, 2018 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-29898004

RESUMEN

Despite having been broadly advertised by the mass media, many negative consequences of the Zika virus have been less significant than originally predicted. It is likely that after a few months from the epidemic's onset, personal experience with the virus has altered the person's way to deal with the disease. This study explores the relation between exposure to Zika virus and the social representation of the epidemic. More specifically, one analyzes if increased exposure to the risk of Zika infection changes the characteristics of the web of meanings surrounding the epidemic. Between August and November of 2016, 150 interviews were conducted in the municipality of Governador Valadares, Minas Gerais State, Brazil. Based on the Free Words Association Technique, data on evocations related to the Zika virus were modeled by social network analysis, allowing the characterization of the web of meanings by level of exposure to the risk of Zika infection. The analysis performed here suggests that those never infected by any disease transmitted by the Aedes aegypti mosquito have a lesser representation, incorporating information from the media through lay thinking. In contrast to those with low levels of exposure, the social representation of people infected by Zika is associated with meanings related to the most common symptoms, such as pain, rash, and itching. Personal experience seems to shape the social representation of the disease, increasing the focus on its proximate consequences. Public campaigns designed to foster protective behavior should take into consideration the heterogeneity in the representations of this epidemic to improve adherence to preventive behavior.


Asunto(s)
Conocimientos, Actitudes y Práctica en Salud , Acontecimientos que Cambian la Vida , Infección por el Virus Zika/epidemiología , Virus Zika , Animales , Brasil/epidemiología , Asociación Libre , Comunicación en Salud/métodos , Humanos , Asunción de Riesgos , Medios de Comunicación Sociales , Infección por el Virus Zika/psicología
20.
Cad. Saúde Pública (Online) ; 34(5): e00003217, 2018. tab, graf
Artículo en Inglés | LILACS | ID: biblio-952384

RESUMEN

Abstract: Despite having been broadly advertised by the mass media, many negative consequences of the Zika virus have been less significant than originally predicted. It is likely that after a few months from the epidemic's onset, personal experience with the virus has altered the person's way to deal with the disease. This study explores the relation between exposure to Zika virus and the social representation of the epidemic. More specifically, one analyzes if increased exposure to the risk of Zika infection changes the characteristics of the web of meanings surrounding the epidemic. Between August and November of 2016, 150 interviews were conducted in the municipality of Governador Valadares, Minas Gerais State, Brazil. Based on the Free Words Association Technique, data on evocations related to the Zika virus were modeled by social network analysis, allowing the characterization of the web of meanings by level of exposure to the risk of Zika infection. The analysis performed here suggests that those never infected by any disease transmitted by the Aedes aegypti mosquito have a lesser representation, incorporating information from the media through lay thinking. In contrast to those with low levels of exposure, the social representation of people infected by Zika is associated with meanings related to the most common symptoms, such as pain, rash, and itching. Personal experience seems to shape the social representation of the disease, increasing the focus on its proximate consequences. Public campaigns designed to foster protective behavior should take into consideration the heterogeneity in the representations of this epidemic to improve adherence to preventive behavior.


Resumo: Apesar de amplamente noticiadas pela grande mídia, muitas das consequências negativas do vírus Zika foram menos significativas em relação às previsões originais. É provável que depois de alguns meses de epidemia, a experiência pessoal com o vírus já tenha alterado a maneira individual de lidar com a doença. Este estudo explora a relação entre a exposição ao vírus Zika e as representações sociais da epidemia. Mais especificamente, analisamos se o aumento da exposição ao risco de infecção pelo vírus Zika altera as características da teia de significados em torno da epidemia. Entre agosto e novembro de 2016, foram realizadas 150 entrevistas no Município de Governador Valadares, Minas Gerais, Brasil. Com base na técnica do Teste de Associação de Palavras, os dados de citações relacionadas ao vírus Zika foram modelados através da análise de redes sociais, permitindo a caracterização da teia de significados de acordo com o nível de exposição ao risco de infecção. A análise feita aqui sugere que pessoas que nunca foram infectadas por qualquer vírus transmitido pelo Aedes aegypti têm uma representação menos completa, incorporando informações da mídia através do pensamento leigo. Ao contrário daquelas com baixos níveis de exposição, a representação social feita por pessoas infectadas com o vírus Zika está associada aos significados relacionados aos sintomas mais comuns, como dor, exantema e prurido. A experiência pessoal parece moldar a representação social da doença, aumentando o foco nas consequências mais próximas. As campanhas públicas para promover o comportamento preventivo devem levar em conta a heterogeneidade das representações dessa epidemia para poder melhorar a aderência.


Resumen: A pesar de haber sido divulgado ampliamente por los medios de comunicación, muchas de las consecuencias negativas del virus del Zika han sido menos significativas de lo que se predijo originalmente. Parece que tras unos cuantos meses desde el inicio de la epidemia, la experiencia personal con el virus ha alterado la percepción personal sobre cómo lidiar con la enfermedad. Este estudio investiga la relación entre la exposición al virus Zika y la representación social de la epidemia. Más específicamente, este estudio analiza si una mayor exposición al riesgo de infección debida al Zika, modifica las características de la red de significados sobre epidemias. Entre agosto y noviembre de 2016, se realizaron 150 entrevistas en el municipio de Governador Valadares, Minas Gerais, Brasil. Basado en la Free Words Association Technique, la información sobre referencias relacionadas con el virus del Zika se modelaron mediante un análisis del entorno social, permitiendo la caracterización de la red de significados por el nivel de exposición al riesgo de la infección debida al Zika. El análisis realizado aquí sugiere que quienes nunca fueron infectados por ninguna enfermedad transmitida por el mosquito Aedes aegypti tienen una menor representación, incorporando información de los medios de comunicación, a través de un pensamiento generalista. En contraposición con quienes tuvieron un bajo nivel de exposición, la representación social de la gente infectada por Zika está asociada con significados relacionados con los síntomas más comunes, como dolor, sarpullido, y picores. La experiencia personal parece configurar la representación social de la enfermedad, aumentando centro de atención en sus consecuencias más próximas. Las campañas públicas diseñadas para fomentar comportamientos de protección deberían tener en consideración la heterogeneidad en las representaciones sociales de esta epidemia para mejorar la adhesión al tratamiento de la misma.


Asunto(s)
Humanos , Animales , Virus Zika , Infección por el Virus Zika/epidemiología , Acontecimientos que Cambian la Vida , Asunción de Riesgos , Brasil/epidemiología , Conocimientos, Actitudes y Práctica en Salud , Comunicación en Salud/métodos , Medios de Comunicación Sociales , Infección por el Virus Zika/psicología , Asociación Libre
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