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https://www.readbyqxmd.com/read/28795372/development-of-a-pharmacophore-for-cruzain-using-oxadiazoles-as-virtual-molecular-probes-quantitative-structure-activity-relationship-studies
#1
Anacleto S de Souza, Marcelo T de Oliveira, Adriano D Andricopulo
Chagas's is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. According to the World Health Organization, 7 million people are infected worldwide leading to 7000 deaths per year. Drugs available, nifurtimox and benzimidazole, are limited due to low efficacy and high toxicity. As a validated target, cruzain represents a major front in drug discovery attempts for Chagas disease. Herein, we describe the development of 2D QSAR ([Formula: see text] = 0.81) and a 3D-QSAR-based pharmacophore ([Formula: see text] = 0...
August 9, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28690148/betulinic-acid-induces-cell-death-by-necrosis-in-trypanosoma-cruzi
#2
Paloma Leão Sousa, Racquel Oliveira da Silva Souza, Louise Donadello Tessarolo, Ramon Róseo Paula Pessoa Bezerra de Menezes, Tiago Lima Sampaio, Jader Almeida Canuto, Alice Maria Costa Martins
Chagas' disease is a neglected disease caused by the protozoan parasite Trypanosoma cruzi and constitutes a serious health problem worldwide. The treatment is limited, with variable efficacy of benznidazole and nifurtimox. Betulinic Acid (BA), a triterpene, can be found in medicinal herbs and has a wide variety of biological and pharmacological activities. The objective was to evaluate betulinic acid effects on the cell death mechanism in Trypanosoma cruzi strain Y. BA inhibited the growth of epimastigotes in periods of 24h (IC50=73...
July 6, 2017: Acta Tropica
https://www.readbyqxmd.com/read/28652235/nifurtimox-is-ineffective-against-drug-resistant-mycobacteria
#3
Mike Marvin Ruth, Jasper Jan Nicolaas Sangen, Heiman Frank Louis Wertheim, Jakko van Ingen
Multi- and extensively drug-resistant tuberculosis (XDR-TB) and diseases caused by the naturally drug-resistant nontuberculous mycobacteria (NTM) are emerging health threats.….
June 26, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28648464/synthesis-and-biological-evaluation-of-2-methyl-1h-benzimidazole-5-carbohydrazides-derivatives-as-modifiers-of-redox-homeostasis-of-trypanosoma-cruzi
#4
Silvia Melchor-Doncel de la Torre, Citlali Vázquez, Zabdi González-Chávez, Lilián Yépez-Mulia, Rocío Nieto-Meneses, Ricardo Jasso-Chávez, Emma Saavedra, Francisco Hernández-Luis
Twelve novel benzimidazole derivatives were synthesized and their in vitro activities against epimastigotes of Trypanosoma cruzi were evaluated. Two derivatives (6 and 7), which have 4-hydroxy-3-methoxyphenyl moiety in their structures, proved to be the most active in inhibiting the parasite growth. Compound 6 showed a trypanocidal activity higher than benznidazole (IC50=5µM and 7.5µM, respectively) and less than nifurtimox (IC50=3.6µM). In addition, the ability of 6 and 7 to modify the redox homeostasis in T cruzi epimastigote was studied; cysteine and glutathione increased in parasites exposed to both compounds, whereas trypanothione only increased with 7 treatment...
August 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28629155/repositioning-fda-drugs-as-potential-cruzain-inhibitors-from-trypanosoma-cruzi-virtual-screening-in-vitro-and-in-vivo-studies
#5
Isidro Palos, Edgar E Lara-Ramirez, Julio Cesar Lopez-Cedillo, Carlos Garcia-Perez, Muhammad Kashif, Virgilio Bocanegra-Garcia, Benjamin Nogueda-Torres, Gildardo Rivera
Chagas disease (CD) is a neglected disease caused by the parasite Trypanosoma cruzi, which affects underdeveloped countries. The current drugs of choice are nifurtimox and benznidazole, but both have severe adverse effects and less effectivity in chronic infections; therefore, the need to discover new drugs is essential. A computer-guided drug repositioning method was applied to identify potential FDA drugs (approved and withdrawn) as cruzain (Cz) inhibitors and trypanocidal effects were confirmed by in vitro and in vivo studies...
June 18, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28614468/-estimating-demand-for-anti-chagas-drugs-a-contribution-for-access-in-latin-america
#6
Gabriela Costa Chaves, Mariana Abi-Saab Arrieche, Joelle Rode, Daniel Mechali, Priscileyne Ouverney Reis, Renato Vieira Alves, Eric Stobbaerts, Nora Girón Aguilar, Isabela Ribeiro
Objective: Describe a tool to estimate demand for benznidazole and nifurtimox to treat Chagas disease, and report on its implementation in a group of Latin American countries. Methods: The project was carried out in the following stages: 1) development of a tool to estimate demand, and definition of the evaluation and decision variables to estimate demand 2) data collection via a questionnaire completed by representatives of control programs, complemented with data from the literature; 3) presentation of the tool, followed by validation, and adaptation by representatives of the control programs in order to plan drug procurement for 2012 and 2013; and 4) further analysis of the obtained data, especially regarding benznidazole, and comparison of country estimates...
June 8, 2017: Revista Panamericana de Salud Pública, Pan American Journal of Public Health
https://www.readbyqxmd.com/read/28591312/identification-of-a-type-i-nitroreductase-gene-in-non-virulent-trypanosoma-rangeli
#7
Marjorie Montenegro, Claudia Cuervo, Constanza Cardenas, Silvia Duarte, Jenny R Díaz, M Carmen Thomas, Manuel C Lopez, Concepcion J Puerta
Trypanosomatid type I nitroreductases (NTRs), i.e., mitochondrial enzymes that metabolise nitroaromatic pro-drugs, are essential for parasite growth, infection, and survival. Here, a type I NTR of non-virulent protozoan Trypanosoma rangeli is described and compared to those of other trypanosomatids. The NTR gene was isolated from KP1(+) and KP1(-) strains, and its corresponding transcript and 5' untranslated region (5'UTR) were determined. Bioinformatics analyses and nitro-drug activation assays were also performed...
July 2017: Memórias do Instituto Oswaldo Cruz
https://www.readbyqxmd.com/read/28587855/pheophorbide-a-a-compound-isolated-from-the-leaves-of-arrabidaea-chica-induces-photodynamic-inactivation-of-trypanosoma-cruzi
#8
Nathielle Miranda, Adriana Passarella Gerola, Cláudio Roberto Novello, Tânia Ueda-Nakamura, Sueli de Oliveira Silva, Benedito Prado Dias-Filho, Noboru Hioka, João Carlos Palazzo de Mello, Celso Vataru Nakamura
BACKGROUND: Approximately 6-7 million people are infected with Trypanosoma cruzi, the etiological agent of Chagas' disease. Only two therapeutic compounds have been found to be useful against this disease: nifurtimox and benznidazole. These drugs have been effective in the acute phase of the disease but less effective in the chronic phase; they also have many side effects. Thus, the search for new compounds with trypanocidal action is necessary. Natural products can be the source of many important substances for the development of drugs to treat this infection...
June 3, 2017: Photodiagnosis and Photodynamic Therapy
https://www.readbyqxmd.com/read/28560955/effects-of-astaxanthin-in-mice-acutely-infected-with-trypanosoma-cruzi
#9
José María Eloy Contreras-Ortiz, Alberto Barbabosa-Pliego, Rigoberto Oros-Pantoja, José Esteban Aparicio-Burgos, José Antonio Zepeda-Escobar, Wael Hegazy Hassan-Moustafa, Laucel Ochoa-García, María Uxúa Alonso-Fresan, Esvieta Tenorio Borroto, Juan Carlos Vázquez-Chagoyán
During Trypanosoma cruzi infection, oxidative stress is considered a contributing factor for dilated cardiomyopathy development. In this study, the effects of astaxanthin (ASTX) were evaluated as an alternative drug treatment for Chagas disease in a mouse model during the acute infection phase, given its anti-inflammatory, immunomodulating, and anti-oxidative properties. ASTX was tested in vitro in parasites grown axenically and in co-culture with Vero cells. In vivo tests were performed in BALB/c mice (4-6 weeks old) infected with Trypanosoma cruzi and supplemented with ASTX (10 mg/kg/day) and/or nifurtimox (NFMX; 100 mg/kg/day)...
2017: Parasite: Journal de la Société Française de Parasitologie
https://www.readbyqxmd.com/read/28560059/the-anti-protozoan-drug-nifurtimox-preferentially-inhibits-clonogenic-tumor-cells-under-hypoxic-conditions
#10
Quhuan Li, Qun Lin, Hoon Kim, Zhong Yun
Tumor hypoxia is an independent prognostic indicator of tumor malignant progression and poor patient survival. Therefore, eradication of hypoxic tumor cells is of paramount importance for successful disease control. In this study, we have made a new discovery that nifurtimox, a clinically approved drug to treat Chagas disease caused by the parasitic protozoan trypanosomes, can function as a hypoxia-activated cytotoxin. We have found that nifurtimox preferentially kill clonogenic tumor cells especially under the hypoxic conditions of ≤0...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28499168/novel-imidazo-4-5-c-1-2-6-thiadiazine-2-2-dioxides-as-antiproliferative-trypanosoma-cruzi-drugs-computational-screening-from-neural-network-synthesis-and-in%C3%A2-vivo-biological-properties
#11
Angela Guerra, Pedro Gonzalez-Naranjo, Nuria E Campillo, Javier Varela, María L Lavaggi, Alicia Merlino, Hugo Cerecetto, Mercedes González, Alicia Gomez-Barrio, José A Escario, Cristina Fonseca-Berzal, Gloria Yaluf, Jorge Paniagua-Solis, Juan A Páez
A new family of imidazo[4,5-c][1,2,6]thiadiazine 2,2-dioxide with antiproliferative Trypanosoma cruzi properties was identified from a neural network model published by our group. The synthesis and evaluation of this new class of trypanocidal agents are described. These compounds inhibit the growth of Trypanosoma cruzi, comparable with benznidazole or nifurtimox. In vitro assays were performed to study their effects on the growth of the epimastigote form of the Tulahuen 2 strain, as well as the epimastigote and amastigote forms of CL clone B5 of Trypanosoma cruzi...
May 1, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28394985/-chagas-disease-affecting-the-central-nervous-system-in-a-patient-with-aids-demonstrated-by-quantitative-molecular-methods
#12
Alberto Fica, Marcia Salinas, María Isabel Jercic, Jeannette Dabanch, Andrés Soto, Sergio Quintanilla, Carlos Flores
Although infrequent, Trypanosoma cruzi reactivation is possible among patients with HIV/AIDS infection that develop a tumor-like or granulomatous lesion in the CNS. We report the case of a 60 years old male patient with HIV/AIDS and low CD4 lymphocytes count with cerebellar symptoms and mild paresis, associated to supra and infratentorial hypodense lesions and positive serology tests both to T. gondii and Trypanosoma cruzi. Empirical therapy against toxoplasmosis was prescribed together with antiretroviral therapy but without a favorable response...
February 2017: Revista Chilena de Infectología: órgano Oficial de la Sociedad Chilena de Infectología
https://www.readbyqxmd.com/read/28364659/an-in%C3%A2-vitro-and-in%C3%A2-vivo-evaluation-of-new-potential-trans-sialidase-inhibitors-of-trypanosoma-cruzi-predicted-by-a-computational-drug-repositioning-method
#13
Edgar E Lara-Ramirez, Julio Cesar López-Cedillo, Benjamin Nogueda-Torres, Muhammad Kashif, Carlos Garcia-Perez, Virgilio Bocanegra-Garcia, Rosalía Agusti, María Laura Uhrig, Gildardo Rivera
Chagas disease is one of the most important neglected parasitic diseases afflicting developed and undeveloped countries. There are currently limited options for inexpensive and secure pharmacological treatment. In this study, we employed a structure-based virtual screening protocol for 3180 FDA-approved drugs for repositioning of them as potential trans-sialidase inhibitors. In vitro and in vivo evaluations were performed for the selected drugs against trypomastigotes from the INC-5 and NINOA strains of T...
May 26, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28359888/characterisation-of-the-fumarate-hydratase-repertoire-in-trypanosoma-cruzi
#14
Ricardo A P de Pádua, Ali Martin Kia, Antonio J Costa-Filho, Shane R Wilkinson, M Cristina Nonato
Nifurtimox and benznidazole represent the only treatments options available targeting Chagas disease, the most important parasitic infection in the Americas. However, use of these is problematic as they are toxic and ineffective against the more severe stages of the disease. In this work, we used a multidisciplinary approach to characterise the fumarases from Trypanosoma cruzi, the causative agent of Chagas Disease. We showed this trypanosome expresses cytosolic and mitochondrial fumarases that via an iron-sulfur cluster mediate the reversible conversion of fumarate to S-malate...
September 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28302040/trypanothione-reductase-a-target-for-the-development-of-anti-trypanosoma-cruzi-drugs
#15
Karina Vázquez, Margot Paulino, Cristian O Salas, Juan J Zarate-Ramos, Brenda Vera, Gildardo Rivera
BACKGROUND & OBJECTIVE: Chagas disease or American trypanosomiasis is a major parasitic disease in Latin America with restricted available treatment: nifurtimox and benznidazole. These two drugs are ineffective in the chronic phase of the disease; therefore, there is a need for the development of new, efficient and safe drugs for the treatment of this pathology. With this goal, one of the promising targets is trypanothione reductase (TR), a key enzyme in the metabolism of Trypanosoma cruzi...
2017: Mini Reviews in Medicinal Chemistry
https://www.readbyqxmd.com/read/28276600/transcriptome-and-functional-genomics-reveal-the-participation-of-adenine-phosphoribosyltransferase-in-trypanosoma-cruzi-resistance-to-benznidazole
#16
Paola García-Huertas, Ana María Mejía-Jaramillo, Laura González, Omar Triana-Chávez
Currently, the only available treatments for Trypanosoma cruzi are benznidazole (Bz) and nifurtimox (Nfx). The mechanisms of action and resistance to these drugs in this parasite are not complete known. In order to identify differentially expressed transcripts between sensitive and resistant parasites, a massive pyrosequencing of the T. cruzi transcriptome was carried out. Additionally, the 2D gel electrophoresis profile of sensitive and resistant parasites was analyzed and the data were supported with functional genomics...
March 9, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28237731/rhenium-i-tricarbonyl-compounds-of-bioactive-thiosemicarbazones-synthesis-characterization-and-activity-against-trypanosoma-cruzi
#17
Esteban Rodríguez Arce, Ignacio Machado, Belén Rodríguez, Michel Lapier, María Carolina Zúñiga, Juan Diego Maya, Claudio Olea Azar, Lucía Otero, Dinorah Gambino
American Trypanosomiasis is a chronic infection discovered and described in 1909 by the Brazilian scientist Carlos Chagas. It is caused by the protozoan parasite Trypanosoma cruzi. Although it affects about 10million people in Latin America, the current chemotherapy is still inadequate. The discovery of new drugs is urgently needed. Our group is focused on the development of prospective metal-based drugs mainly based on bioactive ligands and pharmacologically interesting metal ions. In this work three new rhenium(I) tricarbonyl compounds fac-[Re(I)(CO)3Br(HL)] where HL=5-nitrofuryl containing thiosemicarbazones were synthesized and fully characterized in solution and in the solid state...
January 23, 2017: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/28198632/engineering-oral-and-parenteral-amorphous-amphotericin-b-formulations-against-experimental-trypanosoma-cruzi-infections
#18
Miriam Rolón, Dolores R Serrano, Aikaterini Lalatsa, Esther de Pablo, Juan Jose Torrado, Maria Paloma Ballesteros, Anne Marie Healy, Celeste Vega, Cathia Coronel, Francisco Bolás-Fernández, Maria Auxiliadora Dea-Ayuela
Chagas disease (CD) is a parasitic zoonosis endemic in most mainland countries of Central and South America affecting nearly 10 million people, with 100 million people at high risk of contracting the disease. Treatment is only effective if received at the early stages of the disease. Only two drugs (benznidazole and nifurtimox) have so far been marketed, and both share various limitations such as variable efficacy, many side effects, and long duration of treatment, thus reducing compliance. The in vitro and in vivo efficacy of poly-aggregated amphotericin B (AmB), encapsulated poly-aggregated AmB in albumin microspheres (AmB-AME), and dimeric AmB-sodium deoxycholate micelles (AmB-NaDC) was evaluated...
April 3, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28167559/antitrypanosomal-activity-of-sterol-14%C3%AE-demethylase-cyp51-inhibitors-vni-and-vfv-in-the-swiss-mouse-models-of-chagas-disease-induced-by-the-trypanosoma-cruzi-y-strain
#19
F H Guedes-da-Silva, D G J Batista, C F Da Silva, J S De Araújo, B P Pavão, M R Simões-Silva, M M Batista, K C Demarque, O C Moreira, C Britto, G I Lepesheva, M N C Soeiro
Chagas disease is a life-threatening infection caused by a variety of genetically diverse strains of the protozoan parasite Trypanosoma cruzi The current treatment (benznidazole and nifurtimox) is unsatisfactory, and potential alternatives include inhibitors of sterol 14α-demethylase (CYP51), the cytochrome P450 enzyme essential for the biosynthesis of sterols in eukaryotes and the major target of clinical and agricultural antifungals. Here we performed a comparative investigation of two protozoon-specific CYP51 inhibitors, VNI and its CYP51 structure-based derivative VFV, in the murine models of infection caused by the Y strain of T...
April 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28132566/long-term-comparative-pharmacovigilance-of-orally-transmitted-chagas-disease-first-report
#20
Belkisyolé Alarcón de Noya, Raiza Ruiz-Guevara, Oscar Noya, Julio Castro, John Ossenkopp, Zoraida Díaz-Bello, Cecilia Colmenares, José Antonio Suárez, Oscar Noya-Alarcón, Laura Naranjo, Humberto Gutiérrez, Giuseppa Quinci, Jaime Torres
BACKGROUND: Two old drugs are the only choice against Trypanosoma cruzi and little is known about their secondary effects in the acute stage of oral-transmitted Chagas disease (ChD). METHODS: A cross-sectional analytical surveillance study was conducted in a sizable cohort of patients seen during the largest acute foodborne ChD microepidemic registered so far. Individuals were treated with benznidazole (BNZ) or nifurtimox (NFX). 'Common Terminology Criteria for Adverse Events' was assessed to categorize side effects according to severity...
March 2017: Expert Review of Anti-infective Therapy
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