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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
#1
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
#2
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
#3
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...
March 28, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28359888/characterisation-of-the-fumarate-hydratase-repertoire-in-trypanosoma-cruzi
#4
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...
March 27, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28302040/trypanothione-reductase-a-target-for-the-development-of-anti-trypanosoma-cruzi-drugs
#5
Karina Vázquez, Margot Paulino, Cristian O Salas, Juan J Zarate-Ramos, Brenda Vera, Gildardo Rivera
Chagas disease or American trypanosomiasis is a major parasitic disease in Latin America with treatment available via two drugs: nifurtimox and benznidazole. These two treatments 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 these diseases. With this goal, one of the promising targets proposed is the trypanothione reductase (TR), a key enzyme important in the metabolism of Trypanosoma cruzi. In this review, we analyze the importance of TR as a drug target, as well as their compounds inhibitors reported in the last decade as potential therapeutic agents for Chagas disease...
March 15, 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
#6
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
#7
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
#8
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
#9
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
#10
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
https://www.readbyqxmd.com/read/28119024/antiparasitic-lethality-of-sulfonamidebenzamides-in-kinetoplastids
#11
Amber Hackler, Stephen L Patrick, Elizabeth W Kahney, Daniel P Flaherty, Elizabeth R Sharlow, James C Morris, Jennifer E Golden
A sulfonamidebenzamide series was assessed for anti-kinetoplastid parasite activity based on structural similarity to the antiparasitic drug, nifurtimox. Through structure-activity optimization, derivatives with limited mammalian cell toxicity and increased potency toward African trypanosomes and Leishmania promastigotes were developed. Compound 22 had the best potency against the trypanosome (EC50=0.010μM) while several compounds showed ∼10-fold less potency against Leishmania promastigotes without impacting mammalian cells (EC50>25μM)...
February 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28107703/how-universal-is-coverage-and-access-to-diagnosis-and-treatment-for-chagas-disease-in-colombia-a-health-systems-analysis
#12
Zulma M Cucunubá, Jennifer M Manne-Goehler, Diana Díaz, Pierre Nouvellet, Oscar Bernal, Andrea Marchiol, María-Gloria Basáñez, Lesong Conteh
Limited access to Chagas disease diagnosis and treatment is a major obstacle to reaching the 2020 World Health Organization milestones of delivering care to all infected and ill patients. Colombia has been identified as a health system in transition, reporting one of the highest levels of health insurance coverage in Latin America. We explore if and how this high level of coverage extends to those with Chagas disease, a traditionally marginalised population. Using a mixed methods approach, we calculate coverage for screening, diagnosis and treatment of Chagas...
January 4, 2017: Social Science & Medicine
https://www.readbyqxmd.com/read/28029081/drug-discovery-for-paediatric-chagas-diseases
#13
Sreekanth Thota, Carlos M Morel
Congenital T. cruzi infection occurs in 1-10% of infants of infected mothers. Treatment of Chagas disease focuses on killing the parasite in acute infection and managing signs and symptoms in later stages. Mothers who test positive should not be treated until they have given birth and have finished breast-feeding. Screening of newborns and other children of infected mothers to provide early diagnosis and treatment. There are only two drugs currently available for the treatment of paediatric chagas disease, nifurtimox and benznidazole...
December 26, 2016: Mini Reviews in Medicinal Chemistry
https://www.readbyqxmd.com/read/28025938/trypanothione-reductase-and-superoxide-dismutase-as-current-drug-targets-for-trypanosoma-cruzi-an-overview-of-compounds-with-activity-against-chagas-disease
#14
Iván Beltrán-Hortelano, Silvia Pérez-Silanes, Silvia Galiano
It has been over a century since Carlos Chagas discovered the Trypanosoma cruzi (T. cruzi) as the causative agent of Chagas disease (CD), a neglected tropical disease with several socioeconomic, epidemiological and human health repercussions. Currently, there are only two commercialized drugs to treat CD in acute phase, nifurtimox and benznidazol, with several adverse side effects. Thus, new orally available and safe drugs for this parasitic infection are urgently required. One strategy of great importance in new drug discovery programmes is based on the search of molecules enabling to interfere with enzymes involved in T...
December 26, 2016: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28011170/antiprotozoal-drug-nitazoxanide-enhances-parasitemia-tissue-lesions-and-mortality-caused-by-trypanosoma-cruzi-in-murine-model
#15
Juan Salvador Valle-Reyes, Valery Melnikov, Oxana Dobrovinskaya, Alejandrina Rodriguez-Hernández, Cristina Wookee-Zea, Víctor Pimientel-Rodrigez, Gabriela Rueda-Valdovinos, Iván Delgado-Enciso, Uriel A López-Lemus, Francisco Espinoza-Gómez
Chagas' disease is caused by unicellular parasite Trypanosoma cruzi (T. cruzi). It is endemic throughout Latin America, but nowadays has become a global challenge due to tourism and migration. Non-treated infection may result in health-threatening complications and lead to death. Current medications for this infection are nifurtimox (NFT) and benznidazol. Both drugs may cause side effects and are ineffective in the chronic phase. Therefore, new antichagasic compounds are urgently required. Nitazoxanide (NTZ) is a broad spectrum antiparasitic drug, proposed recently as a potential candidate to be added to the list of essential medicines for integrated neglected tropical disease control and elimination...
January 2017: Experimental Parasitology
https://www.readbyqxmd.com/read/27951486/in%C3%A2-vitro-activity-and-mode-of-action-of-distamycin-analogues-against-african-trypanosomes
#16
Jaime Franco, Andrea Medeiros, Diego Benítez, Karen Perelmuter, Gloria Serra, Marcelo A Comini, Laura Scarone
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)...
January 27, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27908757/synthesis-antioxidant-and-antichagasic-properties-of-a-selected-series-of-hydroxy-3-arylcoumarins
#17
Natalia Robledo-O'Ryan, Maria João Matos, Saleta Vazquez-Rodriguez, Lourdes Santana, Eugenio Uriarte, Mauricio Moncada-Basualto, Francisco Mura, Michel Lapier, Juan Diego Maya, Claudio Olea-Azar
Oxidative stress is involved in several parasitic diseases such as Chagas. Agents able to selectively modulate biochemical processes involved in the disease represent promising multifunctional agents for the delay or abolishment of the progression of this pathology. In the current work, differently substituted hydroxy-3-arylcoumarins are described, exerting both antioxidant and trypanocidal activity. Among the compounds synthesized, compound 8 showed the most interesting profile, presenting a moderate scavenging ability for peroxyl radicals (ORAC-FL=2...
January 15, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27908747/tci-tcii-and-tcvi-trypanosoma-cruzi-samples-from-chagas-disease-patients-with-distinct-clinical-forms-and-critical-analysis-of-in-vitro-and-in-vivo-behavior-response-to-treatment-and-infection-evolution-in-murine-model
#18
Maykon Tavares de Oliveira, Renata Tupinambá Branquinho, Gláucia Diniz Alessio, Carlos Geraldo Campos Mello, Nívia Carolina Nogueira-de-Paiva, Cláudia Martins Carneiro, Max Jean de Ornelas Toledo, Alexandre Barbosa Reis, Olindo Assis Martins Martins-Filho, Marta de Lana
The clonal evolution of Trypanosoma cruzi sustains scientifically the hypothesis of association between parasite's genetic, biological behavior and possibly the clinical aspects of Chagas disease in patients from whom they were isolated. This study intended to characterize a range of biological properties of TcI, TcII and TcVI T. cruzi samples in order to verify the existence of these associations. Several biological features were evaluated, including in vitro epimastigote-growth, "Vero"cells infectivity and growth, along with in vivo studies of parasitemia, polymorphism of trypomastigotes, cardiac inflammation, fibrosis and response to treatment by nifurtimox during the acute and chronic murine infection...
March 2017: Acta Tropica
https://www.readbyqxmd.com/read/27855164/trypanosoma-brucei-cyp51-essentiality-and-targeting-therapy-in-an-experimental-model
#19
Frédéric-Antoine Dauchy, Mélanie Bonhivers, Nicolas Landrein, Denis Dacheux, Pierrette Courtois, Florian Lauruol, Sylvie Daulouède, Philippe Vincendeau, Derrick R Robinson
Trypanosoma brucei gambiense is the main causative agent of Human African Trypanosomiasis (HAT), also known as sleeping sickness. Because of limited alternatives and treatment toxicities, new therapeutic options are urgently needed for patients with HAT. Sterol 14alpha-demethylase (CYP51) is a potential drug target but its essentiality has not been determined in T. brucei. We used a tetracycline-inducible RNAi system to assess the essentiality of CYP51 in T. brucei bloodstream form (BSF) cells and we evaluated the effect of posaconazole, a well-tolerated triazole drug, within a panel of virulent strains in vitro and in a murine model...
November 2016: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/27812217/activation-of-bicyclic-nitro-drugs-by-a-novel-nitroreductase-ntr2-in-leishmania
#20
Susan Wyllie, Adam J Roberts, Suzanne Norval, Stephen Patterson, Bernardo J Foth, Matthew Berriman, Kevin D Read, Alan H Fairlamb
Drug discovery pipelines for the "neglected diseases" are now heavily populated with nitroheterocyclic compounds. Recently, the bicyclic nitro-compounds (R)-PA-824, DNDI-VL-2098 and delamanid have been identified as potential candidates for the treatment of visceral leishmaniasis. Using a combination of quantitative proteomics and whole genome sequencing of susceptible and drug-resistant parasites we identified a putative NAD(P)H oxidase as the activating nitroreductase (NTR2). Whole genome sequencing revealed that deletion of a single cytosine in the gene for NTR2 that is likely to result in the expression of a non-functional truncated protein...
November 2016: PLoS Pathogens
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