Browsing by Author "Coelho, Gleicekelly Silva"

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    Design, synthesis, molecular modelling, and in vitro evaluation of tricyclic coumarins against Trypanosoma cruzi.
    (2019) Coelho, Gleicekelly Silva; Andrade, Josimara Souza; Xavier, Viviane Flores; Sales Júnior, Policarpo Ademar; Araújo, Bárbara Caroline Rodrigues de; Fonseca, Kátia da Silva; Caetano, Melissa Soares; Murta, Silvane Maria Fonseca; Vieira, Paula Melo de Abreu; Carneiro, Cláudia Martins; Taylor, Jason Guy
    Chagas disease is caused by infection with the parasite protozoan Trypanosoma cruzi and affects about 8 million people in 21 countries in Latin America. The main form of treatment of this disease is still based on the use of two drugs, benznidazole and nifurtimox, which both present low cure rates in the chronic phase and often have serious side-effects. Herein, we describe the synthesis of tricyclic coumarins that were obtained via NHC organocatalysis and evaluation of their trypanocidal activity. Molecular docking studies against trypanosomal enzyme triosephosphate isomerase (TIM) were carried out, as well as a theoretical study of the physicochemical parameters. The tricyclic coumarins were tested in vitro against the intracellular forms of Trypanosoma cruzi. Among the 18 compounds tested, 10 were more active than the reference drug benznidazole. The trypanocidal activity of the lead compound was rationalized by molecular docking study which suggested the strong interaction with the enzyme TIM by T. cruzi and therefore indicating a possible mode of action. Furthermore, the selectivity index of eight tricyclic coumarins with high anti-T. cruzi activity was above 50 and thus showing that these lead compounds are viable candidates for further in vivo assays.
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    Síntese, modelagem molecular e avaliação da atividade tripanossomicida in vitro de cumarinas triciclicas bioativas.
    (2018) Coelho, Gleicekelly Silva; Taylor, Jason Guy; Taylor, Jason Guy; Carneiro, Vânia Maria Teixeira; Hilário, Flaviane Francisco
    A doença de Chagas é uma infecção grave causada pelo protozoário Trypanosoma cruzi, através do contato direto com as fezes dos insetos vetores (triatomíneos ou barbeiros). Essa doença acomete cerca de 9,8 a 11 milhões de pessoas em 21 países da América Latina. A principal forma de tratamento dessa doença ainda se baseia no uso de dois fármacos, o benzonidazol e o nifurtimox, que, muitas vezes, apresentam efeitos colaterais graves, e algumas vezes, enfrentam resistência por parte dos protozoários. Com isso, existe uma necessidade de novos estudos objetivando a produção de moléculas com atividade tripanocida para o tratamento da doença de Chagas. A utilização de produtos naturais como fontes de novas estruturas, para a produção de novos fármacos a serem utilizados no tratamento de diversas doenças, tem despertado grande interesse nos últimos anos. Uma classe de moléculas que tem chamado bastante atenção nos últimos anos são as cumarinas, família de compostos heterocíclicos oxigenados, presentes em plantas ou de origem sintética. O grande interesse sobre estes compostos é devido à sua atividade biológica contra diferentes patologias, tais como, leishmaniose, malária, doença de Chagas, dentre outras. Neste trabalho foram sintetizados dezoito cumarinas através de organocatálise carbeno N-heterocíclica (NHC), sendo quinze inéditas. Foram realizados estudos de ancoramento molecular dos compostos com a enzima triosefosfato isomerase (TIM) humana e tripanossomal, além, de estudo in sílico dos parâmetros físico-químicos. As cumarinas obtidas foram submetidas a ensaio biológico in vitro frente às formas intracelulares do Trypanossoma cruzi, com o objetivo de serem futuros precursores no tratamento da doença de Chagas. Dentre os dezessete compostos testados, dez se mostraram mais ativos que o fármaco de referência benzonidazol, sendo que o composto (76) foi o mais ativo contra T. cruzi, condizente com o estudo de ancoramento molecular, no qual o mesmo composto apresentou forte interação com a enzima TIM de T. cruzi (-144,45 kcal.mol-1). O composto (64) foi o mais seletivo da série, com índice de seletividade superior a 262,3. Considerando o conjunto de resultados obtidos, a maior parte dos compostos se mostraram promissores candidatos a ensaios in vivo. Novos estudos devem ser realizados para estabelecer relações de estrutura/atividade e determinar o mecanismo de ação dos compostos mais ativos.
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    Synthesis of 3,5-Diarylisoxazole derivatives and evaluation of in vitro trypanocidal activity.
    (2017) Souza, Aline Aparecida Nunes de; Xavier, Viviane F.; Coelho, Gleicekelly Silva; Sales Júnior, Policarpo Ademar; Romanha, Alvaro José; Murta, Silvane Maria Fonseca; Carneiro, Claudia Martins; Taylor, Jason Guy
    Chagas disease is included in the neglected tropical diseases list and is endemic to 21 Latin American countries. The two drugs currently available for treating Chagas disease are nifurtimox and benznidazole and both result in many significant side effects. The study describes the synthesis and biological evaluation of 3,5-disubstituted isoxazoles. Isoxazoles were obtained by reaction of flavones and hydroxylamine and either alkylated at the free hydroxyl group and/or nitrated at the isoxazole ring. These compounds were evaluated for their in vitro anti-Trypanosoma cruzi activity against trypomastigote and amastigote forms of the parasite in T. cruzi-infected cell lineages. Benznidazole was used as a reference compound for the in vitro assay and mammalian L929 cells were employed to evaluate cytotoxicity. A majority of the compounds tested were very active and the most active isoxazole against amastigote and trypomastigotes of T. cruzi was slightly more potent than the current medicine benznidazole.
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    Synthesis of xylitan derivatives and preliminary evaluation of in vitro trypanocidal activity.
    (2016) Elias, Paula Regina; Coelho, Gleicekelly Silva; Xavier, Viviane Flores; Sales Júnior, Policarpo Ademar; Romanha, Alvaro José; Murta, Silvane Maria Fonseca; Carneiro, Claudia Martins; Camilo, Nilton Soares; Hilário, Flaviane Francisco; Taylor, Jason Guy
    A series of novel xylitan derivatives derived from xylitol were synthesized using operationally simple procedures. A xylitan acetonide was the key intermediate used to prepare benzoate, arylsulfonate esters and 1,2,3-triazole derivatives of xylitan. These compounds were evaluated for their in vitro anti-Trypanosoma cruzi activity against trypomastigote and amastigote forms of the parasite in T. cruzi-infected cell lineages. Benznidazole was used as positive control against T. cruzi and cytotoxicity was determined in mammalian L929 cells. The arylsulfonate xylitan derivative bearing a nitro group displayed the best activity of all the compounds tested, and was slightly more potent than the reference drug benznidazole. The importance of the isopropylidene ketal moiety was established and the greater lipophilicity of these compounds suggests enhancement in cell penetration.