Navegando por Autor "Andrade, Josimara Souza"
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Item 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 GuyChagas 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.Item In vitro evaluation of synthetic flavones against Trypanosoma cruzi.(2021) Andrade, Josimara Souza; Abreu, Leonardo Gomes de; Sales Júnior, Policarpo Ademar; Murta, Silvane Maria Fonseca; Taylor, Jason GuyChagas disease is caused by infection of the parasite protozoan Trypanosoma cruzi and affects about 8 million people in 21 countries in Latin America. Treatment of this disease is still based on the use of benznidazole or nifurtimox, which both present low cure rates in the chronic phase and often have many undesirable side effects. Herein, we describe the synthesis of flavones and evaluation of their trypanocidal activity. The flavones were tested to in vitro against T. cruzi and amongst the 13 compounds tested, 6 of these demonstrated some modest trypanocidal activity in vitro. Enhancements in anti T. cruzi activity were noted for flavones bearing either nitro or methoxy substituents. Moreover, very low cytotoxicities were maintained for flavones with methoxy groups which suggests that this functional group favors more selective trypanocidal compounds. Finally, structural modification at position 3 of the dihydropyrone ring provided the most active flavone, which suggests that the introduction of different functionalities at this position could yield promising new compounds with trypanocidal properties.Item Síntese e avaliação de compostos derivados de cromenopirazóis com atividade anti-Trypanosoma cruzi.(2021) Andrade, Josimara Souza; Taylor, Jason Guy; Taylor, Jason Guy; Valle, Marcelo Siqueira; Souza, Thiago Belarmino deA Doença de Chagas é causada pelo agente etiológico Tripanosoma cruzi. É uma doença negligenciada que ainda continua impactando na sociedade e afetando principalmente a população mais carente. No Brasil, o cenário atual estima cerca de mais de 3 milhões de pessoas infectadas, os números de casos de Doenças de Chagas aguda informados pelo Sinan (Sistema de Informação de Agravos de Notificação) têm aumentado nos últimos anos, apresentando uma média de 350 novos casos por ano, sendo a região norte a mais atingida. O tratamento restringese a dois fármacos que estão no mercado desde a década de 1960, são eles o Nifurtimox e o Benznidazol, entretanto ambos apresentam alta incidência de efeitos colaterais e baixa eficiência na fase crônica da doença. Portanto, há uma necessidade e urgência de novos agentes terapêuticos com potencial satisfatório de cura. Nesse contexto, o objetivo desse trabalho foi sintetizar derivados de 2H-cromenopirazóis e avaliar a atividade biológica antiparasitária por ensaio in vitro frente as formas intracelulares do T. cruzi. Sabe-se que essas classes separadamente (cromeno e pirazol), apresentam extensas atividades biológicas, dentre elas antiparasitária. Os cromenopirazóis são compostos heterocíclicos tendo como núcleo básico um anel benzênico fundido a um anel pirano e um anel pirazol, formando assim um composto tricíclico com particularidade (6, 6, 5) membros. Fomos motivados a partir de um estudo in vitro do composto 3,4-difenil-1,4-diidrocromeno[4,3,c]pirazol, que apresentou uma atividade tripanocida promissora (CI50 = 8,30 µM). Diante deste resultado, um planejamento racional foi realizado na tentativa de aperfeiçoar e buscar melhorar a atividade e/ou seletividade do cromenopirazol, alguns grupos funcionais foram adotadas a fim de atingir os alvos específicos do parasita. Este trabalho resultou na síntese de 18 compostos, sendo 4 derivados de 3-benzoilflavanonas e 14 derivados de cromenopirazóis, com rendimentos que variaram de 10 a 80%. Todos os derivados de cromenopirazóis foram submetidos a ensaio biológico in vitro frente as formas intracelulares do T. cruzi, dentre os compostos que apresentaram atividade tripanocida, destacamos o composto 58 que possui quatro metoxilas em sua estrutura, sendo o mais ativo com o CI50 = 4,61 μM ao comparar com o fármaco de controle benznidazol (CI50 = 3,81 μM) apresentou um resultado significativo. No geral, os cromenopirazóis foram mais ativos que as flavanonas precursoras, podendo torná-los possíveis alvos de interesse com grande potencialidade para atividades farmacológicas.Item Trypanocidal activity of chromenepyrazole derivatives.(2022) Andrade, Josimara Souza; Sales Júnior, Policarpo Ademar; Pereira, Fabio Junio; Murta, Silvane Maria Fonseca; Correa, Rodrigo de Souza; Taylor, Jason GuyChagas disease is caused by the etiological agent Trypanosoma cruzi that impacts negatively on society and mainly afects the poorest populations of the community. The treatment is restricted to two drugs that have been on the market since the 1960s: nifurtimox and benznidazole. However, both have a high incidence of unwanted side efects and low efciency in the chronic phase of the disease. Therefore, in this context, the objective of this work was to synthesize chromenopyrazole derivatives and to evaluate their antiparasitic activity in vitro against the intracellular forms of T. Cruzi. Chromenopyrazoles are heterocyclic compounds having as a basic core a benzene ring fused to a pyran ring and a pyrazole ring, thus forming a tricyclic compound with a 6, 6, 5 arrangement. Reaction of 3-benzoyl-favanone with hydrazine was expected to aford the target compounds, but for a similar synthetic route described in the literature, the proposed product was a pyrazole derivative in an open form that had not undergone the fnal conjugate addition step. Based on NMR and X-ray crystallography analysis, it has been demonstrated that a tricyclic chromenopyrazole is the correct structural representation for the product of this reaction. This study resulted in the synthesis of 15 novel chromenopyrazoles compounds displaying signifcant trypanocidal activity. The majority of the chromenepyrazoles satisfed Lipinski rules, without any violations, whilst only two compounds showed at least one violation of the rule, due to the log P being greater than 5.6. All chromenepyrazoles exhibited anti-T. cruzi activity, and improved potency was observed when comparing them to the precursor 3-benzoyl-favanone. The introduction of an anisole moiety at the pyrazole ring and the inclusion of 3,4,5-trimethoxybenzene at the pyranone resulted in a doubling of potency and improvement in selectivity. The lead compound bearing methoxyl groups was the most active and displayed comparable anti-T. Cruzi activity to the control drug benznidazole. This result, once again, reinforces the same observations reported in the literature in which the introduction of the methoxy groups favoured either more active or more selective trypanocidal compounds.Item Trypanocidal activity of flavanone derivatives.(2020) Diogo, Gabriela Maciel; Andrade, Josimara Souza; Sales Júnior, Policarpo Ademar; Murta, Silvane Maria Fonseca; Santos, Viviane Martins Rebello dos; Taylor, Jason GuyChagas disease, also known as American trypanosomiasis, is classified as a neglected disease by the World Health Organization. For clinical treatment, only two drugs have been on the market, Benznidazole and Nifurtimox, both of which are recommended for use in the acute phase but present low cure rates in the chronic phase. Furthermore, strong side effects may result in discontinuation of this treatment. Faced with this situation, we report the synthesis and trypanocidal activity of 3-benzoyl-flavanones. Novel 3-benzoyl-flavanone derivatives were prepared in satisfactory yields in the 3-step synthetic procedure. According to recommended guidelines, the whole cell-based screening methodology was utilized that allowed for the simultaneous use of both parasite forms responsible for human infection. The majority of the tested compounds displayed promising anti-Trypanosoma cruzi activity and the most potent flavanone bearing a nitrofuran moiety was more potent than the reference drug, Benznidazole.