Planejamento, síntese e avaliação biológica de inibidores de cruzaína para o tratamento da doença de chagas
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Data
2022-05-06
Autores
Torres Peña, Andrés Felipe
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
A doença de Chagas é uma enfermidade tropical negligenciada causada pelo protozoário Tripanosoma Cruzi, que gera sérios problemas de saúde pública para muitos países dos continentes Americano, Africano e subcontinente indiano. O aumento do número de pessoas afetadas pela doença de Chagas, e os efeitos colaterais dos medicamentos atualmente disponíveis, nifurtimox e benznidazol, mostram a necessidade do desenvolvimento de fármacos novos seguros e eficazes. Neste trabalho foi descrito a síntese e caracterização estrutural do composto hit 9, um inibidor de cruzaína irreversível já descrito na literatura. O hit 9 (19a) foi obtido na forma de mistura racêmica, apresentando inibição em cruzaína de 71% comparado ao controle positivo (63%). O estudo de docking molecular permitiu sugerir o modo interação dos compostos sintetizados. Além disso, foi possível prever a estereoquímica R como mais promissora para interação no sítio de cruzaína, a qual apresentou menor valor de ΔG = -30,37 e maior valor de pontuação 27.11. O estudo computacional ainda sugere novos derivados do hit 9 promissores a inibição de cruzaína encontrados por química combinatória, considerando sua configuração R. Os resultados de síntese, docking molecular e atividade biológica descritos nesse trabalho abrem caminhos para a descoberta de novos compostos inibidores de cruzaína úteis ao tratamento da doença de chagas.
Chagas disease is a neglected tropical disease caused by the protozoan Trypanosoma Cruzi, causing serious public health problems for many countries in the American, African, and Indian subcontinent. The increase in the number of people affected by Chagas disease, and the side effects of the currently available drugs, nifurtimox and benznidazole, reveal the need for the development of new safe and effective drugs. In this work, the synthesis and structural characterization of the compound hit 9, an irreversible cruzain inhibitor already described in the literature, was described. Hit 9 (19a) was obtained as a racemic mixture, showing 71% cruzain inhibition compared to the positive control (63%). The molecular docking study allowed us to suggest the interaction mode of the synthesized compounds. In addition, it was possible to predict the R stereochemistry as the most promising for interaction at the cruzain site, which presented the lowest value of ΔG = -30.37 and the highest score value 27.11. The computational study also suggests new derivatives of hit 9 promising the inhibition of cruzain found by combinatorial chemistry, considering its R configuration. The results of synthesis, molecular docking and biological activity described in this work open paths for the discovery of new compounds that are useful cruzain inhibitors to the treatment of Chagas disease.
Chagas disease is a neglected tropical disease caused by the protozoan Trypanosoma Cruzi, causing serious public health problems for many countries in the American, African, and Indian subcontinent. The increase in the number of people affected by Chagas disease, and the side effects of the currently available drugs, nifurtimox and benznidazole, reveal the need for the development of new safe and effective drugs. In this work, the synthesis and structural characterization of the compound hit 9, an irreversible cruzain inhibitor already described in the literature, was described. Hit 9 (19a) was obtained as a racemic mixture, showing 71% cruzain inhibition compared to the positive control (63%). The molecular docking study allowed us to suggest the interaction mode of the synthesized compounds. In addition, it was possible to predict the R stereochemistry as the most promising for interaction at the cruzain site, which presented the lowest value of ΔG = -30.37 and the highest score value 27.11. The computational study also suggests new derivatives of hit 9 promising the inhibition of cruzain found by combinatorial chemistry, considering its R configuration. The results of synthesis, molecular docking and biological activity described in this work open paths for the discovery of new compounds that are useful cruzain inhibitors to the treatment of Chagas disease.
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Palavras-chave
Doenças negligenciadas, Química medicinal, Química combinatória, Doença de Chagas, Tripanosoma Cruzi