Síntese e potencial anti-Chagas de Chalconas O-geraniladas
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Data
2022-02-07
Autores
Martinez, Giovana
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
Doenças negligenciadas são enfermidades que prevalecem em condições de pobreza e que contribuem para a desigualdade social. A doença de Chagas (DC) é um exemplo de doença negligenciada que afeta milhões de pessoas, ocasionando números elevados de mortes. Sendo assim, as doenças infecciosas apresentam elevada necessidade de serem investigadas pela Química Medicinal, visando o planejamento e descoberta de fármacos antichagásicos inovadores. A 4-O-geranilisoliquiritigenina apresentou atividade contra Plasmodium falciparum, um protozoário causador da malária, mas não foi avaliada contra T. cruzi. Além disso, várias chalconas preniladas têm mostrado potencial antichagásico O objetivo geral dessa dissertação consiste na síntese e avaliação atividade contra Trypanosoma cruzi, da 4-O-geranilisoliquiritigenina e seus análogos. Neste contexto, para alcançar os objetivos delineados, foram sintetizadas a 4-O-geranilisoliquiritigenina e 9 análogos chalcônicos, a partir de reações de proteção de acetofenonas, reação de condensação aldólica de Claisen-Schmidt e reações de desproteção. As substâncias foram purificadas por técnicas de recristalização, cromatografia em coluna de gel de sílica, cromatografia em coluna de permeabilização em gel (Sephadex ® LH 20). As estruturas das substâncias foram confirmadas por Ressonância Magnética Nuclear (RMN) de 1H e 13C. A 4’-hidroxi-4-O-geranilchalcona (G3) exibiu atividade contra as formas tripomastigotas e amastigotas de T. cruzi com valores de CE50 de 2,14 µM e 12,28 µM, respectivamente. Os ensaios de toxicidade indicaram um CC50 de 39,10 µM contra fibroblastos NCTC clone 929, bem como uma hemólise ausente na maior concentração testada (200 µM). A substância G3 foi submetida a uma avaliação in silico, utilizando a ferramenta SwissADME, a qual indicou adequadas propriedades farmacocinéticas e druglikeness, como ser moderavelmente solúvel em água, possuir alta absorção gastrointestinal, permeabilidade por via oral e teve valores ideais de flexibilidade, lipofilicidade, tamanho, polaridade, solubilidade e saturação. Além disso, a substância G3 é inédita na literatura, sendo um possível fármaco promissor.
Neglected diseases prevalent in conditions of poverty and contribute to social inequality. Chagas disease (CD) is an example of a neglected disease that affects millions of people, causing high numbers of deaths. Therefore, infectious diseases have a high need to be investigated by Medicinal Chemistry, aiming at the planning and discovery of innovative antichagasic drugs. 4-O-geranilisoliquiritigenin showed activity against Plasmodium falciparum, a protozoan that causes malaria, but was not evaluated against T. cruzi. In addition, several prenylated chalcones have shown antichagasic potential. The general objective of this dissertation is the synthesis and evaluation activity against Trypanosoma cruzi of 4-O-geranilisoliquiritigenin and its analogues. In this context, to achieve the outlined objectives, 4-O-geranilisoliquiritigenin and 9 chalconic analogues were synthesized from acetophenone protection reactions, Claisen-Schmidt aldol condensation reaction and deprotection reactions. The substances were purified by recrystallization techniques, silica gel column chromatography, gel permeabilization column chromatography (Sephadex ® LH 20). The structures of the substances were confirmed by 1H and 13C Nuclear Magnetic Resonance (NMR). 4'-hydroxy-4-O-geranilchalcone (G3) exhibited activity against trypomastigote and amastigote forms of T. cruzi with EC50 values of 2.14 µM and 12.28 µM, respectively. Toxicity assays indicated a CC50 of 39.10 µM against NCTC clone 929 fibroblasts, as well as absent hemolysis at the highest concentration tested (200 µM). Substance G3 was submitted the avaluation in silico using the SwissADME tool, which indicated adequate pharmacokinetic and druglikeness properties, such as being sparingly soluble in water, have high gastrointestinal absorption, oral permeability, having ideal values of flexibility, lipophilicity, size, polarity, solubility, and saturation. In addition, substance G3 is unprecedented in the literature, being a possible promising drug
Neglected diseases prevalent in conditions of poverty and contribute to social inequality. Chagas disease (CD) is an example of a neglected disease that affects millions of people, causing high numbers of deaths. Therefore, infectious diseases have a high need to be investigated by Medicinal Chemistry, aiming at the planning and discovery of innovative antichagasic drugs. 4-O-geranilisoliquiritigenin showed activity against Plasmodium falciparum, a protozoan that causes malaria, but was not evaluated against T. cruzi. In addition, several prenylated chalcones have shown antichagasic potential. The general objective of this dissertation is the synthesis and evaluation activity against Trypanosoma cruzi of 4-O-geranilisoliquiritigenin and its analogues. In this context, to achieve the outlined objectives, 4-O-geranilisoliquiritigenin and 9 chalconic analogues were synthesized from acetophenone protection reactions, Claisen-Schmidt aldol condensation reaction and deprotection reactions. The substances were purified by recrystallization techniques, silica gel column chromatography, gel permeabilization column chromatography (Sephadex ® LH 20). The structures of the substances were confirmed by 1H and 13C Nuclear Magnetic Resonance (NMR). 4'-hydroxy-4-O-geranilchalcone (G3) exhibited activity against trypomastigote and amastigote forms of T. cruzi with EC50 values of 2.14 µM and 12.28 µM, respectively. Toxicity assays indicated a CC50 of 39.10 µM against NCTC clone 929 fibroblasts, as well as absent hemolysis at the highest concentration tested (200 µM). Substance G3 was submitted the avaluation in silico using the SwissADME tool, which indicated adequate pharmacokinetic and druglikeness properties, such as being sparingly soluble in water, have high gastrointestinal absorption, oral permeability, having ideal values of flexibility, lipophilicity, size, polarity, solubility, and saturation. In addition, substance G3 is unprecedented in the literature, being a possible promising drug
Descrição
Palavras-chave
Chalconas preniladas, Doença de Chagas, Trypanosoma cruzi, Prenylated chalcones, Chagas disease