Flavonoid Derivatives as New Potent Inhibitors of Cysteine Proteases: An Important Step toward the Design of New Compounds for the Treatment of Leishmaniasis

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Lourenco, Estela Mariana Guimaraes ; Di Iorio, Juliana Fortes ; da Silva, Fernanda ; Fialho, Felipe Leonardo Bley ; Monteiro, Melquisedeque Mateus ; Beatriz, Adilson ; Perdomo, Renata Trentin ; Barbosa, Euzebio Guimaraes ; Oses, Jean Pierre ; de Arruda, Carla Cardozo Pinto ; Judice, Wagner Alves de Souza ; Rafique, Jamal ; de Lima, Denis Pires

• Tipo de documento: Artigo Científico
• Fonte: MICROORGANISMS; v. 11, n. 1, p. 23-pg., 2023-01-01.

Resumo

Leishmaniasis is a neglected tropical disease, affecting more than 350 million people globally. However, there is currently no vaccine available against human leishmaniasis, and current treatment is hampered by high cost, side-effects, and painful administration routes. It has become a United Nations goal to end leishmaniasis epidemics by 2030, and multitarget drug strategy emerges as a promising alternative. Among the multitarget compounds, flavonoids are a renowned class of natural products, and a structurally diverse library can be prepared through organic synthesis, which can be tested for biological effectiveness. In this study, we synthesised 17 flavonoid analogues using a scalable, easy-to-reproduce, and inexpensive method. All synthesised compounds presented an impressive inhibition capacity against rCPB2.8, rCPB3, and rH84Y enzymes, which are highly expressed in the amastigote stage, the target form of the parasite. Compounds 3c, f12a, and f12b were found to be effective against all isoforms. Furthermore, their intermolecular interactions were also investigated through a molecular modelling study. These compounds were highly potent against the parasite and demonstrated low cytotoxic action against mammalian cells. These results are pioneering, representing an advance in the investigation of the mechanisms behind the antileishmanial action of flavonoid derivatives. Moreover, compounds have been shown to be promising leads for the design of other cysteine protease inhibitors for the treatment of leishmaniasis diseases. (AU)

• Processo FAPESP: 21/01503-2 - Avaliação dos efeitos de glicosaminoglicanos na atividade de inibidores de cisteíno proteases catepsinas
• Beneficiário: Wagner Alves de Souza Júdice
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/25112-4 - Avaliação de moduladores da atividade de proteases envolvidas em processos patológicos
• Beneficiário: Wagner Alves de Souza Júdice
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 14/02205-1 - Estudo do comportamento cinético das convertases
• Beneficiário: Wagner Alves de Souza Júdice
• Modalidade de apoio: Auxílio à Pesquisa - Regular