Synthesis and Structure-Activity Relationship of Dehydrodieugenol B Neolignans against Trypanosoma cruzi

Autor(es)

Sear, Claire E. ^[1] ; Pieper, Pauline ^[1] ; Amaral, Maiara ^{[2, 3]} ; Romanelli, Maiara M. ^[3] ; Costa-Silva, Thais A. ^[3] ; Haugland, Marius M. ^[1] ; Tate, Joseph A. ^[4] ; Lago, Joao H. G. ^[5] ; Tempone, Andre G. ^[3] ; Anderson, Edward A. ^[1]

Afiliação do(s) autor(es)

^[1] Chem Res Lab, Oxford OX1 3TA - England

^[2] Univ Sao Paulo, Fac Med, BR-05403000 Sao Paulo - Brazil

^[3] Adolfo Lutz Inst, Ctr Parasitol & Mycol, BR-01246000 Sao Paulo - Brazil

^[4] Syngenta Ltd, Jealotts Hill Int Res Ctr, Bracknell RG42 6EY, Berks - England

^[5] Fed Univ ABC UFBC, Ctr Nat Sci & Humanities, BR-09210580 Santo Andre, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: ACS INFECTIOUS DISEASES; v. 6, n. 11, p. 2872-2878, NOV 13 2020.
• Citações Web of Science: 0

Resumo

Trypanosoma cruzi is the etiologic agent of Chagas disease, which affects over seven million people, especially in developing countries. Undesirable side effects are frequently associated with current therapies, which are typically ineffective in the treatment of all stages of the disease. Here, we report the first synthesis of the neolignan dehydrodieugenol B, a natural product recently shown to exhibit activity against T. cruzi. Using this strategy, a series of synthetic analogues were prepared to explore structure-activity relationships. The in vitro antiparasitic activities of these analogues revealed a wide tolerance of modifications and substituent deletions, with maintained or improved bioactivities against the amastigote forms of the parasite (50% inhibitory concentration (IC50) of 4-63 mu M) and no mammalian toxicity (50% cytotoxic concentration (CC50) of >200 mu M). Five of these analogues meet the Drugs for Neglected Disease Initiative (DNDi) ``hit criteria{''} for Chagas disease. This work has enabled the identification of key structural features of the natural product and sites where scaffold modification is tolerated. (AU)

• Processo FAPESP: 18/25128-3 - Otimização de protótipos naturais como novos candidatos terapêuticos para Leishmaniose Visceral
• Beneficiário: Maiara Amaral de Oliveira
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 18/10279-6 - Seleção e Otimização de Novos Candidatos a Fármacos para Leishmaniose e Doença de Chagas
• Beneficiário: André Gustavo Tempone Cardoso
• Modalidade de apoio: Auxílio à Pesquisa - Regular