Dehydrodieugenol B derivatives as antiparasitic agents: Synthesis and biological activity against Trypanosoma cruzi

Autor(es):Mostrar menos -

Ferreira, Daiane D. ^[1] ; Sousa, Fernanda S. ^[2] ; Costa-Silva, Thais A. ^[3] ; Reimao, Juliana Q. ^[4] ; Torrecilhas, Ana C. ^[2] ; Johns, Deidre M. ^[5] ; Sear, Claire E. ^[6] ; Honorio, Kathia M. ^[7] ; Lago, Joao Henrique G. ^[3] ; Anderson, Edward A. ^[6] ; Tempone, Andre G. ^[1]

Afiliação do(s) autor(es)

^[1] Adolfo Lutz Inst, Ctr Parasitol & Mycol, BR-01246000 Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Inst Environm Chem & Pharmaceut Sci, BR-09972270 Diadema - Brazil

^[3] Fed Univ ABC, Ctr Nat & Human Sci, BR-09210580 Santo Andre - Brazil

^[4] Fac Med Jundiai, Rua Francisco Telles, 250 Vila Arens 2, BR-13202550 Jundiai, SP - Brazil

^[5] Oregon State Univ, Carlson Coll Vet Med, Dept Biomed Sci, Corvallis, OR 97331 - USA

^[6] Univ Oxford, Chem Res Lab, 12 Mansfield Rd, Oxford OX1 3TA - England

^[7] Univ Sao Paulo, Escola Artes Ciencias & Humanidades, BR-03828000 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 176, p. 162-174, AUG 15 2019.
• Citações Web of Science: 2

Resumo

Chagas disease is a neglected protozoan disease that affects more than eight million people in developing countries. Due to the limited number and toxicity profiles of therapies in current use, new drugs are urgently needed. In previous studies, we reported the isolation of two related antitrypanosomal neolignans from Nectandra leucantha (Lauraceae). In this work, a semi-synthetic library of twenty-three neolignan derivatives was prepared to explore synthetically accessible structure activity relationships (SAR) against Trypanosoma cruzi. Five compounds demonstrated activity against trypomastigotes (IC50 values from 8 to 64 mu M) and eight showed activity against intracellular amastigotes (IC50 values from 7 to 16 M). Eighteen derivatives demonstrated no mammalian cytotoxicity up to 200 mu M. The phenolic acetate derivative of natural dehydrodieugenol B was effective against both parasite forms and eliminated 100% of amastigotes inside macrophages. This compound caused rapid and intense depolarization of the mitochondrial membrane potential, with decreased levels of intracellular reactive oxygen species being observed. Fluorescence assays demonstrated that this derivative affected neither the permeability nor the electric potential of the parasitic plasma membrane, an effect also corroborated by scanning electron microscopy studies. Structure-activity relationship studies (SARs) demonstrated that the presence of at least one allyl side chain on the biaryl ether core was important for antitrypanosomal activity, and that the free phenol is not essential. This set of neolignan derivatives represents a promising starting point for future Chagas disease drug discovery studies. (C) 2019 Elsevier Masson SAS. All rights reserved. (AU)

• Processo FAPESP: 15/50075-2 - Brazilian biodiversity as a source for novel drug scaffolds against neglected protozoan diseases
• Beneficiário: André Gustavo Tempone Cardoso
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 18/07885-1 - Biomoléculas oriundas de espécies vegetais de áreas remanescentes da Mata Atlântica e do Cerrado para tratamento de doenças tropicais negligenciadas - aspectos químicos e farmacológicos
• Beneficiário: João Henrique Ghilardi Lago
• Linha de fomento: Auxílio à Pesquisa - Programa BIOTA - Regular
• Processo FAPESP: 18/10279-6 - Seleção e Otimização de Novos Candidatos a Fármacos para Leishmaniose e Doença de Chagas
• Beneficiário: André Gustavo Tempone Cardoso
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/24524-7 - Análise estrutural e estudos de modelagem molecular para ligantes de origem natural e sintética relacionados a doenças negligenciadas
• Beneficiário: Kathia Maria Honorio
• Linha de fomento: Auxílio à Pesquisa - Regular