Discovery of Synthetic Leishmania Inhibitors by Screening of a 2-Arylbenzothiophene Library

Autor(es)

Bonano, Vivian I. ^[1] ; Yokoyama-Yasunaka, Jenicer K. U. ^[1] ; Miguel, Danilo C. ^[1] ; Jones, Scott A. ^[2] ; Dodge, Jeffrey A. ^[2] ; Uliana, Silvia R. B. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Dept Parasitol, Inst Ciencias Biomed, BR-05508900 Sao Paulo - Brazil

^[2] Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 - USA

• Tipo de documento: Artigo Científico
• Fonte: CHEMICAL BIOLOGY & DRUG DESIGN; v. 83, n. 3, p. 289-296, MAR 2014.
• Citações Web of Science: 7

Resumo

Tamoxifen has been shown to be active in vitro against Leishmania and effective in the treatment for leishmaniasis in murine models. Through the screening of a compound library of estrogen receptor modulator analogs, we identified the major characteristics required for antileishmanial activity. To overcome the difficulties presented by tamoxifen's propensity for E/Z isomerization, we used the 2-arylbenzothiophene compound BTP as a more stable alternative. Directed screening of a small compound library based on BTP led to active compounds against Leishmania. Subsequent structure-activity data for the synthetic 2-arylbenzothiophenes evaluated in this study indicate that optimal antileishmanial potency is dependent on the presence of two basic side chains. In addition, the primary structural features required for estrogen receptor binding, the phenols, are not required for inhibiting parasitic growth. Significantly, the most active antileishmanial benzothiophenes lack the pharmacophore for estrogen receptor activity and therefore address potential concerns about the undesirable effects of using selective estrogen receptor modulators in women and children with leishmaniasis. Three compounds selected from the screening have shown consistent activity against all species and stages of Leishmania in vitro although improvements in selectivity are needed. These compounds represent viable starting points for further optimization as antileishmanial agents. (AU)

• Processo FAPESP: 11/20484-7 - Tamoxifeno no tratamento de leishmaniose: avaliação de eficácia em esquemas de combinação de drogas e estudo do mecanismo de ação
• Beneficiário: Silvia Reni Bortolin Uliana
• Modalidade de apoio: Auxílio à Pesquisa - Regular