Title: Discovery of Synthetic Leishmania Inhibitors by Screening of a 2-Arylbenzothiophene Library
Author: Bonano Vi; Yokoyama-yasunaka, J.K.U.; Miguel, D. C.; Jones, S. A.; Dodge, J. A.; Uliana, Silvia R. B.
Is part of: Chemical Biology & Drug Design (Print), v. 83, p. 289 - 296
Citation: Bonano Vi; Yokoyama-yasunaka, J.K.U.; Miguel, D. C.; Jones, S. A.; Dodge, J. A.; Uliana, Silvia R. B.; Discovery of Synthetic Leishmania Inhibitors by Screening of a 2-Arylbenzothiophene Library. Chemical Biology & Drug Design (Print), v.83, p. 289-296, 2014
Abstract: 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.
Funding: We thank Andrew S. Bell for the critical reading of the manuscript. This work was supported by Grants #2011/20484-7, Sao Paulo Research Foundation (FAPESP) and 473343/2012-6, Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq). V.I.B. was supported by a PNPD/CAPES fellowship (2289/2009).