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Discovery of Synthetic Leishmania Inhibitors by Screening of a 2‐Arylbenzothiophene Library
Author(s) -
Bonano Vivian I.,
YokoyamaYasunaka Jenicer K. U.,
Miguel Danilo C.,
Jones Scott A.,
Dodge Jeffrey A.,
Uliana Silvia R. B.
Publication year - 2014
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12239
Subject(s) - pharmacophore , leishmania , virtual screening , tamoxifen , pharmacology , estrogen receptor , high throughput screening , selective estrogen receptor modulator , chemistry , drug discovery , in vitro , leishmania major , biology , biochemistry , computer science , parasite hosting , cancer , world wide web , breast cancer , genetics
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.