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

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 o...

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Published in:Chemical biology & drug design 2014-03, Vol.83 (3), p.289-296
Main Authors: Bonano, Vivian I., Yokoyama-Yasunaka, Jenicer K. U., Miguel, Danilo C., Jones, Scott A., Dodge, Jeffrey A., Uliana, Silvia R. B.
Format: Article
Language:English
Subjects:
Animals
Antiprotozoal Agents - chemical synthesis
Antiprotozoal Agents - chemistry
Antiprotozoal Agents - pharmacology
Cell Survival - drug effects
Cercopithecus aethiops
Drug Evaluation, Preclinical
Leishmania - drug effects
leishmaniasis
selective estrogen receptor modulator
Stereoisomerism
Structure-Activity Relationship
tamoxifen
Thiophenes - chemical synthesis
Thiophenes - chemistry
Thiophenes - pharmacology
Vero Cells
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Summary: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. The screening of an estrogen receptor modulator related library of compounds allowed the identification of benzothiophenes as a new scaffold with antileishmanial properties. Three compounds devoid of estrogen receptor interaction were identified with increased potency against the parasite. Structure‐activity data for the synthetic benzothiophenes evaluated in this study indicates that optimal antileishmanial potency is dependent on the presence of two basic side chains.
ISSN:1747-0277
1747-0285
DOI:10.1111/cbdd.12239