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.