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

• Published in: Chemical biology & drug design Vol. 83; no. 3; pp. 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: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.03.2014
• 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; leishmaniasis; selective estrogen receptor modulator; tamoxifen
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12239

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.