SAR:s for the Antiparasitic Plant Metabolite Pulchrol. 1. The Benzyl Alcohol Functionality

Abstract

Pulchrol (<b>1</b>) is a natural benzochromene isolated from the roots of <i>Bourreria pulchra</i>, shown to possess potent antiparasitic activity towards both <i>Leishmania</i> and <i>Trypanozoma</i> species. As it is not understood which molecular features of <b>1</b> are important for the antiparasitic activity, several analogues were synthesized and assayed. The ultimate goal is to understand the structure-activity relationships (SAR:s) and create a QSAR model that can be used for the development of clinically useful antiparasitic agents. In this study, we have synthesized 25 2-methoxy-6,6-dimethyl-6<i>H</i>-benzo[<i>c</i>]chromen analogues of <b>1</b> and its co-metabolite pulchral (<b>5a</b>), by semi-synthetic procedures starting from the natural product pulchrol (<b>1</b>) itself. All 27 compounds, including the two natural products <b>1</b> and <b>5a</b>, were subsequently assayed in vitro for antiparasitic activity against <i>Trypanozoma cruzi</i>, <i>Leishmania brasiliensis</i> and <i>Leishmania amazoniensis</i>. In addition, the cytotoxicity in RAW cells was assayed, and a selectivity index (SI) for each compound and each parasite was calculated. Several compounds are more potent or equi-potent compared with the positive controls Benznidazole (<i>Trypanozoma</i>) and Miltefosine (<i>Leishmania</i>). The compounds with the highest potencies as well as SI-values are esters of <b>1</b> with various carboxylic acids.