Leishmaniasis is a neglected, parasitic disease transmitted through the bite of infected
sandflies. In an effort to identify novel compounds demonstrating activity against
the parasite, a multidisciplinary research effort involving natural product isolation,
chemical synthesis, and biological evaluation was initiated. Recently, our group reported
the isolation of several sterols from the roots of Pentalinon andrieuxii, a plant native to Mexico, that show potent antileishmanial activity both in vitro and in vivo. Analysis of these compounds indicated three distinct structural subtypes and afforded
preliminary structure-activity relationship (SAR) data. Semi-synthetic approaches
toward these structural classes from readily available, commercial starting materials
have been carried out to prepare the molecules in quantities sufficient to enable
detailed mechanistic studies and SAR studies. Syntheses of pentalinonsterol and ergosta-4,24(28)-dien-3-one,
members of the first two classes, respectively, have already been accomplished and
the synthesis of an advanced intermediate of 6,7-dihydroneridienone, the compound
displaying the most potent antileishmanial activity and a representative member of
the third class possessing, has also been achieved. These synthetic efforts have also
facilitated the preparation of a number of structurally related analogues and probes
designed to explore the mechanism of action of this class of natural product.
