Identification of a Hit Series of Antileishmanial Compounds through the Use of Mixture-Based Libraries

From a screening campaign that included mixture-based libraries containing more than 6 million compounds, a lead series of bis-cyclic guanidines was identified as the most promising. Lead optimization resulted in the identification of potent (IC₅₀ < 500 nM) and selective compounds within this series as well as potent and selective monoguanidines

Synthesis and Activity of a New Series of Antileishmanial Agents

We have determined that tetrahydroindazoles such as <b>1</b> show potent activity against <i>Leishmania donovani</i>, the causative agent of leishmaniasis. While the Hsp90 activity and anticancer properties of <b>1</b> have previously been explored, we present here our efforts to optimize their activity against <i>L. donovani</i> via the synthesis of novel analogues designed to probe the hydrophobic pocket of the protozoan Hsp90 orthologue, specifically through the auspices of functionalization of an amine embedded into the scaffold

Keikipukalides, Furanocembrane Diterpenes from the Antarctic Deep Sea Octocoral <i>Plumarella delicatissima</i>

During a 2013 cruise in the Southern Ocean we collected specimens of the octocoral <i>Plumarella delicatissima</i> between 800 and 950 m depth. Five new furanocembranoid diterpenes, keikipukalides A–E (<b>1</b>–<b>5</b>), the known diterpene pukalide aldehyde (<b>6</b>), and the known norditerpenoid ineleganolide (<b>7</b>) were isolated from the coral. These <i>Plumarella</i> terpenes lack mammalian cytotoxicity, while <b>2</b>–<b>7</b> display activity against <i>Leishmania donovani</i> between 1.9 and 12 μM. Structure elucidation was facilitated by one- and two-dimensional NMR spectroscopy and mass spectrometry, and keikipukalides A and E were confirmed by X-ray crystallography