Kronopolitides A–F, a Family of 36-Membered Polyol Macrolides with Antiparasitic Activity against Chagas Disease

Six new 36-membered polyol macrolides, kronopolitides A-F (<b>1</b>-<b>6</b>), active against <i>Trypanosoma cruzi</i> were isolated by bioassay-guided fractionation from an extract of the strain <i>Streptomyces kronopolitis</i> CA-143054. Kronopolitides were identified from the screening of microbial natural products libraries using a high-throughput parasite cell-based phenotypic imaging platform targeting identification of new bioactive compounds against the parasites <i>Leishmania donovani</i> and <i>Trypanosoma cruzi</i>. The planar structures were determined using a combination of 1D and 2D NMR data and HRMS. The relative and absolute configuration of their chiral centers was established using a combination of NMR spectroscopy (NOE analysis and coupling constants), the Kishi's universal NMR database, <i>J</i>-based configuration analysis (JBCA), and comparison with NMR data of structurally related macrolides. Genome sequence mining and bioinformatic analysis of their biosynthetic gene cluster (BGC) have shed light on the polyketide biosynthesis and post-PKS (polyketide synthase) modifications. Kronopolitides have shown potent antiparasitic activity against <i>T</i>. <i>cruzi</i> (IC₅₀ = 0.10-1.49 μM) and moderate to low activity against <i>L</i>. <i>donovani</i> (IC₅₀ = 0.84-9.25 μM) with kronopolitide A being the most potent compound. The presence of a glycosylated 2-methyl-1,4-naphthoquinone/2-methyl-1,4-dihydroxynaphthalene moiety seems to be a key structural element in the biological activity displayed by the compounds.