The Oklahoma Farmer and Laborer

Weekly agricultural newspaper from Sapulpa, Oklahoma that includes agricultural and union news and editorials along with advertising

Stereospecific Synthesis of 23-Hydroxyundecylprodiginines and Analogues and Conversion to Antimalarial Premarineosins via a Rieske Oxygenase Catalyzed Bicyclization

Facile and highly efficient synthetic routes for the synthesis of (<i>S</i>)- and (<i>R</i>)-23-hydroxyundecylprodiginines ((23<i>S</i>)-<b>2</b>, and (23<i>R</i>)-<b>2</b>), 23-ketoundecylprodiginine (<b>3</b>), and deuterium-labeled 23-hydroxyundecylprodiginine ([23-<i>d</i>]-<b>2</b>) have been developed. We demonstrated a novel Rieske oxygenase MarG catalyzed stereoselective bicyclization of (23<i>S</i>)-<b>2</b> to premarineosin A (<b>4</b>), a key step in the tailoring process of the biosynthesis of marineosins, using a <i>marG</i> heterologous expression system. The synthesis of various A–C-ring functionalized prodiginines <b>32</b>–<b>41</b> was achieved to investigate the substrate promiscuity of MarG. The two analogues <b>32</b> and <b>33</b> exhibit antimalarial and cytotoxic activities stronger than those of the marineosin intermediate <b>2</b>, against Plasmodium falciparum strains (CQ^S-D6, CQ^R-Dd2, and 7G8) and hepatocellular HepG2 cancer cell line, respectively. Feeding of <b>34</b>–<b>36</b> to Streptomyces venezuelae expressing <i>marG</i> led to production of novel premarineosins, paving a way for the production of marineosin analogues via a combinatorial synthetic/biosynthetic approach. This study presents the first example of oxidative bicyclization mediated by a Rieske oxygenase

Discovery, Synthesis, and Optimization of Antimalarial 4(1<i>H</i>)‑Quinolone-3-Diarylethers

The historical antimalarial compound endochin served as a structural lead for optimization. Endochin-like quinolones (ELQ) were prepared by a novel chemical route and assessed for in vitro activity against multidrug resistant strains of Plasmodium falciparum and against malaria infections in mice. Here we describe the pathway to discovery of a potent class of orally active antimalarial 4­(1<i>H</i>)-quinolone-3-diarylethers. The initial prototype, ELQ-233, exhibited low nanomolar IC₅₀ values against all tested strains including clinical isolates harboring resistance to atovaquone. ELQ-271 represented the next critical step in the iterative optimization process, as it was stable to metabolism and highly effective in vivo. Continued analoging revealed that the substitution pattern on the benzenoid ring of the quinolone core significantly influenced reactivity with the host enzyme. This finding led to the rational design of highly selective ELQs with outstanding oral efficacy against murine malaria that is superior to established antimalarials chloroquine and atovaquone