Total synthesis of dissectol A, using an enediolate-based Tsuji-Trost reaction.

Dissectol A is a rearranged terpene glycoside isolated from several flowering plants. Starting from glucose, the densely functionalized bicyclic structure has been prepared via site-selective oxidation and an intramolecular allylic alkylation reaction with an enediolate as the nucleophile. Despite earlier reports, dissectol A is not effective at inhibiting DevRS signaling in whole-cell Mycobacterium tuberculosis and does not inhibit growth of the bacterium.

High Target Homology Does Not Guarantee Inhibition: Aminothiazoles Emerge as Inhibitors of Plasmodium falciparum.

In this study, we identified three novel compound classes with potent activity against Plasmodium falciparum, the most dangerous human malarial parasite. Resistance of this pathogen to known drugs is increasing, and compounds with different modes of action are urgently needed. One promising drug target is the enzyme 1-deoxy-d-xylulose-5-phosphate synthase (DXPS) of the methylerythritol 4-phosphate (MEP) pathway for which we have previously identified three active compound classes against Mycobacterium tuberculosis. The close structural similarities of the active sites of the DXPS enzymes of P. falciparum and M. tuberculosis prompted investigation of their antiparasitic action, all classes display good cell-based activity. Through structure-activity relationship studies, we increased their antimalarial potency and two classes also show good metabolic stability and low toxicity against human liver cells. The most active compound 1 inhibits the growth of blood-stage P. falciparum with an IC50 of 600 nM. The results from three different methods for target validation of compound 1 suggest no engagement of DXPS. All inhibitor classes are active against chloroquine-resistant strains, confirming a new mode of action that has to be further investigated.

Potential Modulatory Microbiome Therapies for Prevention or Treatment of Inflammatory Bowel Diseases.

A disturbed interaction between the gut microbiota and the mucosal immune system plays a pivotal role in the development of inflammatory bowel disease (IBD). Various compounds that are produced by the gut microbiota, from its metabolism of diverse dietary sources, have been found to possess anti-inflammatory and anti-oxidative properties in in vitro and in vivo models relevant to IBD. These gut microbiota-derived metabolites may have similar, or more potent gut homeostasis-promoting effects compared to the widely-studied short-chain fatty acids (SCFAs). Available data suggest that mainly members of the Firmicutes are responsible for producing metabolites with the aforementioned effects, a phylum that is generally underrepresented in the microbiota of IBD patients. Further efforts aiming at characterizing such metabolites and examining their properties may help to develop novel modulatory microbiome therapies to treat or prevent IBD.