Access to 2,6-disubstituted piperidines: control of the diastereoselectivity, scope, and limitations. Applications to the stereoselective synthesis of (-)-solenopsine A and alkaloid (+)-241D.

Scope and limitations in the diastereoselective preparation of 2,6-cis or 2,6-trans disubstituted piperidines are described, through intramolecular reaction of chiral ß'-carbamate-α,ß-unsaturated ketone. This methodology has been applied to the total synthesis of a few well chosen examples, such as (-)-solenopsine A and alkaloid (+)-241D.

Efficient synthesis of ß'-amino-α,ß-unsaturated ketones.

A general and simple procedure to access chiral ß'-amino-α,ß-enones, in seven steps, from an α,ß unsaturated ester has been described. The use of a Horner-Wadsworth-Emmons reaction as a key step for generating the ß'-amino-α,ß-enones, permits access to a range of substrates under mild conditions and in moderate to high yield.

Identification, Characterization, and Optimization of 2,8-Disubstituted-1,5-naphthyridines as Novel Plasmodium falciparum Phosphatidylinositol-4-kinase Inhibitors with in Vivo Efficacy in a Humanized Mouse Model of Malaria.

A novel 2,8-disubstituted-1,5-naphthyridine hit compound stemming from the open access Medicines for Malaria Venture Pathogen Box formed a basis for a hit-to-lead medicinal chemistry program. Structure-activity relationship investigations resulted in compounds with potent antiplasmodial activity against both chloroquine sensitive (NF54) and multidrug resistant (K1) strains of the human malaria parasite Plasmodium falciparum. In the humanized P. falciparum mouse efficacy model, one of the frontrunner compounds showed in vivo efficacy at an oral dose of 4 × 50 mg·kg-1. In vitro mode-of-action studies revealed Plasmodium falciparum phosphatidylinositol-4-kinase as the target.