ABSTRACT
An efficient approach for the highly diastereoselective construction of functionalized cyclopenta[d][1,2]oxazines via sequential oxyamination and Pauson-Khand reaction of readily accessible propargylic alcohols has been developed. Furthermore, the ring closing metathesis of these N-O linked 1,7-enynes afforded vinylated-[1,2]oxazines in good yields. The reduction of the N-O bond of the obtained cyclopenta[d][1,2]oxazine is accomplished to access cyclopentenone-based amino alcohols.
ABSTRACT
A new series of peptidomimetic pseudo-prolyl-homophenylalanylketones were designed, synthesized and evaluated for inhibition of the Plasmodium falciparum cysteine proteases falcipain-2 (FP-2) and falcipain-3 (FP-3). In addition, the parasite killing activity of these compounds in human blood-cultured P. falciparum was examined. Of twenty-two (22) compounds synthesized, one peptidomimetic comprising a homophenylalanine-based α-hydroxyketone linked Cbz-protected hydroxyproline (39) showed the most potency (IC50 80 nM against FP-2 and 60 nM against FP-3). In silico analysis of these peptidomimetic analogs offered important protein-ligand structural insights including the role, by WaterMap, of water molecules in the active sites of these protease isoforms. The pseudo-dipeptide 39 and related compounds may serve as a promising direction forward in the design of competitive inhibitors of falcipains for the effective treatment of malaria.
