Short Total Synthesis of (+)-Colletotryptins B-D and Mucronatin B Derivative.

The short and first total synthesis of (+)-colletotryptins B-D, ent-colletotryptin A, and diastereomer of mucronatin B, which are a group of natural 3-(indol-2-yl)-3-(indol-3-yl)-1,2-propanediol (IIPDO) analogues containing two stereogenic centers at the C8' and C9' positions, isolated from endophytic fungus Colletotrichum sp. SC1355 and Tetrapterys mucronata, respectively, has been successfully accomplished in two and three steps with overall yields ranging from 28 to 54%. Key features of this synthesis include an innovative Bi(OTf)3-catalyzed stereoselective transindolylation of (S)-3,3'-di(1H-indol-3-yl)propane-1,2-diol. The operational simplicity, environmentally friendly catalyst, and broad functional group tolerance of this modular strategy render it suitable for adoption in both academic and industrial settings.

Discovery of New and Potent InhA Inhibitors as Antituberculosis Agents: Structure-Based Virtual Screening Validated by Biological Assays and X-ray Crystallography.

The enoyl-acyl carrier protein reductase InhA of Mycobacterium tuberculosis is an attractive, validated target for antituberculosis drug development. Moreover, direct inhibitors of InhA remain effective against InhA variants with mutations associated with isoniazid resistance, offering the potential for activity against MDR isolates. Here, structure-based virtual screening supported by biological assays was applied to identify novel InhA inhibitors as potential antituberculosis agents. High-speed Glide SP docking was initially performed against two conformations of InhA differing in the orientation of the active site Tyr158. The resulting hits were filtered for drug-likeness based on Lipinski's rule and avoidance of PAINS-like properties and finally subjected to Glide XP docking to improve accuracy. Sixteen compounds were identified and selected for in vitro biological assays, of which two (compounds 1 and 7) showed MIC of 12.5 and 25 µg/mL against M. tuberculosis H37Rv, respectively. Inhibition assays against purified recombinant InhA determined IC50 values for these compounds of 0.38 and 0.22 µM, respectively. A crystal structure of the most potent compound, compound 7, bound to InhA revealed the inhibitor to occupy a hydrophobic pocket implicated in binding the aliphatic portions of InhA substrates but distant from the NADH cofactor, i.e., in a site distinct from those occupied by the great majority of known InhA inhibitors. This compound provides an attractive starting template for ligand optimization aimed at discovery of new and effective compounds against M. tuberculosis that act by targeting InhA.

Stereospecific synthesis of 1,2-cis glycosides by vinyl-mediated IAD.

[reaction: see text] Stereospecific 1,2-cis glycosylation of 2-O-vinyl thioglycosides, synthesized from the corresponding alcohols by Ir-catalyzed transvinylation with vinyl acetate, is achieved by iodine-mediated tethering of a range of primary and secondary carbohydrate acceptors, followed by intramolecular aglycon delivery (IAD). The use of such an intramolecular glycosylation strategy furnishes the desired alpha-gluco and beta-manno disaccharides in an entirely stereoselective manner.