The design and identification of brain penetrant inhibitors of phosphoinositide 3-kinase α.

Inhibition of phosphoinositide 3-kinase (PI3K) signaling through PI3Kα has received significant attention for its potential in cancer therapy. While the PI3K pathway is a well-established and widely pursued target for the treatment of many cancer types due to the high frequency of abnormal PI3K signaling, glioblastoma multiforme (GBM) is particularly relevant because the pathway is implicated in more than 80% of GBM cases. Herein, we report the identification of PI3K inhibitors designed to cross the blood-brain barrier (BBB) to engage their target where GBM tumors reside.

Rapid synthesis of 1,3,5-substituted 1,2,4-triazoles from carboxylic acids, amidines, and hydrazines.

A general method for the synthesis of 1,3,5-trisubstituted 1,2,4-triazoles has been developed from reaction of carboxylic acids, primary amidines, and monosubstituted hydrazines. This highly regioselective and one-pot process provides rapid access to highly diverse triazoles.

Exploring the positional attachment of glycopeptide/beta-lactam heterodimers.

Further investigations towards novel glycopeptide/beta-lactam heterodimers are reported. Employing a multivalent approach to drug discovery, vancomycin and cephalosporin synthons, 4, 2, 5 and 10, 18, 25 respectively, were chemically linked to yield heterodimer antibiotics. These novel compounds were designed to inhibit Gram-positive bacterial cell wall biosynthesis by simultaneously targeting the principal cellular targets of both glycopeptides and beta-lactams.

Hydrophobic vancomycin derivatives with improved ADME properties: discovery of telavancin (TD-6424).

Novel derivatives of N-decylaminoethylvancomycin (2), containing appended hydrophilic groups were synthesized and their antibacterial activity and ADME properties were evaluated. The compounds were prepared by reacting amines with the C-terminus (C-) of 2 using PyBOP mediated amide formation, or with the resorcinol-like (R-) position of 2 using a Mannich aminomethylation reaction. These analogs retained the antibacterial activity of 2 against methicillin-resistant staphylococci and vancomycin-resistant enterococci.