Structure-based efforts to optimize a non-ß-lactam inhibitor of AmpC ß-lactamase.

ß-Lactams are the most widely prescribed class of antibiotics, yet their efficacy is threatened by expression of ß-lactamase enzymes, which hydrolyze the defining lactam ring of these antibiotics. To overcome resistance due to ß-lactamases, inhibitors that do not resemble ß-lactams are needed. A novel, non-ß-lactam inhibitor for the class C ß-lactamase AmpC (3-[(4-chloroanilino)sulfonyl]thiophene-2-carboxylic acid; Ki 26µM) was previously identified. Based on this lead, a series of compounds with the potential to interact with residues at the edge of the active site were synthesized and tested for inhibition of AmpC. The length of the carbon chain spacer was extended by 1, 2, 3, and 4 carbons between the integral thiophene ring and the benzene ring (compounds 4, 5, 6, and 7). Compounds 4 and 6 showed minimal improvement over the lead compound (Ki 18 and 19µM, respectively), and compound 5 inhibited to the same extent as the lead. The X-ray crystal structures of AmpC in complexes with compounds 4, 5, and 6 were determined. The complexes provide insight into the structural reasons for the observed inhibition, and inform future optimization efforts in this series.

Photochemical synthesis of aldehydes in the solid phase.

A substituted anthraquinone (AQ), previously shown to photochemically generate benzaldehyde in methanol solution, was attached to a commercially available resin via an 11 carbon tether and an amide bond. Photolysis of the polymer-bound AQ with visible or 350 nm UV light resulted in the formation of benzaldehyde in yields of 50-55% as determined by HPLC. The phenolic positions in the polymer were then alkylated using benzyl bromide and 1-iodo-3-(4-nitrophenyl)propane in a coupling reaction with K(2)CO(3) as a base and a solution-phase proton shuttle. Photolysis of these alkylated polymers resulted in the formation of benzaldehyde (54-89%) and 3-(4-nitrophenyl)-propanal (58-67%). The yields of both aldehydes dropped considerably with subsequent realkylation and photolysis, and the polymer beads began to show signs of deterioration. This is the first time that aldehydes have been made photochemically on a solid-supported phase.