34805-17-9Relevant articles and documents
Design, synthesis, and in vitro and biological evaluation of potent amino acid-derived thiol inhibitors of the metallo-β-lactamase IMP-1
Arjomandi, Omid Khalili,Hussein, Waleed M.,Vella, Peter,Yusof, Yusralina,Sidjabat, Hanna E.,Schenk, Gerhard,McGeary, Ross P.
, p. 318 - 327 (2016/04/05)
There are currently no clinically available inhibitors of metallo-β-lactamases (MBLs). These enzymes confer resistance to bacteria against a broad range of commonly used β-lactam antibiotics, and are produced by an increasing number of bacterial pathogens. In this study, several thiol derivatives of l-amino acids were designed and synthesized, and their inhibitory effects against the metallo-β-lactamase IMP-1 (subclass B1) were investigated. The most potent compound, derived from l-tyrosine, exhibited competitive inhibition, with a Ki of 86 nM. The ability of this compound to render MBL-expressing bacteria susceptible to imipenem was examined. Reductions in MIC values up to 5.2 - fold were observed.
Formation of the 7-oxa-1,4,10-triazatricyclo[8.2.25,12]tetradecane-2,14-dione ring system: Misrouted synthesis of a peptidomimetic
Kozlowski,Bartlett
, p. 7681 - 7696 (2007/10/03)
An attempted synthesis of the tricyclic peptidomimetic 1, designed to imitate a β-turn tripeptide in tendamistat, afforded instead the 6,6,8-ring system of 2. The key step in the synthesis entailed acylation of the hindered α,α'-disubstituted morpholine 4.2, which was approached by acylative ring opening of the 3,6-oxazabicyclo[4.2.0]octane 4.3. However, transannular rather than exocyclic cleavage occurred, giving the 1,6-oxazacyclooctane isomer 4.5. Subsequent ring closures to form the bi- and tricyclic intermediates 7.3 and 8.5 were difficult because of the strain being built into the ring systems. After completion of the synthesis, the structures of the intermediates and final product were elucidated by NMR, with three-bond, heteronuclear multiple-bond correlation experiments providing unambiguous evidence for the ring connectivity, and by molecular modeling, which allowed assignment of the stereochemistry. Compound 2 is a modest inhibitor of the target enzyme α-amylase (K(i) = 170 μM in 5% DMSO/water), binding with similar affinity to the tripeptide Ac-Trp-Arg-Tyr-OMe. Although the side-chain attachment points in the ring system of 2 correspond closely to the relative Cα-positions in tendamistat (rmsd = 0.24 A), the alignment of the Cα-Cβ bonds is poor, illustrating the importance of side-chain orientation in a peptidomimetic.
