ABSTRACT
Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-ß-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential ß-lactamase stable ß-lactam mimics. Subsequent structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL-carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.
Subject(s)
beta-Lactamase Inhibitors/pharmacology , beta-Lactams/metabolism , Animals , Gram-Negative Bacteria/drug effects , Humans , Mice , Microbial Sensitivity Tests , Protein Binding , Structure-Activity Relationship , beta-Lactamase Inhibitors/chemistry , beta-Lactamase Inhibitors/metabolismABSTRACT
Investigation of the trans-fluorine effect on the hydrolysis rate of diethyl 2-fluorocyclopropane-1,1-dicarboxylate provides synthetic access to both diastereomers of the fluorocyclopropyl analog of cabozantinib, a c-Met and VEGFR-2 inhibitor used as a first-line treatment for thyroid cancer and as a second-line treatment for renal cell carcinoma. Despite some known potent examples, there are only a few drug molecules that contain fluorocyclopropane moieties. Herein, we present a case study in which the monofluoro analog of a known cyclopropane-containing drug molecule displays an improved in vitro profile compared to the parent nonfluorinated structure. The fluorocyclopropane moiety may offer valuable fine-tuning options for lead optimization in drug discovery.
ABSTRACT
An eight-step stereodivergent synthesis of enantiomerically pure (-)-14-epi-pseudotabersonine and (+)-pseudotabersonine has been developed from a common N-tert-butanesulfinyl ketimine key intermediate.
ABSTRACT
Hydroxymethylation of cyclic tert-butanesulfinylketimine-derived lithium enamides with methoxymethanol proceeds with excellent diastereoselectivity (99:1 dr). Methoxymethanol is a stable and easy-to-handle source of anhydrous monomeric formaldehyde in the reaction with lithium enamides. Cyclic α-hydroxymethyl ketimines undergo highly diastereoselective reduction to syn- or anti-1,3-amino alcohols.