ABSTRACT
The emergence and worldwide prevalence of New Delhi metallo-ß-lactamase 1 (NDM-1) expressing Gram-negative bacteria with resistance against most ß-lactam antibiotics pose a serious threat to human health. However, no NDM-1 inhibitors are clinically approved at present. Herein, based on the lead compound captopril, a series of compounds were designed, synthesized, and evaluated for NDM-1 inhibitory activities. All designed compounds showed single digit micromolar or submicromolar NDM-1 inhibitory activities, which were much more potent than that of captopril. Among them, compounds 14a and 14m exhibited excellent NDM-1 inhibitory activities, with IC50 values of 0.10 and 0.12 µM, respectively. Further studies demonstrated that compound 14m displayed low cytotoxicity, good water solubility, high metabolic stability, and low acute toxicity in mice. Importantly, compound 14m exhibited potent synergistic antimicrobial activities with Meropenem (MEM) for the treatment of clinically isolated NDM-1-expressing strains.
Subject(s)
Amides/chemistry , Amides/pharmacology , Anti-Bacterial Agents/pharmacology , Gram-Negative Bacteria/drug effects , beta-Lactamase Inhibitors/pharmacology , beta-Lactamases/metabolism , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/toxicity , Captopril/chemistry , Captopril/pharmacology , Cell Line , Cell Survival/drug effects , Crystallography, X-Ray , Female , Gram-Negative Bacteria/enzymology , HEK293 Cells , Humans , Inhibitory Concentration 50 , Meropenem/pharmacology , Mice , Mice, Inbred ICR , beta-Lactamase Inhibitors/chemical synthesis , beta-Lactamase Inhibitors/toxicityABSTRACT
An efficient and mild zinc-mediated decarboxylative alkylation of gem-difluoroalkenes with N-hydroxyphthalimide (NHP) esters, to give monofluoroalkenes in moderate to excellent yields with high Z-selectivity is reported. The reaction tolerates a broad range of functional groups and can be easily scaled up, which thus may pave the way for its further applications in medicinal chemistry and materials science.
