Enantioselective Synthesis and Profiling of Two Novel Diazabicyclooctanone β-Lactamase Inhibitors

Abstract

ABSTRACT:The enantioselective synthesis of two novel cyclopropane-fused diazabicyclooctanones is reported here. Starting from butadiene monoxide, the key enone intermediate 7 was prepared in six steps. Subsequent stereoselective introduction of the cyclopropane group and further transformation led to compounds 1a and 1b as their corresponding sodium salt. The great disparity regarding their hydrolytic stability was rationalized by the steric interaction between the cyclopropyl methylene and urea carbonyl. These two novel β-lactamase inhibitors were active against class A, C, and D enzymes. KEYWORDS: β-lactamase inhibitor, asymmetric synthesis, hydrolytic stability S ince the discovery of penicillin in the 1920s, β-lactam antibiotics have become one of the most important groups of antibiotics. The worldwide usage of these antibiotics has rapidly led to the development of bacterial resistance, mainly by the production and evolution of β-lactamases, which are enzymes responsible for efficiently catalyzing the hydrolysis of the β-lactam warheads. According to the Ambler classification, 1−3 β-lactamases are divided into four subfamilies: class A, C, and D enzymes have a key serine residue in the active site, whereas class B enzymes (also called metallo-β-lactamases) employ either one or two zinc ions.The combination use of several mechanism-based β-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) with β-lactam antibiotics is currently one of the most successful strategies in combating such resistance, 4−6 as evident by the wide clinical application of products such as Augmentin, Timentin, Unasyn, Sulperazone, and Zosyn. However, these β-lactamase inhibitors only have activity against class A β-lactamases and weak or no activity against class C and D enzymes. 4 In addition, β-lactamases are rapidly evolving, as evident by the rising number of new β-lactamases reported each year (over 1400 to date). 7 Therefore, this urgent medical need calls for firm commitment to the discovery and development of novel and more efficient inhibitors with broader coverage of β-lactamases.Recently a novel series of β-lactamase inhibitors based on the diazabicyclooctanone (DBO) scaffold was reported. This letter describes our efforts toward the enantioselective synthesis of two new cyclopropane-fused diazabicyclooctanones 1a and 1b aiming to explore whether the introduction of additional ring strain can lead to higher reactivity of the urea carbonyl and broader β-lactamase coverage, while hoping to maintain sufficient hydrolytic stability.

Synthesis of Avibactam Derivatives and Activity on β‐Lactamases and Peptidoglycan Biosynthesis Enzymes of Mycobacteria

“…Reduction of the methyl ester affords alcohol 8 , which is then protected by a silyl group to obtain compound 9 . The bicyclic urea ring of 10 is formed in the presence of triphosgene . Final modification steps of the side‐chain lead to the formation of precursor 13 by deprotection and activation of the alcohol, and addition of sodium azide.…”

The Road to Avibactam: The First Clinically Useful Non-β-Lactam Working Somewhat Like a β-Lactam

“…Notably, NXL-105, which belongs to a tricyclic series, exhibits activity against P. aeruginosa, which is likely due to PBP inhibition [133]. Further, some new DBO analogues [22,141,142], such as FPI-1602 (Fedora) (Figure 9), are reported to possess PBP inhibitory activity, in addition to serine β-lactamase inhibitory activity against class A and some class D enzymes [22].…”

Synthesis of pyrrolidine-based hamamelitannin analogues as quorum sensing inhibitors in Staphylococcus aureus

“…It was essential to introduce the nosyl group only in the last step, since several previous attempts to synthesize 9 failed due to side reactions caused by the strongly electron-withdrawing properties of the nosyl group. The successful synthesis starts with a Pd-catalyzed dynamic kinetic asymmetric transformation of racemic butadiene monoepoxide to 12 , employing phthalimide as nucleophile [ 22 – 23 ]. Attempts to substitute the alcohol functionality of 12 via displacement of the derived mesylate with NaN 3 failed, similar to previously reported difficulties by Trost et al [ 24 ].…”