Diazabicyclooctane Functionalization for Inhibition of β-Lactamases from Enterobacteria

Abstract

Second-generation-lactamase inhibitors containing a dia abic clooctane (DBO) scaffold restore the activit of-lactams against pathogenic bacteria, including those producing class A, C, and D en mes that are not susceptible to first-generation inhibitors containing a-lactam ring. Here, e report optimi ation of a s nthetic route to access tria olecontaining DBOs and biological evaluation of a series of 17 compounds for inhibition of five-lactamases representative of en mes found in pathogenic Gram-negative bacteria. A strong correlation (Spearman coefficient of 0.87; = 4.7 10-21) as observed bet een the inhibition efficac of purified-lactamases and the potentiation of-lactam antibacterial activit indicating that DBO functionali ation did not impair penetration. In comparison to reference DBOs, avibactam and relebactam, our compounds displa ed reduced efficac likel due to the absence of h drogen bonding ith a conserved asparagine residue at position 132. This as partiall compensated b additional interactions involving certain tria ole substituents.

Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

“…The alcohol is then activated with mesylchloride, and the thus formed intermediate is substituted with azide to form 36. The azido derivative 36 undergoes copper(I)-catalyzed Huisgen-Sharpless cycloaddition with the appropriate alkynes to form the corresponding triazoles 37, which can be transformed into corresponding sulfates 38 by reducing the benzyl ethers and subsequent sulfation followed by ion exchange chromatography [72] (Scheme 8). Triazole functionalized DBOs: Unsubstituted and several triazole ring-substituted DBO derivatives (Scheme 8) were synthesized for inhibition against TEM-1, KPC-2, CTX-M-15, AmpC, and OXA-48 BLAs in vitro.…”

“…The unsubstituted triazole derivatives proved to be less effective compared to the substituted ones and the reference compounds, avibactam and relebactam. Of the substituted derivatives, the pyridyl-and phenyl-substituted derivatives showed significant inhibition against KPC-2 carbapenemase and the CTX-M-15 extended-spectrum β-lactamase [72]. The synthesis of the triazole function at the C2 position of the DBO scaffold required the azide derivative 36, which was initially synthesized in 12 steps starting from the oxopyrrolidine [73].…”

1,3‐Diazepine: A privileged scaffold in medicinal chemistry

“…Other DBO derivatives differing either by the nature of substituents at position 5 (e.g., introduction of nitrile 134 or triazole 137 groups) or by the presence of a supplementary ring fused to the DBO moiety, such as compounds NXL105 or ETX0462 (Figure 18), have also been described 138 …”

Azetidinimines as a novel series of non-covalent broad-spectrum inhibitors of β-lactamases with submicromolar activities against carbapenemases KPC-2 (class A), NDM-1 (class B) and OXA-48 (class D)

“…Since 2012 several new broad-spectrum inhibitors of class A and class C β-lactamases have emerged. Of significant interest, avibactam [9,10] and vaborbactam [11] (Figure 1b) were approved by the FDA for clinical use whilst many of their congeners, in particular diazabicyclooctanes, [12][13][14][15][16][17][18][19][20] and various boron derivatives (see below), including benzosiloxaboroles, [21] are currently undergoing preclinical or clinical development. These compounds are mainly able to efficiently inhibit SBLs, including carbapenemases, of class A, C and sometimes D, but generally do not inhibit MBLs (class B).…”