Design and enantioselective synthesis of 3-(α-acrylic acid) benzoxaboroles to combat carbapenemase resistance

Abstract

An organocatalytic MBH cascade reaction was developed to construct new 3-(α-acrylic acid) benzoxaboroles, designed to mimic ‘anchoring’ pharmacophore features of carbapenems, with the aim of helping overcome carbapenemase resistance.

Structure and Mechanism-Guided Design of Dual Serine/Metallo-Carbapenemase Inhibitors

“…The horizontal transfer of plasmid-mediated resistance determinants has become a severe threat to the clinical efficacy of antibiotics, in hospital and community settings, triggering the onset of a worldwide antimicrobial resistance crisis. ,, Among them, subclass B1 MβLs including the clinically important NDM-, IMP-, and VIM-type variants and class A KPC-type and class D OXA-type serine carbapenemases are mostly encoded on plasmids in clinical isolates of Acinetobacter spp ., Pseudomonas spp., and Enterobacteriaceae , giving rise to the emergence and spread of MDR Gram-negative pathogens, which threaten the ability to effectively treat hospital-acquired infections. − Global antibiotic resistance has reached critical levels, with major bacterial pathogens, including Gram-negative organisms such as A. baumannii , P. aeruginosa , E. coli , and K. pneumoniae , quickly evolving toward pan-drug-resistant phenotypes. , There is an urgent medical need for strategies that address this carbapenem resistance. , …”

A Practical and Scalable Preparation of Lusianthridin

“…5-(Benzyloxy)-2-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde was prepared according to the literature. 25…”

Targeting Metalloenzymes by Boron-Containing Metal-Binding Pharmacophores

“…110 Since such benzoxaborole compounds do not have corresponding negatively charged features to interact with the positively charged residue in the MBL active site, which is important for recognition of β-lactam antibiotics, we designed a series of C3-acrylic acid substituted benzoxaboroles by mimicking carbapenem antibiotics. 111 Meanwhile, in order to obtain the optical isomers, we presented an asymmetric Morita−Baylis−Hillman (MBH) cascade reaction and synthesized a series of optical C3 acrylic acid substituted benzoxaboroles. 111 Some of these compounds (e.g., 75 and 76) showed nanomolar inhibitory activities to KPC-2 SBL and micromolar inhibitory activity toward various class B1MBLs (Figure 28), providing a new starting point to develop benzoxaborole-based MBL inhibitors.…”

“…111 Meanwhile, in order to obtain the optical isomers, we presented an asymmetric Morita−Baylis−Hillman (MBH) cascade reaction and synthesized a series of optical C3 acrylic acid substituted benzoxaboroles. 111 Some of these compounds (e.g., 75 and 76) showed nanomolar inhibitory activities to KPC-2 SBL and micromolar inhibitory activity toward various class B1MBLs (Figure 28), providing a new starting point to develop benzoxaborole-based MBL inhibitors.…”

“…Recently, our group disclosed a series of 3-aryl substituted benzoxaborole derivatives ( e.g ., 73 and 74 ) as dual SBL and MBL inhibitors (Figure ). Since such benzoxaborole compounds do not have corresponding negatively charged features to interact with the positively charged residue in the MBL active site, which is important for recognition of β-lactam antibiotics, we designed a series of C3-acrylic acid substituted benzoxaboroles by mimicking carbapenem antibiotics . Meanwhile, in order to obtain the optical isomers, we presented an asymmetric Morita–Baylis–Hillman (MBH) cascade reaction and synthesized a series of optical C3 acrylic acid substituted benzoxaboroles .…”