Boronic acids

Boronic acid-based b-lactamase inhibitors were first reported in 1978 [1], and these were gradually improved to mimic the structures of the natural b-lactamase substrates [2]. A patent involving boronic acid inhibitors designed to structurally mimic the penicillin side chain was filed in 2007 [3].The chemical complexity of boronic acids has gradually increased, as shown in Figure 1 [4].

Figure 1. Chemical structure of recent boronic acids.

Initial studies showed that sulfonamide boronic acid inhibitors can reduce the MIC of ceftazidime by 4- to 16-fold against b-lactamase producing Gram-negative strains, including P. aeruginosa [5]. Further refinement using a fragment-based approach led to the tetrazole shown, which can lower MICs in AmpC-overproducing E. coli by as much as 256-fold and shows efficacy in a murine model [6]. Last, a library of triazole-substituted boronic acids was generated using a ‘click chemistry’ approach and selected boronic acids were shown to have ability to inhibit class A and class C b-lactamases, including the KPC-2 carbapenemase, and to display synergy with ampicillin against several strains of b-lactamase producing E. coli [7].

The cyclic boronates (i.e., 1,5,2-dioxaborepane-2-ols) were shown to lower the MIC of tigemonam against class A ESBLs as well as C- and D-producing strains of E. coli and K. pneumoniae [8].


1. Kiener PA, Waley SG. "Reversible inhibitors of penicillinases". Biochem. J. 169: 197-204, 1978.

2. Ness S, Martin R, Kindler AM, et al. "Structure-based design guides the improved efficacy of deacylation transition state analogue inhibitors of TEM-1 beta-lactamase". Biochemistry 39: 5312-21, 2000.

3. Shoichet BK, Prati F. "alpha-boronated N-acyl-3-aminomethylbenzoates and N-benzylamides as beta-lactamase inhibitors active in nanomolar concentrations". US7271186; 2007.

4. Burns CJ, Jackson RW, Goswami R, Xu H. "Preparation of alpha-aminoboronic acids as beta-lactamase inhibitors". US20100120715; 2010.

5. Eidam O, Romagnoli C, Caselli E, et al. "Design, synthesis, crystal structures, and antimicrobial activity of sulfonamide boronic acids as beta-lactamase inhibitors". J. Med. Chem. 53: 7852-63, 2010.

6. Eidam O, Romagnoli C, Dalmasso G, et al. "Fragment-guided design of subnanomolar beta-lactamase inhibitors active in vivo". Proc. Natl. Acad. Sci. USA 109: 17448-53, 2012.

7. Prati F, Caselli E. "Boronic acid inhibitors of beta-lactamases as therapeutic agents in treatment of antibiotic-resistant infection diseases". WO2013053372; 2013.

6. Reddy R, Boyer S, Totrov M, Hecker S. "Heterocyclic boronic acid ester derivatives and therapeutic uses thereof". WO2013033461; 2013.



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