Synthesis and SAR of novel benzoxaboroles as a new class of β-lactamase inhibitors

Xia, Yi; Cao, Kathy; Zhou, Yasheen; Alley, M.R.K.; Rock, Fernando; Mohan, Manisha; Meewan, Maliwan; Baker, Stephen J.; Lux, Sarah; Ding, Charles Z.; Jia, Guofeng; Kully, Maureen; Plattner, Jacob J.

doi:10.1016/j.bmcl.2011.02.024

Cited by 70 publications

(71 citation statements)

References 10 publications

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“…As revealed by a crystal structure of the CTX-M-15-avibactam complex [161], the nitrogen of the N-sulfate group of the ring opened avibactam and a [149], 10.2, 10.3 [150], 10.4 [148], 10.5 [151], 10.6 [152], 10.7 [148] and 10.8 [153]). (B) Examples of 'new' β-lactam scaffolds also show promise, but they have not been commercially developed (AM-112 (10.9) [154] and LK-157 (10.10) [155]).…”

Section: Avibactam Mode Of Actionmentioning

confidence: 99%

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

et al. 2016

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Avibactam, which is the first non-β-lactam β-lactamase inhibitor to be introduced for clinical use, is a broad-spectrum serine β-lactamase inhibitor with activity against class A, class C, and, some, class D β-lactamases. We provide an overview of efforts, which extend to the period soon after the discovery of the penicillins, to develop clinically useful non-β-lactam compounds as antibacterials, and, subsequently, penicillin-binding protein and β-lactamase inhibitors. Like the β-lactam inhibitors, avibactam works via a mechanism involving covalent modification of a catalytically important nucleophilic serine residue. However, unlike the β-lactam inhibitors, avibactam reacts reversibly with its β-lactamase targets. We discuss chemical factors that may account for the apparently special nature of β-lactams and related compounds as antibacterials and β-lactamase inhibitors, including with respect to resistance. Avenues for future research including non-β-lactam antibacterials acting similarly to β-lactams are discussed.

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Section: Avibactam Mode Of Actionmentioning

confidence: 99%

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

et al. 2016

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“…used two recent publications as starting points to come up with 2‐(1‐hydroxy‐6‐phenoxy‐1,3‐dihydrobenzo[ c ][1,2]oxaborol‐3‐yl)acetic acid ( 59 ) as an initial scaffold (Figure 41). 185, 186 An SAR study revealed the importance of the carboxylic acid and ether substituents. While the phenyloxy‐substituted analogue showed slightly higher affinity against a panel of representative β‐lactamases, the pyrazine analogues were synthetically less challenging and were therefore preferred for further optimization studies.…”

Section: β‐Lactamase Inhibitorsmentioning

confidence: 99%

Targeting Antibiotic Resistance

2016

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Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human‐pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last‐resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.

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“…The highly electrophilic nature of the boron component of these compounds leads to interaction with a variety of protein targets via reversible covalent bonds1314, with identified targets including leucyl-tRNA synthetase (LeuRS)67, phosphodiesterase 4 (PDE4)1516 and β-lactamase17. Tavaborole, the first benzoxaborole to receive FDA approval, is an inhibitor of fungal LeuRS that is used to treat onychomycosis18.…”

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confidence: 99%

A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue

et al. 2017

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Benzoxaboroles are effective against bacterial, fungal and protozoan pathogens. We report potent activity of the benzoxaborole AN3661 against Plasmodium falciparum laboratory-adapted strains (mean IC50 32 nM), Ugandan field isolates (mean ex vivo IC50 64 nM), and murine P. berghei and P. falciparum infections (day 4 ED90 0.34 and 0.57 mg kg−1, respectively). Multiple P. falciparum lines selected in vitro for resistance to AN3661 harboured point mutations in pfcpsf3, which encodes a homologue of mammalian cleavage and polyadenylation specificity factor subunit 3 (CPSF-73 or CPSF3). CRISPR-Cas9-mediated introduction of pfcpsf3 mutations into parental lines recapitulated AN3661 resistance. PfCPSF3 homology models placed these mutations in the active site, where AN3661 is predicted to bind. Transcripts for three trophozoite-expressed genes were lost in AN3661-treated trophozoites, which was not observed in parasites selected or engineered for AN3661 resistance. Our results identify the pre-mRNA processing factor PfCPSF3 as a promising antimalarial drug target.

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Synthesis and SAR of novel benzoxaboroles as a new class of β-lactamase inhibitors

Cited by 70 publications

References 10 publications

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

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

Targeting Antibiotic Resistance

A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue

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