ACS Medicinal Chemistry Letters
Letter
(
8) Stachyra, T.; Pechereau, M. C.; Bruneau, J. M.; Claudon, M.;
Table 1. Enzyme Inhibition against Different Classes of β-
Lactamases
̀
Frere, J. M.; Miossec, C.; Coleman, K.; Black, M. T. Mechanistic
studies of the inactivation of TEM-1 and P99 by NXL104, a novel
non-β-lactam β-lactamase inhibitor. Antimicrob. Agents Chemother.
2010, 54, 5132.
class C IC50
(μM)
class D IC50
class A IC50 (μM)
(μM)
CTX-M-15
KPC-2
AmpC
OXA-48
(9) Livermore, D. M.; Mushtaq, S.; Warner, M.; Zhang, J.; Maharjan,
S.; Doumith, M.; Woodford, N. Activity of NXL104 in combination
with β-lactams against genetically characterized Escherichia coli and
Klebsiella pneumoniae isolates producing class A extended-spectrum β-
lactamases and class C β-lactamases. Antimicrob. Agents Chemother.
compound
K. pneumoniae
E. cloacae P. aeruginosa K. pneumoniae
Tazobactam
<0.007
0.14
39
3.4
4.5
2.0
3.6
1.3
28
1
1
a
0.85
6.7
b
0.48
2
011, 55, 390.
10) Coleman, K. Diazabicyclooctanes (DBOs): a potent new class of
(
non-β-lactam β-lactamase inhibitors. Curr. Opin. Microbiol. 2011, 14,
design the next generation of DBO-based β-lactamase
inhibitors. The increased hydrolytic stability for those new
inhibitors will also represent an advantage in terms of
formulation development and manufacturing.
In summary, the enantioselective synthesis of two novel
tricyclic DBO analogues was accomplished in 17 linear steps
550 and references therein..
(11) Bonnefoy, A.; Dupuis-Hamelin, C.; Steier, V.; Delachaume, C.;
Seys, C.; Stachyra, T.; Fairley, M.; Guitton, M.; Lampilas, M. In vitro
activity of AVE1330A, an innovative broad-spectrum non-β-lactam β-
lactamase inhibitor. J. Antimicrob. Chemother. 2004, 54, 410.
(12) Boyd, J. A.; Cherryman, J. H.; Golden, M.; Kalyan, Y. B.;
Lawton, G. R.; Milne, D.; Phillips, A. J.; Racha, S.; Ronsheim, M. S.;
Telford, A. Process for preparing heterocyclic compounds including
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxa-
mide and salts thereof. Patent WO2012172368, 2012.
(13) Ehmann, D. E.; Jahic, H.; Ross, P. L.; Gu, R. F.; Hu, J.; Kern, G.;
Walkup, G. K.; Fisher, S. L. Avibactam is a covalent, reversible, non-β-
lactam β-lactamase inhibitor. Proc. Natl. Acad. Sci. U.S.A. 2012, 109,
(
1.8% and 0.6% overall yield, respectively). Compound 1b has
demonstrated excellent aqueous stability at physiological pH,
demonstrating the fundamental differences between ring strain
and stability. Additionally, the biochemical data presented
herein further illustrates the lack of direct correlation between
reactivity and enzymatic activity for covalent inhibitors.
Additional SAR exploration will be required to better
understand the stability and improve the enzymatic activity of
this exciting new class of β-lactamase inhibitors.
1
(
1663.
14) Mangion, I. K.; Ruck, R. T.; Rivera, N.; Huffman, M. A.; Shevlin,
M. A concise synthesis of a β-lactamase inhibitor. Org. Lett. 2011, 13,
480.
15) Miller, S. P.; Zhong, Y.-L.; Liu, Z.; Simeone, M.; Yasuda, N.;
5
(
ASSOCIATED CONTENT
Supporting Information
Representative assay protocols, experimental procedures, and
■
Limanto, J.; Chen, Z.; Lynch, J.; Capodanno, V. Practical and cost-
effective manufacturing route for the synthesis of a β-lactamase
inhibitor. Org. Lett. 2014, 16, 174.
(16) Blizzard, T. A.; Chen, H.; Kim, S.; Wu, J.; Bodner, R.; Gude, C.;
Imbriglio, J.; Young, K.; Park, Y.-W.; Ogawa, A.; Raghoobar, S.;
Hairston, N.; Painter, R. E.; Wisniewski, D.; Fitzgerald, P.; Sharma, N.;
Lu, J.; Ha, S.; Hermes, J.; Hammond, M. L. Discovery of MK-7655, a
β-lactamase inhibitor for combination with Primaxin. Bioorg. Med.
Chem. Lett. 2014, 24, 780.
*
S
AUTHOR INFORMATION
Corresponding Author
■
(17) Trost, B. M.; Horne, D. B.; Woltering, M. J. Palladium-catalyzed
DYKAT of vinyl epoxides: enantioselective total synthesis and
assignment of the configuration of (+)-Broussonetine G. Angew.
Chem., Int. Ed. 2003, 42, 5987.
(18) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
Efficient and recyclable monomeric and dendritic Ru-based metathesis
catalysts. J. Am. Chem. Soc. 2000, 122, 8168.
Notes
The authors declare the following competing financial
interest(s): The authors are all current or former employees
of AstraZeneca and may possess AstraZeneca stock.
ACKNOWLEDGMENTS
(19) Gemal, A. L.; Luche, J. L. Lanthanoids in organic synthesis. 6.
Reduction of alpha-enones by sodium borohydride in the presence of
lanthanoid chlorides: synthetic and mechanistic aspects. J. Am. Chem.
Soc. 1981, 103, 5454.
■
We thank Nancy DeGrace for assistance with the NMR
experiments, Lise Gauthier for the RP-HPLC purification, Ying
Liu for the HRMS studies, and Tiffany Palmer for generating
the β-lactamase inhibition data.
(
20) Denmark, S. E.; Edwards, J. P. A comparison of (chloromethyl)-
and (iodomethyl)zinc cyclopropanation reagents. J. Org. Chem. 1991,
6, 6974.
21) Grieco, P. A.; Hon, Y. S.; Perez-Medrano, A. Convergent,
5
(
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dx.doi.org/10.1021/ml500284k | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX