Modifications of the C6-substituent of penicillin sulfones with the goal of improving inhibitor recognition and efficacy

Micheal Nottingham, Christopher R. Bethel, Sundar Ram Reddy Pagadala, Emily Harry, Abishai Pinto, Zachary A. Lemons, Sarah M. Drawz, Focco Van Den Akker, Paul R. Carey, Robert A. Bonomo, John D. Buynak

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20 Scopus citations


In order to evaluate the importance of a hydrogen-bond donating substituent in the design of β-lactamase inhibitors, a series of C6-substituted penicillin sulfones, lacking a C2′ substituent, and having an sp 3 hybridized C6, was prepared and evaluated against a representative classes A and C β-lactamases. It was found that a C6 hydrogen-bond donor is necessary for good inhibitory activity, but that this feature alone is not sufficient in this series of C6β-substituted penicillin sulfones. Other factors which may impact the potency of the inhibitor include the steric bulk of the C6 substituent (e.g., methicillin sulfone) which may hinder recognition in the class A β-lactamases, and also high similarity to the natural substrates (e.g., penicillin G sulfone) which may render the prospective inhibitor a good substrate of both classes of enzyme. The best inhibitors had non-directional hydrogen-bonding substituents, such as hydroxymethyl, which may allow sufficient conformational flexibility of the acyl-enzyme for abstraction of the C6 proton by E166 (class A), thus promoting isomerization to the β-aminoacrylate as a stabilized acyl-enzyme.

Original languageEnglish (US)
Pages (from-to)387-393
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Issue number1
StatePublished - Jan 1 2011
Externally publishedYes

Bibliographical note

Funding Information:
J.D.B. was supported by the Robert A. Welch Foundation (Grant N-0871 ). R.A.B. was supported by the Veterans Affairs Merit Review Program, GRECC , and the NIH ( R01 AI063517-01 ). F.v.d.A. was supported by NIH ( R01 AI062968 ). P.R.C. was supported by NIH ( R01 GM54072 ).


  • Antibiotic
  • Inhibitor
  • Penicillin
  • β-Lactamase


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