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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:21

Article

Nottingham, Micheal¹  Bethel, Christopher R.²  Pagadala, Sundar Ram Reddy¹  Harry, Emily¹  Pinto, Abishai¹  Lemons, Zachary A.¹  Drawz, Sarah M.³  van den Akker, Focco⁴  Carey, Paul R.⁴  Bonomo, Robert A.²  Buynak, John D.¹ 

[1] So Methodist Univ, Dept Chem, Dallas, TX 75275 USA

[2] Louis Stokes Vet Affairs Med Ctr, Res Serv, Cleveland, OH 44106 USA

[3] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA

[4] Case Western Reserve Univ, Dept Biochem, Cleveland, OH 44106 USA

关键词: beta-Lactamase;    Inhibitor;    Antibiotic;    Penicillin;   

DOI  :  10.1016/j.bmcl.2010.10.134

来源: Elsevier

【 摘 要 】

In order to evaluate the importance of a hydrogen-bond donating substituent in the design of beta-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 beta-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 C6 beta-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 beta-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 beta-aminoacrylate as a stabilized acyl-enzyme. (c) 2010 Elsevier Ltd. All rights reserved.

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