Modifications of the C6-substituent of penicillin sulfones with the goal of improving inhibitor recognition and efficacy.
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.
Department of Chemistry, Southern Methodist University, Dallas, TX 75275-0314, USA.
Micheal
M
Nottingham
Christopher R
CR
Bethel
Sundar Ram Reddy
SR
Pagadala
Emily
E
Harry
Abishai
A
Pinto
Zachary A
ZA
Lemons
Sarah M
SM
Drawz
Focco van den
Fv
Akker
Paul R
PR
Carey
Robert A
RA
Bonomo
John D
JD
Buynak
D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry*; D010400:Penicillin G / Q000737:chemistry; D010406:Penicillins / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism
D004791:Enzyme Inhibitors; D010406:Penicillins; D013450:Sulfones; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases; D010400:Penicillin G