Bioorganic and Medicinal Chemistry Letters p. 387 - 393 (2011)
Update date:2022-08-03
Topics:
Nottingham, Micheal
Bethel, Christopher R.
Pagadala, Sundar Ram Reddy
Harry, Emily
Pinto, Abishai
Lemons, Zachary A.
Drawz, Sarah M.
Akker, Focco Van Den
Carey, Paul R.
Bonomo, Robert A.
Buynak, John D.
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.
View MoreShanghai Boyners Pharmaceutical co., LTD.
Contact:+86-02131329586/02154581719
Address:No.328,1#315,Wuhe Road, Shanghai, ,shanghai,China (Mainland)
Binzhou Holly Pharmaceutical Co.,Ltd.
Contact:74517
Address:No.15 Dapu Road,Huangpu District Shanghai,P.R.China
Chengdu Biopurify Phytochemicals Ltd.
website:http://www.phytopurify.com
Contact:+86-28-82633397
Address:2F,No.11 Building,No.388 Rongtaidadao CNSTP,Wenjiang Zone,Chengdu,Sichuan, China
Huangshi Shennong Chemical Technology Co., Ltd
Contact:+86-714-3072290
Address:Eastern industrial park , Tieshan district , Huangshi city ,Hubei province , China
QINGDAO DEVELOP chemistry Co.,Limited
Contact:+86-532-85807910
Address:98#Nanjing Road, Qingdao, China 266071
Doi:10.1021/jo01256a089
(1969)Doi:10.1055/s-1997-1156
(1997)Doi:10.1248/cpb.45.36
(1997)Doi:10.1002/jhet.5570330671
(1996)Doi:10.1246/bcsj.20180353
(2019)Doi:10.1016/S0960-894X(96)00606-3
(1997)