75527-84-3Relevant academic research and scientific papers
C type beta-lactamase inhibitor, and preparation method and applications thereof
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, (2019/03/28)
The invention provides a C type beta-lactamase inhibitor. The C type beta-lactamase inhibitor is 6 alpha-(1R-hydroxy-3(2-thiophene-yl)propyl) penicillic acid, and the structure of the C type beta-lactamase inhibitor is represented by formula 1 in the invention.
Preparation method of tazobactam intermediate 6-bromo-diphenylmethyl penicillanic acid sulfoxide
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Paragraph 0074; 0077; 0078, (2018/11/27)
The invention provides a preparation method of a tazobactam intermediate 6-bromo-diphenylmethyl penicillanic acid sulfoxide. The method includes the steps of: with 6-APA as a raw material, performingbromination with a hydrobromic acid solution, sodium nitrite and H2O2 to generate a 6-APA-dibrominated product; performing esterification with diphenyl diazomethane; performing a reaction with sodiumpyrosulfite to generate a diphenylmethyl penicillanic acid monobromide; and performing oxidization with H2O2 to obtain the tazobactam intermediate, 6-bromo-diphenylmethyl penicillanic acid sulfoxide.The preparation method employs low-cost and accessible raw materials and simple operations in whole synthetic route, is high in yield and low in operation cost, is green and environment-friendly, is very suitable for industrial production and has excellent industrial application value.
Modifications of the C6-substituent of penicillin sulfones with the goal of improving inhibitor recognition and efficacy
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.
scheme or table, p. 387 - 393 (2011/03/17)
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.
Rational design of a β-lactamase inhibitor achieved via stabilization of the trans-enamine intermediate: 1.28 A crystal structure of wt SHV-1 complex with a penam sulfone
Padayatti, Pius S.,Sheri, Anjaneyulu,Totir, Monica A.,Helfand, Marion S.,Carey, Marianne P.,Anderson, Vernon E.,Carey, Paul R.,Bethel, Christopher R.,Bonomo, Robert A.,Buynak, John D.,Van Den Akker, Focco
, p. 13235 - 13242 (2008/03/11)
β-Lactamases are one of the major causes of antibiotic resistance in Gram negative bacteria. The continuing evolution of β-lactamases that are capable of hydrolyzing our most potent β-lactams presents a vexing clinical problem, in particular since a number of them are resistant to inhibitors. The efficient inhibition of these enzymes is therefore of great clinical importance. Building upon our previous structural studies that examined tazobactam trapped as a trans-enamine intermediate in a deacylation deficient SHV variant, we designed a novel penam sulfone derivative that forms a more stable trans-enamine intermediate. We report here the 1.28 A resolution crystal structure of wt SHV-1 in complex with a rationally designed penam sulfone, SA2-13. The compound is covalently bound to the active site of wt SHV-1 similar to tazobactam yet forms an additional salt-bridge with K234 and hydrogen bonds with S130 and T235 to stabilize the frans-enamine intermediate. Kinetic measurements show that SA2-13, once reacted with SHV-1 β-lactamase, is about 10-fold slower at being released from the enzyme compared to tazobactam. Stabilizing the trans-enamine intermediate represents a novel strategy for the rational design of mechanism-based class A β-lactamase inhibitors.
Penicillin-derived inhibitors that simultaneously target both metallo- and serine-β-lactamases
Buynak, John D.,Chen, Hansong,Vogeti, Lakshminaryana,Gadhachanda, Venkat Rao,Buchanan, Christine A.,Palzkill, Timothy,Shaw, Robert W.,Spencer, James,Walsh, Timothy R.
, p. 1299 - 1304 (2007/10/03)
The synthesis and β-lactamase inhibitory activity of four 6-(mercaptomethyl)penicillinates and the four corresponding 6-(hydroxymethyl) penicillinates are described. These penicillins include both C6 stereoisomers as well as the sulfide and sulfone oxidation states of the penam thiazolidine sulfur. All compounds were evaluated as inhibitors of representative metallo- and serine-β-lactamases enzymes. Selected (mercaptomethyl)penicillinates are shown to inactivate both metallo- and serine-β-lactamases and to display synergism with piperacillin against β-lactamase producing strains.
