Synthesis of a potent β-lactamase inhibitor- 1,1-dioxo-6-(2-pyridyl)methylenepenicillanic acid and its reaction with sodium methoxide

Chen, Yuhpyng L.; Chang, Chi‐Wen; Hedberg, Kirk

doi:10.1016/s0040-4039(00)84819-4

Cited by 50 publications

(14 citation statements)

References 22 publications

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“…This proton is lost from C-5 (not from C-6, as is the case for clavulanic acid and sulbactam), which is directly adjacent to the newly basic nitrogen (formerly the ␤-lactam nitrogen). This mechanism of intramolecular rearrangements leading to the JDB/LN-1-255 bicyclic intermediate is probably common to SHV class A and OXA class D ␤-lactamases (21,48). However, the details of ␤-lactam acylation and deacylation differ between these two enzyme classes.…”

Section: Discussionmentioning

confidence: 88%

Penicillin Sulfone Inhibitors of Class D β-Lactamases

Drawz¹,

Bethel

Doppalapudi

et al. 2010

Antimicrob Agents Chemother

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Section: Discussionmentioning

confidence: 88%

Penicillin Sulfone Inhibitors of Class D β-Lactamases

Drawz¹,

Bethel

Doppalapudi

et al. 2010

Antimicrob Agents Chemother

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“…As mentioned earlier, in their studies on the penicillin analog, Chen and co-workers observed that 6-[(2'-pyridyl)methylenelpenam sulfone as well as several other 6-[(heterocyclic)methylenelpenicillin sulfones were effective p-lactamase inhibitors .13 In their case, insight was gained into the inhibitory mechanism by reacting the allyl ester of 6-[(2'-pyridyl)methylenelpenam sulfone (8, R = CHzCH=CHz) with methanolic sodium methoxide to produce the highly stabilized system 9 as shown in Scheme 3. 22 Presumably a similar rearrangement occurs in biological systems producing a stabilized acyl-enzyme. This intermediate incorporates the elements of a P-aminoacrylate (vinylogous urethane) into an aromatic system.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and Biological Activity of 7-Alkylidenecephems

Buynak

Wu²,

Bachmann³

et al. 1995

J. Med. Chem.

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Several 7-alkylidenecephalosporins were synthesized and biologically evaluated as beta-lactamase inhibitors. The three beta-lactamase enzymes used in this study included two type C beta-lactamases, derived from Enterobacter cloacae P99 and E. cloacae SC12368, and one type A beta-lactamase, derived from Escherichia coli WC3310. Of the cephalosporins prepared, compound 7e, the sodium salt of 7-[(Z)-(2'-pyridyl)methylene]cephalosporanic acid sulfone, was found to have excellent inhibitory properties against both type C enzymes. Also, compound 7f, the sodium salt of 7-[(Z)-(tert-butoxycarbonyl)methylene]cephalosporanic acid sulfone showed high activity as an inhibitor of the type A enzyme. The inhibition kinetics of 7e were further explored. The IC50 value of 7e indicated that this compound was approximately 20-fold more active than tazobactam against the enzyme derived from E. cloacae P99 and 167-fold more active than tazobactam against the enzyme derived from E. cloacae SC12368. A plot of enzymatic activity vs incubation time with stoichiometric amounts of inhibitor reveals a rapid deactivation of the enzyme followed by an extremely slow reactivation. 7e exhibited a second-order rate constant of k3' = 5.3 x 10(6) L/mol.min, and a partition ratio of approximately 20:1 inhibitor:enzyme was determined for this inhibitor. After separation of excess inhibitor with Sephadex filtration, a rate constant of enzyme reactivation was measured at kreactiv = 1.0 x 10(-3) s-1. Following 24 h of incubation of enzyme with a large excess of inhibitor and sephadex filtration to remove excess inhibitor, the enzyme was able to recover only 43% of its original activity, indicating an irreversible component to the inhibition. Potential mechanisms of inhibition for both 7e and 7f are suggested.

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“…designed the 6Z -(α-pyridylmethylidene) penicillin sulfone series and showed them to be potent compounds with the ability to inactivate a wide spectrum of serine β-lactamases (19). Buynak, et al .…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Crystal Structures of 6-Alkylidene-2′-Substituted Penicillanic Acid Sulfones as Potent Inhibitors of Acinetobacter baumannii OXA-24 Carbapenemase

et al. 2010

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Class D β-lactamases represent a growing and diverse class of penicillin inactivating enzymes that are usually resistant to commercial β-lactamase inhibitors. As many such enzymes are found in multi-drug resistant (MDR) Acinetobacter baumannii and Pseudomonas aeruginosa, novel β-lactamase inhibitors are urgently needed. Five unique 6-alkylidene-2'-substituted penicillanic acid sulfones (1, 2, 3, 4, and 5) were synthesized and tested against OXA-24, a clinically important β-lactamase that inactivates carbapenems and found in A. baumannii. Based upon the roles Tyr112 and Met223 play in the OXA-24 β-lactamase, we also engineered two variants (Tyr112Ala and Tyr112Ala,Met223Ala) to test the hypothesis that the hydrophobic tunnel formed by these residues influences inhibitor recognition. IC 50 values, against OXA-24, and two OXA-24 β-lactamase variants ranged from 10 ± 1 (4 vs. WT) to 338 ± 20 nM (5 vs. Tyr112Ala, Met223Ala). Compound 4 possessed the lowest K i (500 ± 80 nM vs. WT) and 1 possessed the highest inactivation efficiency (k inact /K i = 0.21 ± 0.02 μM -1 s -1 ). Electrospray ionization mass spectrometry revealed a single covalent adduct, suggesting the formation of an acyl-enzyme intermediate. X-ray structures of OXA-24 complexed to four inhibitors (2.0-2.6 Å) reveal there is formation of stable bicyclic aromatic intermediates with their carbonyl oxygen in the oxyanion hole. These data provide the first structural evidence that 6-alkylidene-2'-substituted penicillin sulfones are effective mechanism-based inactivators of class D β-lactamases. Their unique chemistry makes them developmental candidates. Mechanisms for class D hydrolysis and * Corresponding authors:

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Synthesis of a potent β-lactamase inhibitor- 1,1-dioxo-6-(2-pyridyl)methylenepenicillanic acid and its reaction with sodium methoxide

Cited by 50 publications

References 22 publications

Penicillin Sulfone Inhibitors of Class D β-Lactamases

Penicillin Sulfone Inhibitors of Class D β-Lactamases

Synthesis and Biological Activity of 7-Alkylidenecephems

Design, Synthesis, and Crystal Structures of 6-Alkylidene-2′-Substituted Penicillanic Acid Sulfones as Potent Inhibitors of Acinetobacter baumannii OXA-24 Carbapenemase

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