Structure-activity relationships of 6-(heterocyclyl)-methylene penam sulfones. A new class of .BETA.-lactamase inhibitors.

Chen, Yuhpyng L.; Chang, Cnm-Wu; Hedberg, Kirk; Guarino, Karen J.; Welch, Willard M.; Kiessling, Laura L.; Retsema, James A.; Haskell, Suzanne L.; Anderson, Misty; Manousos, Mary; Barrett, John

doi:10.7164/antibiotics.40.803

Cited by 40 publications

(11 citation statements)

References 13 publications

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“…In the process of completing this research, we became aware of the paucity of information (both biological and chemical) available on simple 7-unsaturated cephalosporins (7-alkylidenecephems, 2). This situation is in contrast to that of the corresponding 6-unsaturated penicillins, which were prepared and studied by Chen et al 13 We thus decided to prepare representative 7-alkylidenecephems and study their properties as p-lactamase inhibitors.…”

Section: Introductionmentioning

confidence: 92%

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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Section: Introductionmentioning

confidence: 92%

Synthesis and Biological Activity of 7-Alkylidenecephems

Buynak

Wu²,

Bachmann³

et al. 1995

J. Med. Chem.

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“…Like the penems above, alkylidene group containing reactive groups were added at the C6 position of penam sulfones (Chen et al, 1987 ; Buynak et al, 1999 ; Phillips et al, 2005 ; Kalp et al, 2007 ; Che et al, 2012 ). In particular, the pyridylemethylidene moiety in LN-1-255 is potent since, when in the imine intermediate, the nitrogen of the pyridyl group reacts with the carbon atom of the imine bond to form a bicyclic ring (Figure 1D ; Buynak et al, 1999 ; Pattanaik et al, 2009 ).…”

Section: -Alkylidene-2′β-substituted Penam Sulfones: Ln-1-255 and Nomentioning

confidence: 99%

Exploring Additional Dimensions of Complexity in Inhibitor Design for Serine β-Lactamases: Mechanistic and Intra- and Inter-molecular Chemistry Approaches

Akker

Bonomo

2018

Front. Microbiol.

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As a bacterial resistance strategy, serine β-lactamases have evolved from cell wall synthesizing enzymes known as penicillin-binding proteins (PBP), by not only covalently binding β-lactam antibiotics but, also acquiring mechanisms of deacylating these antibiotics. This critical deacylation step leads to release of hydrolyzed and inactivated β-lactams, thereby providing resistance for the bacteria against these antibiotics targeting the cell wall. To combat β-lactamase-mediated antibiotic resistance, numerous β-lactamase inhibitors were developed that utilize various strategies to inactivate the β-lactamase. Most of these compounds are “mechanism-based” inhibitors that in some manner mimic the β-lactam substrate, having a carbonyl moiety and a negatively charged carboxyl or sulfate group. These compounds form a covalent adduct with the catalytic serine via an initial acylation step. To increase the life-time of the inhibitory covalent adduct intermediates, a remarkable array of different strategies was employed to improve inhibition potency. Such approaches include post-acylation intra- and intermolecular chemical rearrangements as well as affecting the deacylation water. These approaches transform the inhibitor design process from a 3-dimensional problem (i.e., XYZ coordinates) to one with additional dimensions of complexity as the reaction coordinate and time spent at each chemical state need to be taken into consideration. This review highlights the mechanistic intricacies of the design efforts of the β-lactamase inhibitors which so far have resulted in the development of “two generations” and 5 clinically available inhibitors.

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“…Although the introduction of a thienylmethylene group at position 6 of the penem skeleton [10] and the introduction of similar 6-(heterocyclyl)methylene groups in the penam sulfone nucleus [11] provided potent 13-1actamase inhibitors, a monobactam skeleton having the thienylmethylene group at position 3, like I and II, lacks 13-1actamase inhibitory activity, thus suggesting the necessity of the oxyimino substituted amido side chain at position 3 of aztreonam for 13-1actamase inhibitory activity.…”

Section: Resultsmentioning

confidence: 98%

Studies on monobactams II. Synthesis and β-lactamase inhibitory activity of 4α-methyl-3-[(thien-2-yl)-methylene]-2-azetidinone-1-sulfonate

Phillips¹,

Setti²,

Reddy³

et al. 1998

Chem Heterocycl Compd

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Two raonobactam derivatives, potassium 4rand its (3Z)-isomer, were prepared and evaluated for their l~-lactamase inhibitory activities. These compounds were devoid of 13-1actamase inhibitory activity.The apparently endless capacity of 13-1actamases to develop the ability to degrade new I~-lactams has led to the alternative strategy of seeking inhibitors to block their action. The discovery of clavulanic acid, sulbactam, and tazobactam has confirmed the success of this approach, but none inhibits the class C enzymes. Because of the widespread use of third-generation cephalosporins, resistance caused by chromosomally-mediated class C cephalosporinase is increasing rapidly and may pose a threat in the future. Aztreonam, the f'trst monocyclic l~-lactam antibiotic to be clinically used, has long been known to act as a competitive and progressive inhibitor of class C cephalosporinase [1][2][3]. Continuing efforts in our laboratory have focussed on the design and synthesis of novel l~-lactamase inhibitors. Our interest in the monobactam area was in response to the 13-1actamase inhibitory activity displayed by several monobactam derivatives [4,5], including aztreonam [1] and carumonam [6]. Our earlier chemical modification of monobactam [7] revealed that 3-[(N-methyl-l,2,3-triazol-4-yl)methylene]-2-azetidinone-l-sulfonates having various substituents at the C-4 position generally lack the activity against 13-1actamases. To correct this deficiency we explored new derivatives with the a-methyl group at the C-4 position. This paper deals with the synthesis and I]-lactamase inhibitory activity of potassium 4a-methyl-(3E)-[(thien-2-yl)methylene]-2-azetidinone-l-sulfonate (I) and its (3Z)-isomer (II) as the representative compounds of this class. CHEMISTRYThe starting material for the synthesis of these compounds was the previously described (3S) -trans-3-[(tert-butoxycarbonyl)amino]-4-methyl-2-azetidinone (III) [8]. The azetidinone derivative III was reacted with 2,2,2-trichloroethyl chloroformate under standard conditions to provide the adduct IV in good yield, m.p. 156-157~ This material was then treated with TFA to remove the amine protecting group to afford the monobactam intermediate V in 97% yield. Then the I]-lactam V was reacted with 2.5 N H2SO4, NaNO2, and bromine in dichloromethane (Scheme 1) to give the dibromo derivative VI in 63% yield, m.p. 82-83"C. The dibromo derivative VI underwent metal halogen exchange with methylmagnesium bromide in THF at -78~ to give an enolate intermediate which, on quenching with thiophene-2-carboxaldehyde afforded an inseparable diastereomer mixture of hydroxy adducts VII. Acetylation of this mixture gave the acetyl derivative VIII. Reductive elimination using powdered zinc in DMF

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Structure-activity relationships of 6-(heterocyclyl)-methylene penam sulfones. A new class of .BETA.-lactamase inhibitors.

Cited by 40 publications

References 13 publications

Synthesis and Biological Activity of 7-Alkylidenecephems

Synthesis and Biological Activity of 7-Alkylidenecephems

Exploring Additional Dimensions of Complexity in Inhibitor Design for Serine β-Lactamases: Mechanistic and Intra- and Inter-molecular Chemistry Approaches

Studies on monobactams II. Synthesis and β-lactamase inhibitory activity of 4α-methyl-3-[(thien-2-yl)-methylene]-2-azetidinone-1-sulfonate

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