162252-93-9Relevant academic research and scientific papers
Chphalosporin-derived mercaptans as inhibitors of serine and metallo-beta-lactamases
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Page/Page column 5, (2008/06/13)
Compounds of formula I: See Formula I in Figures Section wherein R1, R2, R3, R4 and n have any of the values defined in the specification, and their pharmaceutically acceptable salts, are useful for inhibiting s
Catalytic approaches to the synthesis of β-lactamase inhibitors
Buynak, John D.,Doppalapudi, Venkata Ramana,Frotan, Mohammed,Kumar, Ramon,Chambers, Alison
, p. 5709 - 5718 (2007/10/03)
Catalytic couplings were utilized to stereospecifically synthesize several 7E- and 7Z-alkylidenecephalosporins. Members of this class are known inhibitors of β-lactamase. Zinc/NH4Cl reduction of dibromide 14 stereospecifically produced E-monobromide, 15. In contrast, treatment of 14 with isopropylmagnesium bromide, followed by mild acid, stereospecifically produced Z-monobromide 27. These reactions involve stable, intermediate α-(metalloalkylidene)-β-lactams. Monobromides 15 and 27 were stereospecifically coupled to organostannanes, or were converted to the corresponding organostannanes, 22 and 32, which coupled with organohalides. (C) 2000 Elsevier Science Ltd.
Stille coupling approaches to the stereospecific synthesis of 7- [(E)- alkylidene]cephalosporins
Buynak, John D.,Doppalapudi, Venkata Ramana,Frotan, Mohammed,Kumar, Ramon
, p. 1281 - 1284 (2007/10/03)
Stille coupling methodology is used to stereospecifically synthesize 7- [(E)-alkylidene]cephalosporins, potential enzyme inhibitors which are unavailable via other synthetic methodology. Two procedures are described, utilizing either a stannylalkylidene c
7-alkylidenecephalosporin esters as inhibitors of human leukocyte elastase
Buynak, John D.,Srinivasa Rao,Ford, George P.,Carver, Christa,Adam, Greg,Geng, Bolin,Bachmann, Brian,Shobassy, Samir,Lackey, Stephanie
, p. 3423 - 3433 (2007/10/03)
A series of 7-alkylidenecephalosporins and 7-vinylidenecephalosporins, as their benzhydryl esters, have been tested as inhibitors of both porcine pancreatic elastase and human leukocyte elastase. Selected 7- alkylidenecephalosporin esters are found to be potent inhibitors of HLE. One category of new inhibitors is the 7-(haloalkylidene)cephalosporins. In contrast to previously reported cephalosporin-based elastase inhibitors, these haloalkylidene cephems show optimum inhibitory activity as sulfides, rather than as sulfones. They are efficient and irreversible inhibitors. A second class of active compounds is represented by the benzhydryl ester 7- (cyanomethylidene)cephalosporin sulfone. In contrast to the activity of these new inhibitors, the benzhydryl ester of the mechanism-based β-lactamase inhibitor, 7-[(2'-pyridyl)methylidene]-cephalosporin sulfone showed little inhibitory activity as an elastase inhibitor. 7-Vinylidenecephalosporins were also relatively poor inhibitors, although the terminally unsubstituted allene sulfide showed activity as an inhibitor of PPE. A modeling analysis suggests the 7-alkylidene substituents can be readily accommodated in the S1 pocket. A potential mechanism of inhibition is proposed.
Synthesis and biological activity of 7-alkylidenecephems
Buynak,Wu,Bachmann,Khasnis,Hua,Nguyen,Carver
, p. 1022 - 1034 (2007/10/02)
Several 7-alkylidenecephalosporins were synthesized and biologically evaluated as β-lactamase inhibitors. The three β-lactamase enzymes used in this study included two type C β-lactamases, derived from Enterobacter cloacae P99 and E. cloacae SC12368, and one type A β-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 106 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 k(reactiv) = 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.
