Penam sulfones

Penam Sulfone B-Lactamase Inhibitors. Natural product discoveries stimulated the rational design of p-lactamase inhibitors based on the readily accessible penicillin nucleus. An early success was penicillanic acid sulfone, (2(5)-cis)-3,3-dimethyl-7-oxo-4,4-dioxide-4-thia-l-a2abicyclo [3.2.0]heptane-2-carboxylic acid [68373-14-8] (sulbactam) (25, R = = H, R" = R" = CH ), CgH NO S. The synthesis (118), microbiology (119—121),... 

Table 5. Activity of Penam Sulfone B-Lactamase Inhibitors ...

In comparison to sulbactam, penam sulfones 12a and b exhibited excellent activity against TEM-1 and AmpC enzymes, respectively, with over 2500-fold improvement against the class C enzyme. Within the same series, 12a and 12b are appreciably more potent than their corresponding diastereomers. In particular, they are potent against the AmpC enzyme suggesting the stereochemical preference of the alkoxy substituent of the cyclopropyl ring, which plays a critical role in binding with the enzymes. Further, in vitro evaluations in a cell-based assay (MIC) established the effectiveness of 12a. hi... 

Further, using a combination of X-ray crystallography and mass spectroscopy, Knox et al. [73] has firmly established a central role for Ser-130 in the inhibition of SHV-1 /1-lactamase (class A) by tazobactam. Many additional modifications (Table 3) were carried out on tazobactam with the aim of increasing inhibitory activity against AmpC enzymes, but none of these derivatives (e.g., 13c, 13d, and 13e) had any advantage over tazobactam [74— 77]. Renewed interest in the modification at the C-2 position of sulbactam was developed when scientists from Hoffmann-La Roche disclosed a series of 2/J-alkenyl penam sulfones that possess the ability to simultaneously inactivate both class A penicillinase as well as class C cephalosporinase. Compound... 

Figure 22 Penam sulfone 39, a mechanism-based inhibitor of /3-lactamase, used as a hapten to generate scFv antibodies, FT6 and FT12, with a /3-lactamase activity.

The following protocol is described for the selection of phage-displayed serine / -lactamase with a biotinylated penam-sulfone [5] suicide substrate. For other activities, the concentrations of substrate and suicide substrate and the times of reaction should probably be adjusted. 

Figure 8 Biotechnological tools derived from penam sulfones.

Current commercial inhibitors of /3-lactamases include clavulanic acid (an oxapenam see Table 1), sulbactam, and tazobactam (two penam sulfones see Table 1). They are effective only against the class A serine /3-lactamases and they are administrated in the form of antibiotic/inhibitor combinations <2006BP930> Augmentin (amoxicillin/clavulanic acid), Timentin (ticarcillin/clavulanic acid), Unasyn (ampicillin/Sulbactam), Zosyn (piperacillin/tazobactam). 

This strategy has been applied to select catalytic antibodies from phage-displayed libraries. Two catalytic single-chain antibodies catalyzing the hydrolysis of ampicillin with rate accelerations kcit/kunc lt of 5200 and 320 (kcat = 0.29 and 0.018min-1) were isolated from combinatorial libraries prepared from mice immunized with penam sulfone conjugates and selected with a biotinylated penam sulfone [61]. 

Nitrileoxidomethyl)penam sulfone, prepared in a few steps from commercially available (- -)-6-aminopenicilla-nic acid by treatment of oxime 617 with NCS and followed by dehydrochlorination with bis(tributyltin)oxide, underwent smooth 1,3-dipolar cycloaddition reactions with various alkynes, and alkenes, to give cycloadducts 618 in moderate to good yields. Some acid derivatives 618 (R = H) showed potent /3-lactamase inhibitory activity (Scheme 148) <20000L3087>. 

While 1,2-cleavage of penams by base-promoted P-elimination requires activation with thiophiles, penam sulfones readily react with DBN to give azetidinone sulfinic acids by an ElcB mechanism [98]. Stoodley et al., who discovered this reaction, also developed the sulfinic acid chemistry necessary for application to penem synthesis, namely the conversion of the ring-opened products into either 4-alkylsulfonyl- or 4-acyldithioazetidinone derivatives. 

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