Sulbactam 3-lactamase inhibitory activity

Bycroft et al. [83] have reported a series of semisynthetic penicillin derivatives such as, 6-spiro-epoxypenicillins F, G (Fig. 8) possessing both (3-lactamase inhibitory and antibacterial activity (Fig. 8). It has been found that novel chlorinated 6-spiro-epoxypenicillins F are potent in vitro inhibitors of a range of chemically important (3-lactamases [84], whereas, 6-spirocyclopropylpenems, G, show a reduced level of (3-lactamase inhibitory activity. The significance of the five fold difference between the turnover numbers for F(a) and G(b) (differ only in their stereochemistry at one center) was found to be in close comparison with the turnover number of 20,000, reported for the established (3-lactamase inhibitor, sulbactam [140]. Thus, the notable (3-lactamase inhibitory and antibacterial properties of these spiro-(3-1 actams depend upon the substituents and the stereochemistry of the epoxide. 

The first notable success was that of penicillanic acid sulphone (sulbactam CP-45,899) (23) [40], which was synthesized by Pfizer chemists from 6-APA (8) and shown to possess potent -lactamase inhibitory activity. Many other semi-synthetic yS-lactamase inhibitors have been... 

Table 6.7. -LACTAMASE INHIBITORY ACTIVITY OF SULBACTAM, 6-)9-HALOPENICILLANIC ACIDS AND 6-ACETYLMETHYLENE PENICILLANIC ACID COMPARED WITH CLAVULANIC ACID, WITH AND WITHOUT PRE-INCUBATION [18]...

The discovery of the /8-lactamase inhibitory activity of sulbactam signalled a resurgence of interest in the nuclear modification of 6-APA (8). Micetich and co-workers concentrated their efforts on the synthesis of 2-/8-... 

Whilst most attention focused upon the antibacterially active 6-(l-hydroxyethyl) penems (87), Osborne (SmithKline Beecham) found in 1981 that the dehydration of such penems Scheme 6.16) provided compounds which had only weak antibacterial activity, but good y5-lactamase inhibitory activity [86, 87]. Their spectrum ofj8-lactamase inhibitory activity is broader than that of clavulanic acid and they have greater potency than sulbactam. 

The yS-lactamase inhibitory activity of the 6-ethylidenepenems, in comparison with potassium clavulanate and sulbactam is shown in Table 6.1 l. i can be seen that both (Z)- and ( )- isomers of the penems inhibited all four -lactamases, including the class la enzyme of Enterobacter cloacae. 

The -lactamase inhibitory activity of BRL 42715, in comparison with clavulanic acid, sulbactam and tazobactam is shown in Table 6.14. It can be seen that BRL 42715 displays potent and progressive broad spectrum yff-lactamase inhibitory activity which represents a significant improvement over that of clavulanic acid, sulbactam and tazobactam. This was most noticeable with the chromosomal class I cephalosporinases, against which clavulanic acid is poorly active and sulbactam and tazobactam show only moderate activity. 

After clavulanic acid, the penicillanic acid derivatives (particularly the corresponding sulfone analogs) have been the subject of intense research in the -lactamase inhibitor area. From this extensive investigation, two compounds (sulbactam and tazobactam) from this class have been successfully introduced into clinical use. The penicillanic acid sulfones are /3-laclamasc inhibitors that are quite homologous to clavulanate in both their mechanism of action and in the spectrum of -lactamases susceptible to their action. The first notable success in this field was the discovery of sulbactam 7 (Fig. 7), which was reported by Pfizer chemists in 1978 and shown to possess potent inhibitory activity, principally for class A //-lactamases. It had greater affinity for class C types than clavulanate. From careful comparison of its structure to clavulanate, a rational basis for the similarities between the two is apparent. Both lack a C-6 substituent. Since the absence (or presence) of this substituent is an important, but not exclusive, factor in //-lactamase recogni-... 

The mechanism suggests that the presence of an c/,/l-unsalurated system at the C-6 position of sulbactam would be an essential component for enhancing the inhibitory activity towards various /3-lactamases. Thus, several compounds with an exocyclic double bond at the C-6 position of the penicil-lanic acid, with and without sulfone, were prepared (Table 2). 

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... 

Over the past decade the essential goal in the modification of sulbactam or tazobactam has been to extend their activity towards the class C cephalosporinases. In spite of an enormous amount of effort, there has not been much success in achieving this goal. The penicillanic acid derivatives, as a class, show a good /3-lactamase inhibitory profile against class A... 

A synthetic penem-type -lactam (149) exhibited antibacterial activities similar to (+ )-thienamycin (77) (82JA6138). Sulbactam (ISO) showed fairly strong inhibitory activity against )3-lactamase (78AAC414). Based on the background mentioned above, we developed a new convenient method for the synthesis of penam-type )S-lactams. 

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