Sulbactam structure

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-... 

In a recent report [67], the spirocyclopropyloxy structural motif was incorporated in sulbactam, and the compounds 12a and 12b had good activity against various -lactamases. The mechanism of inhibition of /3-lactamase by 12a or 12b is unique. After the initial acylation, the cyclopropyloxy group can promote the subsequent chemical events to form the aldehyde or the oxycar-benium moiety for further cross-linking with other active site residues of the enzyme (Scheme 5). 

Beta-lactamase inhibitors include clavulanic acid, sulbactam and tazobactam. They are structurally related to the beta-lactam antibiotics however the antibacterial activity of these compounds is very weak or negligible. They are strong inhibitors of bacterial beta-lactamases and can protect beta-lactam antibiotics from hydrolysis by these enzymes. 

Enzymatic inactivation or modification of antibiotics has been discussed by many authors [179-182, 186-188], As described earlier, /(-lactams may be susceptible to /(-lactamases. During the past 30-odd years, several -lactams have been synthesized that are less susceptible to these enzymes. Such drugs include (i) newer types of /(-lactam structures, e.g. carbapenems (37), cephamycins (40) and carbacephems (53), and (ii) modifications of the side-chains of existing penams (38) or cephems (39) [317]. Nevertheless, the wide diversity of /(-lactamases [180,181,318] means that organisms producing enzymes with broad-spectrum activity may be able to resist some members of the /(-lactam group, /(-lactamase inhibitors such as clavulanic acid (36), and the penicillanic acid sulphone (54) derivatives, tazobactam (55) and sulbactam (56) have been combined with, and protect, appropriate /(-lactamase-susceptible penicillins, with useful clinical results. Most extended-spectrum /(-lactamases are susceptible to these inhibitors, but newer -lactamase inhibitors may still be needed. 

Imipenem caused positive dipstick tests for leukocytes in patients with agranulocytosis and normal urinary sediments. This phenomenon was reproducible in vitro with imipenem, meropenem, and clavulanic acid. Sulbactam, tazobactam, three penicillins, three cephalosporins, and the basic structures of penicillins, cephalosporins, and monobactams tested negative (50). 

Tazobactam, USP. Tazobactam is a penicillanic acid sulfone that is similar in structure to sulbactam. It is a nioK potent /3-lactamase inhibitor than sulbactam and ha.- 3 slightly broader spectrum of activity than clavulanic acid. Ii has very weak antibacterial activity. Tazobactam is available in fixed-dose, injectable combinations with piperacillin, a broad-spectrum penicillin consisting of an 8 I ratio of pipci- acillin sodium to tazobactam sodium by weight and ma-keted under the trade name Zosyn. The pharmacokineticsprotein bound, experience ven little metabolism, and are excreted in active forms in the urine in high concentrations. 

Sulbactam (Fig. 10.6G) is a semisynthetic 6-desaminopenicillin sulphone structurally related to tazobactam. Not only is it an effective inhibitor of many P-lactamases but it is also active alone against certain Gram-negative bacteria. It is used clinically in combination with ampicillin. 

The 6-methoxymethylene penicillanic acid [93040-42-7] (31, R = CH3OCH1 (z)-isomer, R" = R/// = CH3) was designed to mimic the aminoacrylate species found using clavulanic acid and sulbactam. Upon the reaction of this compound with the enzyme, the potential exists for further Michael addition to inactivate the enzyme. The compound is indeed a p-lactamase inhibitor but no synergy data have been reported. The related imine structure... 

The stability of the acylated enzyme may be rationalized to be due to vinylogous structure of the urethane-type product formed. Analogous mechanisms have been proposed for sulbactam and clavulinic acid. Clavulinic acid can also form an acylated equilibrium between an enamine and imino intermediate. The nonvinylogous, and presumably, some-... 

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