Penicillanic acid sulphone

Fig. 5.6 A, Nocardicin A B, 3-aminomonobactamic acid (3-AMA) C, aztreonam D, penicillanic acid sulphone (sodium salt) E, / -bromopenicillamc acid (sodium salt) F, tazobactam G, sulbactam.

Penicillanic acid sulphone (Tig. 5.6D) protects ampicillin flom hydrolysis by staphylococcal Alactamase and some, but not all, of the Mactamases produced by Gram-negative bacteria, but is less potent than clavulanic acid. /3-bromopenicillanic acid (Tig. 5.6E) inhibits some types of Alactamases. 

Tazobactam (Tig. 5.6F) is a penicillanic acid sulphone derivative marketed as a combination with piperacillin. Alone it has poor intrinsic antibacterial activity but is comparable to clavulanic acid in inhibiting /J-lactamase activity. 

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. 

SEMI-SYNTHETIC yff-LACTAMASE INHIBITORS Clavulanic acid derivatives Penicillanic acid sulphone 6- -Halopenicillanic acid derivatives 6-Acetylmethylene penicillanic acid 6-Methoxymethylene penicillanic acid 6-Heterocyclylmethylene penam sulphones 2-y8-(Substituted methyl) penam sulphones 6-(Substituted methylene) penems... 

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... 

Penicillanic acid sulphones, such as sulbactam, are believed to inhibit yS-lactamases by a similar mechanism to that of clavulanic acid Scheme 6.6) [31, 37]. The initially formed acyl enzyme (38) is thought to partition... 

A mechanism of action for the r-deficient 2-heteroaryl derivatives was postulated based upon the reaction of 6-(2-pyridyl)methylene penicillanic acid sulphone (28) with sodium methoxide (Scheme 6.14) [46]. Chen and co-workers proposed that after bimolecular interaction between the enzyme and (28), an aromatic acyl-enzyme ester (76) is obtained. This conjugated... 

Scheme 6.14. Proposed mechanism of action of 6-(2-pyridy ) methylene penicillanic acid sulphone.

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