Penams 3-lactamase inhibitors

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 ...

Penam P-Lactamase Inhibitors. Penam is the trivial name given derivatives of the penicillin nucleus (31) the chemical name of which is 4-thia-l-a2abicyclo[3.2.0]heptane. Table 6 gives activity data for a diverse group of penams. The report that 6-P-bromopeniciU.anic acid [26631-90-3] [2(3)-(2a,5a,6P)]-6-bromo-3,3-dimethyl-7-oxo-4-thia-l-a2abicyclo[3.2.0]heptane-2-carboxyhc acid, (31, R = Br, R =H, R" = R " = CH3) a potent... 

Penam p-Lactamase Inhibitors. Penam is the trivial name of 4-thia-l-azabicyclo[3.2.0]heptane. The report that 6-/3-bromopenicillanic acid, [2(5)-(2or. 5 . 6/8)]-6-bromo-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo [3.2.0]lieptane-2-carboxylic acid, (R = Br, R1 = H. R = R1 = CHi) is a potent inhibitor led to intense study both of this compound and analogues. The microbiology profile of 6-/3-bromopenicillanic acid has been reported and the compound has progressed to clinical trials. Mechanistic studies have demonstrated that the dihydrothiazine derivative is responsible for inactivation of /3-lactamases. 

Oxidation reactions on the sulfur atom of penicillins remain the most important reactivity of S-1 encountered in the literature. Penam sulfoxides and sulfones are indeed important compounds as they confer to the skeleton an ease of thiazolidine ring opening by weakening the C(5)-S(l) and S(l)-C(2) bonds (see Section 2.03.5.9) <2004CHE816>. In particular, the former constitute key intermediates in ring-expansion transformations from penams to cephems (see Section 2.03.5.9), while the latter have a special biological interest as /3-lactamase inhibitors (e.g., sulbactam, tazobactam see Sections 2.03.1, 2.03.5.2, and 2.03.12.4). Since CHEC-II(1996) covers all the aspects of these oxidation reactions on the S-1 atom of penicillins, this section focuses on the most relevant recent papers. As there is no particular change in the subject, only a few articles have been released since 1995. 

Methylene penems constitute good /3-lactamase inhibitors as their hydrolytic metabolism leads to the formation of 1,4-thiazepines, strengthening the thus-formed acyl-enzyme complex link (see Sections 2.03.6.9 and 2.03.12.4). However, compared to penams, penem sulfones are not as good /3-lactamase inhibitors as their half-lives of hydrolysis are too short, making them labile under physiological conditions <1997BML2217>. 

In a trend to develop new antibiotics and /3-lactamase inhibitors, comparable to that for the penam, the synthesis of new penem structures and their oxidation reactions on the S-1 atom have been jointly investigated during the last three decades. The first isolated penem sulfoxide was reported in 1979 <1979TL3777>. However, its synthesis was not performed by direct oxidation of a penem but a 2-exomethylene penicillanate 41 (1-thioclavulanic ester), involving a migration of the double bond to afford the penem nucleus (Scheme 23). 

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 (Z)-6-heterocyclylmethylene penam sulphones were shown to be effective 5-lactamase inhibitors and potent ampicillin and cefazolin potentiators against both Gram-positive and Gram-negative yff-lactamase producing bacteria [79]. In particular, several of these analogues having a r-deficient 2-heteroaryl substituent attached to the C-6 methylene positon, such as the 6-(2-pyridyl)methylene derivative (28), displayed exceptional activity. In combination with ampicillin or cefazolin they exhibited... 

R = />-CH3C6H5N, ( -isomer, has also been reported to inhibit type I Cephases. The 6-P-[bistrifluoromethane sulfonyl] amidopenicillanic acid [82954-44-7] (31, R = (CF3S02)2N), R/ = H, R" = R/// = CH3) was speculated to inhibit the penase from B. cereus by triflation or generation of an imine that reacts further with the enzyme. Several C-6 substituted amino penams have been reported to inhibit type I Cephases the complex hydroxyalkyl penicfllanic acid derivatives are reported to be potent P-lactamase inhibitors and synergists. In combination with amoxicillin, compound (31, R =... 

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.

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). 

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