Antibacterials cephalosporins

Because they cause prolonged inactivation of certain fi-lactamases. class I inhibitors ate particularly useful in combination with extended-spectrum, lactamase-sen.sitive penicillins to treat infections caused by lactamase-producing bacteria. Three such inhibitors, clavulanic acid, sulbactam, and tazobactam. are currently marketed in the United States for this purpose. A class II inhibitor, the carbapenem derivative imipenem. has potent antibacterial activity in addition to its ability to cause transient inhibition of some /3-lactamases. Certain antibacterial cephalosporins with a leaving group at the C-3 position can cause transient inhibition of lactamases by forming stabilized acylenzyme intermiediates. These are discu.ssed more fiilly below in this chapter. 

Coumarins + Antibacterials Cephalosporins and related beta lactams... 

It is extremely important that fluoroquinolones have a specific mechanism of action, different from antibiotics and other groups of antibacterials (cephalosporins, aminoglycosides, etc.), which allows one to apply fluoroquinolones for treatment of infectious diseases caused by strains resistant to many other classes of antibacterials drugs. 

Quinolone-Gephalosporin Godrugs. Quinolones have been covalently linked to cephalosporins in order to generate a codmg containing one molecule of each type of antibacterial agent. An example is the fleroxacin—cefotaxime [63527-52-6] combination, Ro 23-9424 [115622-58-7] (23). 

In essence, the cephalosporin acts as a carrier (63) for the quinolone. The quinolone is replaced in the bacterial ceU after the action of P-lactamase on the cephalosporin portion of the molecule. This codmg combination represents a relatively new class of antibacterial agents which appear to offer advantages over the separated components (64). A good introductory discussion of these exciting agents can be found (65) (see also Antibiotics P-lactams ... 

The development of new antibiotics to combat resistance, and to provide easier oral administration and improved pharmacokinetics has been successful through synthetic modifications. This approach has been particularly rewarding in the area of P-lactams. The commercial importance of the P-lactams is evident from Table 3 which gives the market share of antibacterials. Fully 62% of the 1989 world antibacterial market belonged to the cephalosporin and penicillin P-lactams (20). 

Steroid Antibiotics. The steroid antibiotics are a stmcturaHy diverse class of steroids that have a common biological function, ie, antibacterial, antifungal, antiviral, or antitumor activities. This group of compounds can overlap with other steroid classes Hsted above. Eusidic acid [6990-06-3] (67), helvohc acid [29400-42-8] (68), and cephalosporin [13258-72-5] (69) exemplify a set of antibacterial steroids that contain a prolanostane skeleton with an... 

Table 9. Cephalosporin In I%ro Antibacterial Activity, pg/mL, and Pharmacokinetic Data ...

Another interesting approach to obtaining potent, broad-spectmm activity has been reported (127). The "dual-action" antibacterial concept involves incorporation of two moieties having complimentary antibacterial modes of action into the same molecule, and uses the mode of action of one part to release the second antibacterial at the site of action. This approach is exemplified in Ro 23—9424 (47) (127), which uses the mode of action and reactivity of the cephalosporin moiety (Fig. 2) to release the quinolone portion. 

The antibacterial spectmm of moxalactam (Table 9) is similar in breadth and potency to that of cefotaxime (36). Hence, moxalactam (48) is classified with the third-generation cephalosporins. In general 1-oxacephalosporins are considerably more susceptible to P-lactamases than their sulfur counterparts... 

On a worldwide basis, total pharmaceutical sales for 1983 were 71 biUion, antibiotic sales totaled 9.2 biUion, and cephalosporins accounted for 1.2 biUion, or 13% of the antibacterial market (87). By 1986 the worldwide antibiotic market was valued at around 11 biUion and cephalosporins... 

Clavulanic acid has only weak antibacterial activity, but is a potent irreversible inhibitor for many clinically important P-lactamases (10—14,57,58) including penases, and Richmond-Sykes types 11, 111, IV, V, VI ([Bacteroides). Type I Cephases are poorly inhibited. Clavulanic acid synergizes the activity of many penicillins and cephalosporins against resistant strains. The chemistry (59—63), microbiology (64,65), stmcture activity relationships (10,13,60—62,66), biosynthesis (67—69), and mechanism of action (6,26,27,67) have been reviewed. 

All of the naturally-occurring monobactams discovered as of this writing have exhibited poor antibacterial activity. However, as in the case of the penicillins and cephalosporins, alteration of the C-3 amide side chain led to many potent new compounds (12). Furthermore, the monobactam nucleus provides a unique opportunity to study the effect of stmctural modifications at the N-1 and C-4 positions of the a2etidinone ring on biological activity. In contrast to the bicycHc P-lactams, these positions on the monocyclic ring system are readily accessible by synthesis. 

Pharmacologically useful isoxazoles (B-82MI41600) include antibacterial sulfonamides (614), (615) and (616), semisynthetic penicillins (617), (618), (619) and (620), semisynthetic cephalosporin (621), anabolic steroid (622), the monoamine oxidase inhibitor (623) (used in psychotherapy), antiinflammatory agent (624) and antitumor agent (625). 

Azetidin-2-ones are the most extensively studied derivatives of azetidine, largely as a result of the discovery of the antibacterial properties of penicillins, cephalosporins and... 

One of the major differences between penicillins and cephalosporins is the possibility for a concerted elimination of the C-3 substituent in the case of cephalosporins (6->7). There is now considerable evidence to support the idea that an increase in the ability of the C-3 substituent to act as a leaving group results in an increased reactivity of the 8-lactam carbonyl (75JMC408). Thus, both the hydrolysis rate of the 8-lactam and antibacterial activity... 

At Smith Kline French a general approach to cephalosporin and penicillin nuclear analogs was developed that utilizes a monocyclic /3-lactam (59) with the correct cis stereochemistry as a key intermediate. This is prepared by reaction of the mixed anhydride of azidoacetic acid and trifluoroacetic acid with imine (58) followed by oxidative removal of the dimethoxybenzyl group. This product could be further elaborated to intermediate (60) which, on reaction with a -bromoketones, provides isocephalosporins (61). These nuclear analogs displayed antibacterial properties similar to cephalosporins (b-79MI51000). 

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