Tetracyclines antibacterial activity

Conversion of the C-2 amide to a biologically inactive nitrile, which can be further taken via a Ritter reaction (29) to the corresponding alkylated amide, has been accomphshed. When the 6-hydroxyl derivatives are used, dehydration occurs at this step to give the anhydro amide. Substituting an A/-hydroxymethylimide for isobutylene in the Ritter reaction yields the acylaminomethyl derivative (30). Hydrolysis affords an aminomethyl compound. Numerous examples (31—35) have been reported of the conversion of a C-2 amide to active Mannich adducts which are extremely labile and easily undergo hydrolysis to the parent tetracycline. This reverse reaction probably accounts for the antibacterial activity of these tetracyclines. 

The hemiketal products (11) and (12) have been converted to the corresponding oximes, hydra2ones, and substituted amines (40,41). Although many of these derivatives exhibit substantial antibacterial activity, they are generally less active than the parent tetracyclines. 

The isolation of the 6-deoxytetracyclines (44) led to other chemical modifications of (1). 6P-Deoxytetracycline [5614-03-9] (13), prepared by catalytic hydrogenolysis of tetracycline (1), resulting ia an iaversion (45) of the configuration at the C-6 position, but retention of antibacterial activity. Catalytic reduction (7,8) of the 6-methylene derivative (14) yields both the 6a-methyl (15) and 6P-methyl compound (13). The 6a-isomer (15) is reported (7,45) to be more active than the 6P isomer (13). The a-isomer, doxycycline (6), is an example of a semisynthetic tetracycline that has become commercially useful. 

X-ray crystallographic studies (59) have defined the conformations and hydrogen bonding of the tetracyclines under nonpolar and polar conditions. These are shown ia Figure 3. It is beheved that the equiUbrium between the 2witterionic and nonioni2ed forms is of importance for the broad-spectmm antibacterial activity, membrane permeation, and pharmacokinetic properties. 

Efforts have been made to correlate electronic stmcture and biological activity in the tetracycline series (60,61). In both cases, the predicted activities are of the same order as observed in vitro with some exceptions. The most serious drawback to these calculations is the lack of carryover to in vivo antibacterial activity. Attempts have also been made (62) to correlate partition coefficients and antibacterial activity. The stereochemical requirements are somewhat better defined. Thus 4-epitetracycline and 5a-epitetracycline [65517-29-5] C22H24N20g, are inactive (63). The 6-epi compound [19369-52-9] is about one-half as active as the 6a (or natural) configuration. 

The broad antibacterial activity of rifaximin as well as its topical action make this antibiotic suitable for intrapocket administration in periodontal disease. As a matter of fact, local application of rifaximin compares well with tetracyclines and metronidazole in other extra-GI diseases, i.e. skin infections and BY, respectively (see above). On the other hand, rifampicin (rifampin), another rifamy-cin derivative, has been successfully used in the treatment... 

The tetracyclines Form an important group of antibiotics. The activity appears to result from their ability to chelate metal ions since the extent of antibacterial activity parallels the ability to form stable chelates. The metal in question appears to be magnesium or calcium since the addition of large amounts of magnesium can inhibit the antibiotic effects. In addition, it is known that in blood plasma the tetracyclines exist as calcium and magnesium complexes.,JS... 

For almost half a century, tetracycline (68) has been well-known as a major antibiotic from the viewpoint of its unique structural features as well as antibacterial activities 24). The total synthesis of tetracycline families was initiated by Woodward s 6-demethyl-6-deoxytetracycline synthesis in 1962 (25), followed by Muxfeldt s terramycin synthesis in 1968 (26), and culminated by Stork s 12a-deoxytetracycline synthesis in 1996 (27). However, all these syntheses have been accomplished only in racemic forms. The total synthesis of... 

Concurrent administration with phenylbutazone increases plasma concentrations, but lowers tissue concentrations, of penicillin G. Bacteriostatic antimicrobial agents, such as chloramphenicol and the tetracyclines, antagonize the antibacterial activity of penicillin G. 

Finally we mention the tetracyclines, which are derivatives of the fonr-ring aromatic compound represented in Figure 7.33c. These drugs have the broadest spectrum of antibacterial activity found to date. 

Insights were sought at Pfizer by which molecular structure and shape, electronic properties, acid strength, chelating ability, and lipo-philicity might be related to potency or range of antibacterial activity. These studies were complicated by the fact that large differences observed in vitro were often reduced or completely nullified in vivo. Such observations focused attention upon the interplay of structural and pharmacokinetic properties of tetracyclines. 

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