Antibiotics structural modification

Kirst, H. A., and Sides, G. D. (1989). New directions for macrolide antibiotics Structural modifications and in vitro activity. Antimicrob. Agents Chemother. 33, 1413-1418. 

Another basic drug where minor structural modification results in a dramatic increase in volume of distribution is the macrolide antibiotic, azithromycin. The traditional agent in this class is erythromycin, which contains one basic nitrogen, in the sugar side-chain. 

The most important tool in the arsenal of the product innovators is the ability to make predictions on which structure would lead to what properties, as well as what structure modifications would lead to what property modifications. The reverse research from a given set of properties to material that has these properties is even more important in creating new products and in modifying existing products. In most cases of molecular properties, it is more realistic to depend on empirical correlations between structure and properties. Forward and reverse searches are currently only available for simple physical-chemical properties, such as boiling points and densities such a facility is still not available for biological properties, such as narcotic and antibiotic activities. The development of such search engines would have a tremendous impact on the productivity of product innovators. 

Malabarba A, Nicas TI, Thompson RC (1997) Structural modifications of glycopeptide antibiotics. Med Res Rev 17 69-137... 

These results indicated that clinical PA isolates from various infections display marked heterogeneity with respect to the acylation state of their lipid A, reflecting differences in selective pressure that these infections impose on PA lipid A synthesis and structural modifications. Further study of the synthesis and regulation of lipid A modifications that are associated with CF lung disease is needed to understand their role in antibiotic resistance and other adaptations that are relevant to this specialized niche. 

STRUCTURAL MODIFICATIONS OF GLYCOPEPTIDE ANTIBIOTICS AND STRUCTURE ACTIVITY RELATIONSHIP (SAR) STUDIES... 

Fig. 13.6 Structural modifications at the 9 position of the tetracycline antibiotic minocycline conferring increased stability against resistance mechanisms.

The sulfonamides were discovered in Germany in the middle of the twentieth century subsequent to investigation of diazo dyes (7,8). There have been a number of structural modifications of sulfonamides producing numerous medicinal agents including antibiotics, thiazide diuretics and carbonic anhydrase inhibitors (8). One modification of the sulfonamides involving the addition of indoline was responsible for the production of indapamide. The first patent and USA patent citations may be found in References 9 and 10, respectively. One of the first non-patent literature references to indapamide appeared in 1974 (II). 

The first compound to arouse interest in the laboratory is the sulfamyl derivative of p-aminobenzoic acid. This was followed by carinamide, which was found to produce high plasma levels of penicillin for long periods of time even when relatively low doses of the antibiotic were administered orally. Probenecid, a structural modification of carinamide, was much more potent on a weight basis and on a dosage basis practical for oral administration. In fact, the combination of penicillin and probenecid was a practical oral formulation and was widely used for the treatment of infections until the costs and availability of penicillin were no longer factors and the better orally active penicillins became available. 

Several structural modifications of the C-9 ketone of erythromycin have been explored oximes and hydrazones are less prone to intramolecular cydization, but they often have less antibiotic activity than erythromycin (140). Synthesis of more complex oxime derivatives resulted in the development of roxithromycin, the 9-[0-(2-methoxyethoxy)methyl]oxime (33) (141). Reduction of the oximes and hydrazones produced 9(S)-erythromycylamine (34) as the principal product, with minor amounts of the 9(R)-isomer (140) however, clinical studies showed that 9(5)-erythromycyclamine and its N-benzylidene derivative were poody absorbed in humans (142). Evaluation of more complex oxazine derivatives of erythromycylamine led to dirithromycin, the 2-(2-methoxyethoxy)ethylidene oxazine derivative (35) (143). A third route to modification of the ketone utilized a Beckmann rearrangement of the 9-oxime to expand the 14-membered ring to a 15-membered intermediate, which was subsequently reduced and AT-methylated to yield azithromycin (36) (144,145). The term azalide was proposed to denote these 15-membered azalactones (10,145). 

The successes achieved in the past decade with chemically modified penicillins, tetracyclines, and lincomycin, undoubtedly influenced the judgment of the panel that preparation of structural analogs of useful antibiotics by chemical or other means should be ranked as one of the two most promising discovery approaches for the next decade. Before proceeding further with the evaluation made by the respondents of the five approaches (Table VII), some aspects of the history and nature of the structural modification approach are examined. 

Structural Modification of Antibiotics. Historical Review. Writing in 1945, Waksman (7) set forth in prophetic terms the role that the medicinal chemist was to play in the antibiotic field. 

From the point of view of importance and chemical feasibility, chloramphenicol (Figure 9) presented an excellent subject for structural modification. It was the first truly broad-spectrum antibiotic isolated, and its structure and total synthesis were both reported two years after the discovery was announced (40, 41, 42). The synthesis of chloramphenicol analogs proved to be one of the great disappointments of early chemical research in the antibiotic field. Hundreds of analogs were synthesized, but none was found superior to the parent drug in terms either of antimicrobial activity or therapeutic index (43). The palmitate and hemisuccinate esters have provided superior dosage forms for oral and parenteral use. One synthetic analog, thiamphenicol (44) has achieved limited use in human and veterinary medicine. 

Structural Modification of Toxic or Poorly Efficacious Antibiotics. 

Guiding Principles for Structural Modification of Existing Antibiotics. Some general principles emerge from the foregoing discussion of drug discovery via structural modification of existing antibacterial antibiotics (presently useful or otherwise). 

Drug discovery usually requires prior mastery of the chemistry of the parent antibiotic structure reasonably facile methods for making selective and systematic structural modifications must be perfected. A versatile intermediate from which a variety of congeners may be synthesized is exceedingly useful in this regard. 

Macrolide antibiotics contain a many-membered lactone ring (14-membered rings for erythromycin and clarithromycin, and a 15-membered ring for azithromycin) to which are attached one or more deoxy sugars. Clarithromycin differs from erythromycin only by methylation of the hydroxyl group at the 6 position, and azithromycin differs by the addition of a methyl-substituted nitrogen atom into the lactone ring. These structural modifications improve acid stability and tissue penetration and broaden the spectrum of activity. 

In summary, research on structural modification of macrolide antibiotics appears to have a bright future. 

Kirst, H. A. (1990). Structure modification of macrolide antibiotics. In Recent Progress in the Chemical Synthesis of Antibiotics (G. Lukacs and M. Ohno, Eds.), pp. 40-63. Springer-Verlag, Heidelberg. 

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