Lactone ring azithromycin

Azithromycin is rapidly absorbed and well tolerated orally. It should be administered 1 hour before or 2 hours after meals. Aluminum and magnesium antacids do not alter bioavailability but delay absorption and reduce peak serum concentrations. Because it has a 15-member (not 14-member) lactone ring, azithromycin does not inactivate cytochrome P450 enzymes and therefore is free of the drug interactions that occur with erythromycin and clarithromycin. 

Azithromycin is an azalide antibiotic, a sub-class of the macrolides. Azithromycin differs chemically from erythromycin in that a methyl substituted nitrogen atom is incorporated into the lactone ring. 

The macrolides are a group of closely related compounds characterized by a macrocyclic lactone ring (usually containing 14 or 16 atoms) to which deoxy sugars are attached. The prototype drug, erythromycin, which consists of two sugar moieties attached to a 14-atom lactone ring, was obtained in 1952 from Streptomyces erythreus. Clarithromycin and azithromycin are semisynthetic derivatives of erythromycin. 

The macrolides form an important group of clinically useful antibiotics. Older members include erythromycin (6), oleandomycin, triacetyloleando-mycin and spiramycin, now joined by clarithromycin (44), roxithromycin (45) and azithromycin (46) [196]. Enterobacteria which show a high level of insusceptibility to erythromycin can inactivate the antibiotic by plasmid-encoded esterases that hydrolyse the lactone ring [197],... 

Fig. 4.7 Superposition of macrolides. A cutaway view of a space-filled representation of rRNA (gray) and protein (light blue) show the peptide exit tunnel (left) and the peptidyl transferase center (upper right) of H. maris-mortui. The lactone rings of tylosin (orange sticks), carbomycin A (red sticks), spiramycin (yellow sticks) and azithromycin (light blue sticks) become superimposed when rRNA is superimposed among these structures. The lactone rings bind to the hydrophobic crevice...

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. 

Macrolide antibiotics are a homogeneous group of antimicrobial drugs that have been used to treat clinical infections for several decades. The most clinically useful classification of the macrolides is based on the size of the lactone ring that forms the chemical nucleus of each macrolide molecule [1, 2]. The 14- and 15-membered macrolides include erythromycin, clarithromycin, dirithromycin, roxithromycin, and azithromycin. Erythromycin is the oldest and still the most important of the macrolide antibiotics because it is a useful alternative to penicillin G. It is one of the safest antibiotics available. Clarithromycin and azithromycin have shown some advantages over erythromycin in their antibacterial activity,... 

The pKi, values, 4.2 and 8.6, in ABT-773 depend on the N in quinoline and C3 -dimethylamino group, respectively [44]. Those of azithromycin, 8.1 and 8.8, given by the 9a-imido in the lactone ring and C3 -dimethylamino group, respectively, were obtained from Zithromac Chemistry and Pharmacy. (2000). In Interviewform, 2nd ed., pp. 11-12. Pfizer Pharmaceuticals, Tokyo. 

The antibacterial spectrum of these macrolides is broader. For example, the clinical modification at C6 [e.g., O-methylation (clarithromycin)] or at C9 [e.g., some 9-ether oxime derivatives (roxithromycin and dirithromycin)] stabilizes 14-membered lactone rings in acidic media, even when the modified drugs have been orally administered. Drugs with an expanded erythromycin A-lactone ring (e.g., azithromycin) are also more stable in acidic media and display better antigram-negative activity than does erythromycin A. 

Macrolides are lipophilic molecules composed of a characteristic 12- to 16-membered lactone ring as the aglycon and several amino and/or neutral sugars. Erythromycin, clarithromycin, and roxithromycin with 14-membered rings azithromycin with a 15-membered ring and rokitamycin, josamycin, and mideca-mycin (MDM) with 16-membered rings have been so far used in clinical practice. 

Azithromycin, called an azalide, has been formed by semisynthetic conversion of erythromycin to a ring-expanded analogue in which an N-methyl group has been inserted between carbons 9 and 10, and the carbonyl moiety thus is absent (Fig. 38.28). Azithromycin has a 15-membered lactone ring. 

Fig. 6.1 Structure of the macrolide antibiotic erythromycin (a) which contains a 14-membeied lactone ring. The azalide, azithromycin (b), derived from erythromycin, has an iV-methyl group incorporated into the lactone ring, making it a 15-membered ring (compare highlighted sections)...

The solution conformation of azithromycin, which contains desosamine and cladinose attached to a IS-membered aza-lactone ring, has been determined from n.m.r. data and... 

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