Azalides from Azithromycin to New Azalide Derivatives

Abstract

Azalides are semi-synthetic macrolides, in which a nitrogen atom is introduced into a macrolactone ring via a Beckmann rearrangement. Starting from erythromycin, oximes, depending on the reaction conditions lactams, or bicyclic-imino-ethers were formed, which were further reduced to aminolactones. The cyclic amine 9a-became the precursor for novel, significantly more active derivatives, especially for 9-dihydro-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A with the generic name azithromycin. It showed a broad spectrum of antibacterial activity covering all significant bacteria causing respiratory tract infections. The greatest advantages of azithromycin are its unusual pharmacokinetics (high tissue distribution), metabolic stability and high tolerability. These properties have led in recent years to the widespread use of the azalide scaffold for the synthesis of new compounds with advantageous pharmacokinetics.The azalide scaffold possesses an amino and several hydroxyl groups, which could be substituted or transformed to obtain new compounds. Different derivatives were obtained by substitution on the nitrogen but a large variety of derivatives, such as ethers, esters and carbamates, were made by reactions with various hydroxyl groups. Substitutions on both nitrogen and hydroxyl or two hydroxyl groups yielded new, bridged compounds. The 4Љ-hydroxy group was oxidized to 4-oxo-, which was transformed via the oxime to 4-amino, or via epoxide to 4Љ-methylamino compounds. Cleavage of the cladinose sugar and further transformations gave 3-acyl or 3-oxo compounds, which were less active than 14-membered acylides or ketolides. Beckmann rearrangement of some 16-membered macrolide oximes yielded only 17-membered lactams, which were less active than starting macrolides, and could not be reduced to amines.Intramolecular rearrangement of azalide imino-ethers yielded 13-membered azalides. Some new 11a-azalides were obtained after oxidative cleavage of some 16-membered macrolides and additional cyclisation.

Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

“…However, since the general pharmacokinetic properties of roxithromycin are similar to those of erythromycin A, the search for more active and stable derivatives continued and ultimately, azithromycin (trade name: Zithromax, Table 1), which was the first azalide, was discovered [172,173]. Azithromycin (also CP 62,993 or XZ-450) differed from the other erythromycin derivatives due to its nitrogen-containing macrolactone ring [78,172,173]. In addition to its high stability and sustained tissue concentrations, azithromycin also had an extended activity spectrum, covering both Gram-positive and Gram-negative bacteria associated with respiratory tract infections [62,78,79,172].…”

“…Azithromycin (also CP 62,993 or XZ-450) differed from the other erythromycin derivatives due to its nitrogen-containing macrolactone ring [78,172,173]. In addition to its high stability and sustained tissue concentrations, azithromycin also had an extended activity spectrum, covering both Gram-positive and Gram-negative bacteria associated with respiratory tract infections [62,78,79,172]. Interestingly, azithromycin was the first derivative identified with a MOA different to that of erythromycin.…”

Biotic acts of antibiotics

“…On the other hand, there are continuous efforts to modify the existing macrolides to contain pathogens that are becoming resistant to older macrolides. Recent developments, for example, have been based on the use of azalide scaffold (Ištuk, 2011; Sugimoto et al, 2012), which was originally implemented in 9-dihydro-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A (azithromycin), the antibiotic with outstanding pharmacokinetic properties (Amsden, 2001; Mutak, 2007). …”

Recent Advances in the Medicinal Chemistry of Novel Erythromycin- Derivatized Antibiotics

“…Therefore, development of azithromycin derivatives has become popular in recent years [46]. GSK researcher recently designed and synthesized a variety of novel azithromycin analogues (Scheme 15) [47].…”