Synthesis, in vitro and in vivo activity of novel 9-deoxo-9a-aza-9a-homoerythromycin A derivatives; A new class of macrolide antibiotics, the azalides.

Abstract

A series of erythromycin A-derived semisynthetic antibiotics, featuring incorporation of a basic nitrogen atom into a ring expanded (15-membered) macrocyclic lactone, have been prepared and biologically evaluated. Semisynthetic modifications focused upon (1) varied substitution at the macrocyclic ring nitrogen and (2) epimerization or amine substitution at the C-4" hydroxyl site within the cladinose sugar. In general, the new azalides exhibit improved Gram-negative potency, expanding the spectrum of erythromycin A to fully include Haemophilus influenzae and Neisseria gonorrhoeae. Whencompared to erythromycin A, the azalides exhibit substantially increased half-life and area-under-the-curve values in all species studied. The overall in vitro/in vivo performance of TV-methyl, C-4" epimers 3a and 9; and C-4" amine ll identify these compounds as the most interesting erythromycin Asuperior agents. Compound3a has been advanced to clinical study. 1029Erythromycin A is a widely used antibiotic in oral outpatient therapy, including pediatrics. It is frequently the agent of choice for treatment of respiratory, cutaneous, Chlamydia, and Campylobacter infections. However, erythromycin A is not indicated for the treatment of Haemophilus influenzae except with co-administration of sulfonamides. Erythromycin A is also unstable at gastric pH, and is poorly absorbed with oral dosing.In our effort to expand the antimicrobial spectrum and to improve upon the pharmacokinetic properties of erythromycin A, the syntheses of erythromycin A-derived 15-membered aza-macrolides depicted in Schemes 1 and 2 were undertaken. Herein are presented the antibacterial profiles of the series, which features varied alkyl substitution at the 9a-aza site within the macrocyclic ring, and modifications at the C-4" site within the cladinose sugar. Additionally, for selected compounds, antiinfective activity against Staphylococcus aureus in mice, and pharmacokinetic profiles in several species are presented.

Azithromycin, a Lysosomotropic Antibiotic, Has Distinct Effects on Fluid-Phase and Receptor-Mediated Endocytosis, but Does Not Impair Phagocytosis in J774 Macrophages

“…Using primary cultures of rat fetal fibroblasts, we recently reported that the dicationic acid-stable macrolide antibiotic, azithromycin [31,32], markedly inhibits fluid-phase uptake of horseradish peroxidase (HRP) and subsequent transfer to lysosomes, without affecting regurgitation [33]. It was also noticed that azithromycin caused an extensive vacuolation of late endocytic compartments.…”

Hyperactivity of cathepsin B and other lysosomal enzymes in fibroblasts exposed to azithromycin, a dicationic macrolide antibiotic with exceptional tissue accumulation

“…Azithromycin is a dicationic derivative of erythromycin A [1,2] which avidly accumulates in tissues [3,4] and in cultured mammalian cells, reaching intracellular to extracellular concentrations ratios of 100 and more [5]. Cell fractionation studies show that the bulk of the drug accumulated by cells localizes in the lysosomes [6].…”

Azalides from Azithromycin to New Azalide Derivatives

“…In 1986 Pfizer, whose scientists also worked on this compound class [24,25], decided to licence-in azithromycin from PLIVA for worldwide markets. During the process development, 8 was first isolated as the anhydrous substance [14].…”

“…Initial derivatives targeting the hydroxyl groups were esters: mono-, di-or tri-acetyl on the 2Ј-O-, 4Љ-O-and 11-O-hydroxyl groups, which were prepared using acetic anhydride with pyridine [32]. Reaction of 8 or its diacetyl derivative with ethylene carbonate and potassium carbonate yielded the corresponding 11,12-carbonates (25) or its diacetyl derivatives (Fig. 7).…”

“…Using reductive alkylation with formaldehyde or acetaldehyde, 8 or its 9a-ethyl analogue were prepared. To avoid the formation of quaternary ammonium salt, some N-alkyl substituted derivatives were prepared by reaction (Scheme 6) of the corresponding halides and the N-hydroxy derivative 14 was generated from amine 7 [25].…”