Synthesis and biological properties of 4″-O-acyl derivatives of 8a-Aza-8a-homoerythromycin

Abstract

A series of 4 00 -O-acyl derivatives of 8a-aza-8a-homoerythromycins A were synthesized and tested against Gram-positive and Gram-negative bacteria. Derivatives of 8a-aza-8a-homoerythromycin A have potent anti-bacterial activity against not only azithromycin-susceptible strains, but also efflux (M) and inducible macrolide-lincosamide-streptogramin-resistant Gram-positive pathogens. These compounds show moderate to high clearance and low oral bioavailability in preliminary in vivo pharmacokinetic studies in rat.

4″-O-(ω-Quinolylamino-alkylamino)propionyl derivatives of selected macrolides with the activity against the key erythromycin resistant respiratory pathogens

“…7,8 In the past we have performed chemical modification of macrolides first by varying substituents at 9a-N-position of the azithromycin scaffold, 9 and then by modifying 8a-lactam at C(3)-OH 10 and C(4 00 )-OH positions. 11 Our recent communication reported on synthesis and antibacterial activities of the first macrolide compounds with 4 00 -O-(3-amino)propionyl unit as a part of the linker tethering the second structural unit. 12 This position was lately explored by other groups as well and they have shown that introducing carbamate functionality on position 4 00 of azithromycin lead to improved in vitro antibacterial activity against resistant Streptococcus pneumoniae.…”

Synthesis, activity and pharmacokinetics of novel antibacterial 15-membered ring macrolones

“…Among 14-membered derivatives, cethromycin [10e13], a 3-keto derivative, seems to exhibit antibacterial potency against resistant pathogens comparable/exceeding to telithromycin. In the past decade, we have explored 15-membered macrolide cores, including modifications on the N-9 position of aglycone ring [14e16], 3-decladinosyl derivatives [17,18] and acyl derivatives on 4 00 -position of cladinose [19] without achieving desirable antimicrobial profile.…”

Directed Evolution of a Modular Polyketide Synthase Thioesterase for Generation of a Hybrid Macrocyclic Ring System

“…39,40 In choosing a new hexaketide target, we were motivated by amidecontaining derivatives of erythromycin that show antibiotic activity comparable to azithromycin. [71][72][73][74][75] Thus, the impact of exchanging a central native C-Me functionality to N-H, creating an amide group in the chain-elongation intermediate (Scheme 1B) became a central objective. This choice was also made to assess the impact of a single heteroatom replacement in the chain on TE-mediated cyclization.…”