Synthesis and Antibacterial Activity of Isomeric 15-Membered Azalides

Abstract

A series of 3-keto and 3-O-acyl derivatives of both 6-O-alkyl-8a-aza-8a-homoerythromycin A and 6-O-alkyl-9a-aza-9a-homo-erythromycin A were synthesised and tested against Gram-positive and Gram-negative bacteria. Derivatives of 8a-aza-8a-homoerythromycin A have potent antibacterial activity against not only azithromycin-susceptible strains, but also efflux (M) and inducible macrolide-lincosamide-streptogramin (iMLS B ) resistant Gram-positive pathogens, while the corresponding 9a-isomers were less active. Introduction of an additional ring such as 11,12-cyclic carbonate reduced antibacterial activity of both series. 3-Keto and 3-O-(4-nitrophenyl)-acetyl derivatives of 6-O-methyl-8a-aza-8a-homoerythromycin A show typical macrolide pharmacokinetics in preliminary in vivo studies in mice, and their in vivo efficacy is demonstrated.

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

“…Erythromycin, clarithromycin and azithromycin are the most extensively explored macrolides in the search for new classes of broad spectrum antibacterial agents. 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.…”

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

“…Starting compounds for the synthesis were 6-O-alkyl-8a-aza-8a-homoerythromycins A 5 (1)(2)(3)(4)(5) having acetyl as 2¢-hydroxy-protecting group. Compounds 6, 13-18, 22, 24, 27 and 29 were prepared by condensation of 2¢-protected compounds 1-5 with the corresponding (hetero)arylalkyl-carboxylic acid using 1-[(3-(dimethyl-amino)propyl]-3-ethyl-carbodiimide hydrochloride (EDC) in the presence of 4-(dimethyl-amino)pyridine (DMAP) in dichloromethane.…”

“…4 We recently reported on the synthesis of 3-keto and 3-O-acyl derivatives of 9a-and 8a-aza-8a-homoerythromycins A having antibacterial activity against sensitive pathogens as well as against macrolide-resistant Gram-positive pathogens. 5 In this report we describe a novel series of 4 00 -O-acyl derivatives of 8a-aza-8a-homoerythromycin A (8a-lactams), having (hetero)arylalkyl side chain on 4 00 -O atom, which showed potent anti-bacterial properties against sensitive pathogens and improved activity against several species of efflux (M) and inducible (iMLS B ) macrolideresistant Gram-positive pathogens.…”

Od vitamina do antibiotika – sjećanja jednog kemičara II. dio

“…Nakon što su naši 4''-supstituirani derivati 12 laktama i azitromicina pokazali izvrsno antibakterijsko djelovanje na rezistentne spojeve, 13,14 uključili su se u pripravu takvih kinolonskih spojeva na klaritromicinu 15 i roksitromicinu i kolege iz Verone. Sintetizirali su veći broj novih 4''-supstituranih derivata, među kojima su neki također imali odlično djelovanje na rezistentne mikroorganizme.…”