Naslov
Design, Synthesis, and in Vitro Activity of Novel 2′-O-Substituted 15-Membered Azalides

Autori
Pešić, Dijana ; Starčević, Kristina ; Toplak, Ana ; Herreros, Esperanza ; Vidal, Jaume ; Jesus Almela, Maria ; Jelić, Dubravko ; Alihodžić, Sulejman ; Spaventi, Radan ; Perić, Mihaela

Izvornik
Journal of medicinal chemistry (0022-2623) 55 (2012), 7; 3216-3227

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
malaria; antimalarial; azalide; quinoline; hybrid molecules; Plasmodium falciparum

Sažetak
Malaria remains one of the most widespread human infectious diseases, and its eradication will largely depend on antimalarial drug discovery. Here, we present a novel approach to the development of the azalide class of antimalarials by describing the design, synthesis, and characterization of novel 2′-O-substituted-9-deoxo-9a-methyl-9a-aza-9ahomoerythromycin A derivatives consisting of different quinoline moieties covalently liked to a 15-membered azalide scaffold at position 2′. By multistep straightforward synthesis, 19 new, stable, and soluble compounds were created and biologically profiled. Most active compounds from the 4-amino-7-chloroquinoline series showed high selectivity for P. falciparum parasites, and in vitro antimalarial activity improved 1000-fold over azithromycin. Antimalarial potency was equivalent to chloroquine against the sensitive strain (3D7A) and up to 48-fold enhanced over chloroquine against the chloroquine-resistant strain (W2). Concurrently, the antibacterial activity of the compounds was eliminated, thus facilitating the development of malaria-specific macrolide agents.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti, Farmacija

POVEZANOST RADA