Design, synthesis, and in vitro activity of novel 2'-O-substituted 15-membered azalides |
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Authors: | Pešić Dijana Starčević Kristina Toplak Ana Herreros Esperanza Vidal Jaume Almela Maria Jesus Jelić Dubravko Alihodžić Sulejman Spaventi Radan Perić Mihaela |
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Institution: | GlaxoSmithKline Research Centre Zagreb Ltd., Prilaz baruna Filipovi?a 29, 10000 Zagreb, Croatia. |
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Abstract: | 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-9a-homoerythromycin 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. |
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