Novel hybrid molecules based on 15-membered azalide as potential antimalarial agents

Malaria remains the most prevalent tropical disease, and due to the spread of resistant parasites novel therapeutics are urgently needed. Azithromycin has shown potential in malaria treatment so we designed hybrid azalide molecules with the aim to improve activity against and selectivity for the malaria parasite. Novel hybrid molecules comprising 4-aminoquinoline moiety covalently liked to 15-membered azalide scaffold at position C-3′ were synthesized and biologically evaluated. Antimalarial testing against Plasmodium falciparum sensitive and resistant strains confirmed the improved in vitro activity over azithromycin and chloroquine. Selectivity of the compounds (HepG2 IC50/P. falciparum IC50 ratio) for the parasite was high (100–2700) and their antibacterial activity diminished. Even though oral bioavailability determined for compound 12 was low, novel quinoline C-3′-substituted 15-membered azalides represent an interesting subclass of antimalarial macrolides that need further research and evaluation.

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► Synthesis of C-3′-substituted azalide derivatives with 4-aminoquinoline moiety.
► Novel compounds show high in vitro activity and selectivity for Plasmodium falciparum.
► Increased antimalarial activity over azithromycin and chloroquine.
► Compounds exhibit diminished antibacterial action compared to azithromycin.