Novel class of fast acting antimalarial agents: substituted 15‐membered azalides

BACKGROUND AND PURPOSE Efficacy of current antimalarial treatments is declining as a result of increasing antimalarial drug resistance so new and potent antimalarial drugs are urgently needed. Azithromycin, a blockbuster azalide antibiotic, was found useful in malaria therapy but its efficacy in humans is low. EXPERIMENTAL APPROACH Four compounds belonging to structurally different azalide classes were tested and their activities compared to azithromycin and chloroquine. In vitro evaluation included testing against sensitive and resistant P. falciparum, cytotoxicity against HepG2, accumulation and retention in human erythrocytes, antibacterial activity, and mode of action studies (delayed death phenotype and heme polymerization). In vivo assessment enabled determination of pharmacokinetic profiles in mice, rats, dogs and monkeys and in vivo efficacy in humanized mouse model. KEY RESULTS Novel fast acting azalides are highly active in vitro against Plasmodium falciparum strains exhibiting various resistance patterns, including chloroquine resistant strains. Excellent antimalarial activity was confirmed in a P. falciparum murine model by strong inhibition of hemozoin-containing trophozoites and quick clearance of parasites from the blood. Pharmacokinetic analysis revealed compounds are metabolically stable, have moderate oral bioavailability, long half-lives, low clearance and substantial exposures, with blood cells as the preferred compartment, especially infected erythrocytes. Fast antiplasmodial action is achieved by the high accumulation into infected erythrocytes and interference with parasite heme polymerization, a mode of action different from slow acting azithromycin. CONCLUSION AND IMPLICATIONS The hybrid derivatives described here represent excellent antimalarial drug candidates with the potential for clinical use in malaria therapy.