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Azithromycin, an azalide antibiotic, was found useful in malaria therapy, but its efficacy in humans is low.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>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 <jats:styled-content style=\"fixed-case\"><jats:italic>Plasmodium falciparum<\/jats:italic><\/jats:styled-content>, cytotoxicity against HepG2 cells, accumulation and retention in human erythrocytes, antibacterial activity, and mode of action studies (delayed death phenotype and haem polymerization). in vivo assessment enabled determination of pharmacokinetic profiles in mice, rats, dogs, and monkeys and in vivo efficacy in a humanized mouse model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Novel fast\u2010acting azalides were highly active in vitro against <jats:styled-content style=\"fixed-case\"><jats:italic>P. falciparum<\/jats:italic><\/jats:styled-content> strains exhibiting various resistance patterns, including chloroquine\u2010resistant strains. Excellent antimalarial activity was confirmed in a <jats:styled-content style=\"fixed-case\"><jats:italic>P. falciparum<\/jats:italic><\/jats:styled-content> murine model by strong inhibition of haemozoin\u2010containing trophozoites and quick clearance of parasites from the blood. Pharmacokinetic analysis revealed that compounds are metabolically stable and have moderate oral bioavailability, long half\u2010lives, low clearance, and substantial exposures, with blood cells as the preferred compartment, especially infected erythrocytes. Fast anti\u2010plasmodial action is achieved by the high accumulation into infected erythrocytes and interference with parasite haem polymerization, a mode of action different from slow\u2010acting azithromycin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>The hybrid derivatives described here represent excellent antimalarial drug candidates with the potential for clinical use in malaria therapy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15292","type":"journal-article","created":{"date-parts":[[2020,10,21]],"date-time":"2020-10-21T19:25:29Z","timestamp":1603308329000},"page":"363-377","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A novel class of fast\u2010acting antimalarial agents: Substituted 15\u2010membered azalides"],"prefix":"10.1111","volume":"178","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1904-2193","authenticated-orcid":false,"given":"Mihaela","family":"Peric","sequence":"first","affiliation":[{"name":"GlaxoSmithKline Research Centre Zagreb Ltd.  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