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

  • Perić, Mihaela1, 2
  • Pešić, Dijana1, 3
  • Alihodžić, Sulejman1, 3
  • Fajdetić, Andrea1, 3
  • Herreros, Esperanza4, 5
  • Gamo, Francisco Javier4
  • Angulo-Barturen, Iñigo4, 6
  • Jiménez-Díaz, Mª Belén4, 6
  • Ferrer-Bazaga, Santiago4
  • Martínez, María S4
  • Gargallo-Viola, Domingo4, 7
  • Mathis, Amanda8, 9
  • Kessler, Albane4
  • Banjanac, Mihailo1, 3
  • Padovan, Jasna1, 3
  • Mihaljević, Vlatka Bencetić1, 3
  • Munic Kos, Vesna1, 10
  • Bukvić, Mirjana1, 3
  • Eraković Haber, Vesna1, 3
  • Spaventi, Radan1, 11
  • 1 GlaxoSmithKline Research Centre Zagreb Ltd., Prilaz baruna Filipovića 29, 10000, Zagreb, Croatia. , (Croatia)
  • 2 Present address: University of Zagreb School of Medicine, Center for Translational and Clinical research, Department for Intercellular Communication, Šalata 2, 10000, Zagreb, Croatia. , (Croatia)
  • 3 Present address: Fidelta Ltd., Prilaz baruna Filipovića 29, 10000, Zagreb, Croatia. , (Croatia)
  • 4 GlaxoSmithKline, Tres Cantos Medicines Development Campus, Diseases of the Developing World, Severo Ochoa 2, 28760, Tres Cantos, (Madrid), Spain. , (Spain)
  • 5 Present address: Medicines for Malaria Venture, 20 Route de Pré-Bois, 1215, Geneva 15, Switzerland. , (Switzerland)
  • 6 Present address: The Art if Discovery, Biscay Science and Technology Park, Astondo Bidea, BIC Bizkaia building, n° 612, Derio 48160, Bizkaia, Basque Country, Spain. , (Spain)
  • 7 Present address: ABAC Therapeutics, Joan XXIII, 10, E-08950, Esplugues de Llobregat, Barcelona, Spain. , (Spain)
  • 8 GlaxoSmithKline, Five Moore Drive, Research Triangle Park, North Carolina, 27709-3398, USA.
  • 9 Present address: BioCryst Pharmaceuticals, 4505 Emperor Blvd., Durham, NC, 27703.
  • 10 Present address: Department of Physiology and Pharmacology, Karolinska Institutet, Solnavägen 9, SE-171 77, Stockholm, Sweden. , (Sweden)
  • 11 Present address: Triadelta Partners Ltd, Međimurska 19/2, 10090, Zagreb, Croatia. , (Croatia)
Published Article
British Journal of Pharmacology
Wiley (Blackwell Publishing)
Publication Date
Oct 21, 2020
DOI: 10.1111/bph.15292
PMID: 33085774


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. 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. 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. The hybrid derivatives described here represent excellent antimalarial drug candidates with the potential for clinical use in malaria therapy. This article is protected by copyright. All rights reserved.

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