2. Academic Validation
  3. Antimalarial activity of 9a-N substituted 15-membered azalides with improved in vitro and in vivo activity over azithromycin

Antimalarial activity of 9a-N substituted 15-membered azalides with improved in vitro and in vivo activity over azithromycin

  • J Med Chem. 2012 Feb 9;55(3):1389-401. doi: 10.1021/jm201615t.
Mihaela Perić 1,  Andrea Fajdetić,  Renata Rupčić,  Sulejman Alihodžić,  Dinko Ziher,  Mirjana Bukvić Krajačić,  Kirsten S Smith,  Zrinka Ivezić-Schönfeld,  Jasna Padovan,  Goran Landek,  Dubravko Jelić,  Antun Hutinec,  Milan Mesić,  Arba Ager,  William Y Ellis,  Wilbur K Milhous,  Colin Ohrt,  Radan Spaventi
Affiliations

Affiliation

  • 1 GlaxoSmithKline Research Centre Zagreb Ltd., Prilaz baruna Filipovića 29, 10000 Zagreb, Croatia. mihaela.peric@mef.hr
PMID: 22148880 DOI: 10.1021/jm201615t
Abstract

Novel classes of antimalarial drugs are needed due to emerging drug resistance. Azithromycin, the first Macrolide investigated for malaria treatment and prophylaxis, failed as a single agent and thus novel analogues were envisaged as the next generation with improved activity. We synthesized 42 new 9a-N substituted 15-membered azalides with amide and amine functionalities via simple and inexpensive chemical procedures using easily available building blocks. These compounds exhibited marked advances over azithromycin in vitro in terms of potency against Plasmodium falciparum (over 100-fold) and high selectivity for the Parasite and were characterized by moderate oral bioavailability in vivo. Two amines and one amide derivative showed improved in vivo potency in comparison to azithromycin when tested in a mouse efficacy model. Results obtained for compound 6u, including improved in vitro potency, good pharmacokinetic parameters, and in vivo efficacy higher than azithromycin and comparable to chloroquine, warrant its further development for malaria treatment and prophylaxis.

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