Antimalarial Activity of 9a-N Substituted 15-Membered Azalides with Improved in Vitro and in Vivo Activity over Azithromycin

作者：Peric Mihaela^*; Fajdetic Andrea; Rupcic Renata; Alihodzic Sulejman; Ziher Dinko; Krajacic Mirjana Bukvic; Smith Kirsten S; Ivezic Schoenfeld Zrinka; Padovan Jasna; Landek Goran; Jelic Dubravko; Hutinec Antun; Mesic Milan; Ager Arba; Ellis William Y; Milhous Wilbur K; Ohrt Colin; Spaventi Radan

来源：Journal of Medicinal Chemistry, 2012, 55(3): 1389-1401.

DOI：10.1021/jm201615t

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.

• 出版日期2012-2-9