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

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Perić M,Fajdetić A,Rupčić R,Alihodžić S,Ziher D,Bukvić Krajačić M,Smith KS,Ivezić-Schönfeld Z,Padovan J,Landek G,Jelić D,Hutinec A,Mesić M,Ager A,Ellis WY,Milhous WK,Ohrt C,Spaventi R

doi

10.1021/jm201615t

subject

Has Abstract

pub_date

2012-02-09 00:00:00

pages

1389-401

issue

3

eissn

0022-2623

issn

1520-4804

journal_volume

55

pub_type

杂志文章

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