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4-N-, 4-S-, and 4-O-chloroquine analogues: influence of side chain length and quinolyl nitrogen pKa on activity vs chloroquine resistant malaria.

Abstract：

:Using predictions from heme-quinoline antimalarial complex structures, previous modifications of chloroquine (CQ), and hypotheses for chloroquine resistance (CQR), we synthesize and assay CQ analogues that test structure-function principles. We vary side chain length for both monoethyl and diethyl 4-N CQ derivatives. We alter the pKa of the quinolyl N by introducing alkylthio or alkoxy substituents into the 4 position and vary side chain length for these analogues. We introduce an additional titratable amino group to the side chain of 4-O analogues with promising CQR strain selectivity and increase activity while retaining selectivity. We solve atomic resolution structures for complexes formed between representative 4-N, 4-S, and 4-O derivatives vs mu-oxo dimeric heme, measure binding constants for monomeric vs dimeric heme, and quantify hemozoin (Hz) formation inhibition in vitro. The data provide additional insight for the design of CQ analogues with improved activity vs CQR malaria.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Natarajan JK,Alumasa JN,Yearick K,Ekoue-Kovi KA,Casabianca LB,de Dios AC,Wolf C,Roepe PD

doi

10.1021/jm701478a

subject

Has Abstract

pub_date

2008-06-26 00:00:00

pages

3466-79

issue

12

eissn

0022-2623

issn

1520-4804

journal_volume

51

pub_type

杂志文章

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