Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 51, Issue 12, Pages 3466-3479Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm701478a
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Funding
- NIAID NIH HHS [R01 AI045957, R01 AI045957-05A1, R01 AI060792, R01AI060792, R01 AI060792-04] Funding Source: Medline
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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 pK(a) 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.
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