TY - JOUR
T1 - 4-N-, 4-S-, and 4-O-chloroquine analogues
T2 - Influence of side chain length and quinolyl nitrogen pKa on activity vs chloroquine resistant malaria
AU - Natarajan, Jayakumar K.
AU - Alumasa, John N.
AU - Yearick, Kimberly
AU - Ekoue-Kovi, Kekeli A.
AU - Casabianca, Leah B.
AU - De Dios, Angel C.
AU - Wolf, Christian
AU - Roepe, Paul D.
PY - 2008/6/26
Y1 - 2008/6/26
N2 - 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 μ-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.
AB - 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 μ-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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U2 - 10.1021/jm701478a
DO - 10.1021/jm701478a
M3 - Article
C2 - 18512900
AN - SCOPUS:45749094225
SN - 0022-2623
VL - 51
SP - 3466
EP - 3479
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 12
ER -