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

Jayakumar K. Natarajan, John Alumasa, Kimberly Yearick, Kekeli A. Ekoue-Kovi, Leah B. Casabianca, Angel C. De Dios, Christian Wolf, Paul D. Roepe

Research output: Contribution to journalArticle

86 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)3466-3479
Number of pages14
JournalJournal of Medicinal Chemistry
Volume51
Issue number12
DOIs
StatePublished - Jun 26 2008

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Chloroquine
Malaria
Nitrogen
Heme
Antimalarials

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Natarajan, Jayakumar K. ; Alumasa, John ; Yearick, Kimberly ; Ekoue-Kovi, Kekeli A. ; Casabianca, Leah B. ; De Dios, Angel C. ; Wolf, Christian ; Roepe, Paul D. / 4-N-, 4-S-, and 4-O-chloroquine analogues : Influence of side chain length and quinolyl nitrogen pKa on activity vs chloroquine resistant malaria. In: Journal of Medicinal Chemistry. 2008 ; Vol. 51, No. 12. pp. 3466-3479.
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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 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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4-N-, 4-S-, and 4-O-chloroquine analogues : Influence of side chain length and quinolyl nitrogen pKa on activity vs chloroquine resistant malaria. / Natarajan, Jayakumar K.; Alumasa, John; Yearick, Kimberly; Ekoue-Kovi, Kekeli A.; Casabianca, Leah B.; De Dios, Angel C.; Wolf, Christian; Roepe, Paul D.

In: Journal of Medicinal Chemistry, Vol. 51, No. 12, 26.06.2008, p. 3466-3479.

Research output: Contribution to journalArticle

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AU - Natarajan, Jayakumar K.

AU - Alumasa, John

AU - Yearick, Kimberly

AU - Ekoue-Kovi, Kekeli A.

AU - Casabianca, Leah B.

AU - De Dios, Angel C.

AU - Wolf, Christian

AU - Roepe, Paul D.

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