4-N-, 4-S-, and 4-O-chloroquine analogues: influence of side chain length and quinolyl nitrogen pKa on activity vs chloroquine resistant malaria.
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.
Department of Chemistry, Center for Infectious Disease, Georgetown University, 37th and O Streets, Washington, DC 20057, USA.
Jayakumar K
JK
Natarajan
John N
JN
Alumasa
Kimberly
K
Yearick
Kekeli A
KA
Ekoue-Kovi
Leah B
LB
Casabianca
Angel C
AC
de Dios
Christian
C
Wolf
Paul D
PD
Roepe
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D052160:Benzothiazoles; D002738:Chloroquine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D003959:Diamines; D004351:Drug Resistance; D005456:Fluorescent Dyes; D007364:Intercalating Agents; D008958:Models, Molecular; D009930:Organic Chemicals; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D011804:Quinolines; D013329:Structure-Activity Relationship
D000962:Antimalarials; D052160:Benzothiazoles; D003959:Diamines; D005456:Fluorescent Dyes; D007364:Intercalating Agents; D009930:Organic Chemicals; D011804:Quinolines; C098022:SYBR Green I; D002738:Chloroquine