Overcoming Drug Resistance to Heme-Targeted Antimalarials by Systematic Side Chain Variation of 7-Chloro-4-aminoquinolines

Abstract

Systematic variation of the branching and basicity of the side chain of chloroquine yielded a series of new 7-chloro-4-aminoquinoline derivatives exhibiting high in vitro activity against four different strains of P. falciparum. Many of the compounds tested showed excellent potency against chloroquine sensitive and resistant strains. In particular 4b, 5a, 5b, 5d, 17a, and 17b were found to be significantly more potent than chloroquine against the resistant strains Dd2 and FCB.

“Recycling” Classical Drugs for Malaria

“…174 This study aimed at understanding the influence of different structural parameters, namely the length of the linker between the trioxane and 4-AQ motifs (146e,f) and the nature of the starting diene (147). These molecules presented antimalarial activities in the low nanomolar range (IC 50 = 5−181 nM) against both CQ-sensitive and resistant strains.…”

Relative to Quinine and Quinidine, Their 9-Epimers Exhibit Decreased Cytostatic Activity and Altered Heme Binding but Similar Cytocidal Activity versus Plasmodium falciparum

“…Synthesis and chemical characterization of CQ analogues 1 to 5 have been reported previously (24,(41)(42)(43). Compounds 6 to 9 were synthesized as described below.…”

“…Briefly, cultures were maintained under an atmosphere containing 5% O 2 , 5% CO 2 , 90% N 2 gaseous mix at 2% hematocrit and 1 to 2% parasitemia in RPMI 1640 supplemented with 10% type O-positive human serum, 25 mM HEPES (pH 7.4), 23 mM NaHCO 3 , 11 mM glucose, 0.75 mM hypoxanthine, and 20 g/liter gentamicin with regular medium changes every 48 h. Antiplasmodial cytocidal (LD 50 ) and cytostatic (IC 50 ) activities against the chloroquinesensitive (CQS) HB3 strain and CQR Dd2 strain were assessed. Cytostatic antiplasmodial activities have previously been reported for some drugs used in this study (24,(41)(42)(43), and additional activities were determined as described previously (47,48), with minor modifications.…”

Gold(I) complex of 1,1′-bis(diphenylphosphino) ferrocene–quinoline conjugate: a virostatic agent against HIV-1

“…1,1'-Bis(diphenylphosphino)ferrocene-quinoline conjugate (2) was successfully synthesized by the amide coupling of a carboxylic acid derivative of 1,1'-bis(diphenylphosphino)ferrocene (1) (Bjelosevic et al 2006) with N1-(7-chloroquinolin-4-yl)ethane-1,2-diamine (Yearick et al 2008) (Scheme 1). The reaction of compound 2 with chloro(tetrahydrothiophene)gold(I), [Au(tht)Cl] in 1:2 molar ratio in dichloromethane at room temperature gave the corresponding gold complex (3) in 88% yield (Scheme 2) (Uson et al 1989).…”