4-Aminoquinolines Active against Chloroquine-Resistant Plasmodium falciparum: Basis of Antiparasite Activity and Quantitative Structure-Activity Relationship Analyses

Abstract

Chloroquine (CQ) is a safe and economical 4-aminoquinoline (AQ) antimalarial. However, its value has been severely compromised by the increasing prevalence of CQ resistance. This study examined 108 AQs, including 68 newly synthesized compounds. Of these 108 AQs, 32 (30%) were active only against CQ-susceptible Plasmodium falciparum strains and 59 (55%) were active against both CQ-susceptible and CQ-resistant P. falciparum strains (50% inhibitory concentrations [IC 50 s], <25 nM). All AQs active against both CQ-susceptible and CQ-resistant P. falciparum strains shared four structural features: (i) an AQ ring without alkyl substitution, (ii) a halogen at position 7 (Cl, Br, or I but not F), (iii) a protonatable nitrogen at position 1, and (iv) a second protonatable nitrogen at the end of the side chain distal from the point of attachment to the AQ ring via the nitrogen at position 4. For activity against CQ-resistant parasites, side chain lengths of <3 or >10 carbons were necessary but not sufficient; they were identified as essential factors by visual comparison of 2-dimensional (2-D) structures in relation to the antiparasite activities of the AQs and were confirmed by computer-based 3-D comparisons and differential contour plots of activity against P. falciparum. The advantage of the method reported here (refinement of quantitative structure-activity relationship [QSAR] descriptors by random assignment of compounds to multiple training and test sets) is that it retains QSAR descriptors according to their abilities to predict the activities of unknown test compounds rather than according to how well they fit the activities of the compounds in the training sets.The annual burden of malaria is overwhelming, with more than 300 to 500 million cases and 2 million deaths each year (3). In addition, its impact is exacerbated by the increasing prevalence of antimalarial resistance, which was the single most important factor in its recent worldwide resurgence (22,41). The most important resistance is that of Plasmodium falciparum to 7-chloro-4-(4-diethylamino-1-methylbutylamino)-quinoline (chloroquine [CQ]), because P. falciparum is responsible for most morbidity and mortality, and especially for the deaths of children under the age of 5 years in sub-Saharan Africa (3). For these reasons, and because resistance to the artemisinins and to the combination of atovaquone and proguanil (Malarone) is now emerging (14,20,33), the development of antimalarials that are effective against drug-resistant parasites-and that are affordable for the people in the greatest need-is an urgent global health priority.The established safety record of CQ, its ease of synthesis, and its low cost led us to examine the structure-activity relationships (SARs) responsible for the antiparasite activity of the 4-aminoquinolines (AQs) (10,11,26) with the goal of identifying the factors responsible for their activity against CQ-resistant parasites. The design and synthesis of AQ analogues during the past 5 to 10 years, in combination with biological te...

PfCRT and its role in antimalarial drug resistance

“…The HIV protease inhibitor saquinavir was also recently reported to have antimalarial activity by virtue of inhibiting PfCRT and acting as a CQR reversal agent [81]. Chemical modifications to CQ are also being engineered to develop potent analogs that overcome mutant PfCRT-mediated drug efflux [82, 83]. These chemical approaches illustrate the practical benefit gained from defining the molecular basis of CQR.…”

Know your enemy: understanding the role of PfCRT in drug resistance could lead to new antimalarial tactics

“…For example, shortening or lengthening the diaminoalkane side chain of CQ improves its activity against CQR parasites [193][194][195]. One of these short side-chain analogues of CQ, AQ13 (Fig.…”

Saquinavir Inhibits the Malaria Parasite's Chloroquine Resistance Transporter

“…CQ and SQV are both largely discarded drugs-the emergence of resistant parasites has rendered CQ largely ineffective (except when double-dose regimens are employed [35]), and SQV has been superseded by next-generation APIs. Nevertheless, new CQlike drugs that are effective against CQ-resistant parasites are being developed (6,15,17,24) and are undergoing clinical trials (22), and these could be paired with a next-generation SQV that possesses intrinsic antimalarial activity as well as the ability to inhibit mutant PfCRT. This would place an additional CQR -mediated CQ transport was calculated by subtracting the uptake measured in oocytes expressing D10 PfCRT CQS from that in oocytes expressing Dd2 PfCRT CQR .…”