Objectives:To determine: (1) the pharmacokinetics and safety of an investigational aminoquinoline active against multidrug–resistant malaria parasites (AQ-13), including its effects on the QT interval, and (2) whether it has pharmacokinetic and safety profiles similar to chloroquine (CQ) in humans. Design:Phase I double-blind, randomized controlled trials to compare AQ-13 and CQ in healthy volunteers. Randomizations were performed at each step after completion of the previous dose.Setting:Tulane–Louisiana State University–Charity Hospital General Clinical Research Center in New Orleans.Participants:126 healthy adults 21–45 years of age.Interventions:10, 100, 300, 600, and 1,500 mg oral doses of CQ base in comparison with equivalent doses of AQ-13.Outcome Measures:Clinical and laboratory adverse events (AEs), pharmacokinetic parameters, and QT prolongation.Results:No hematologic, hepatic, renal, or other organ toxicity was observed with AQ-13 or CQ at any dose tested. Headache, lightheadedness/dizziness, and gastrointestinal (GI) tract–related symptoms were the most common AEs. Although symptoms were more frequent with AQ-13, the numbers of volunteers who experienced symptoms with AQ-13 and CQ were similar (for AQ-13 and CQ, respectively: headache, 17/63 and 10/63, p = 0.2; lightheadedness/dizziness, 11/63 and 8/63, p = 0.6; GI symptoms, 14/63 and 13/63; p = 0.9). Both AQ-13 and CQ exhibited linear pharmacokinetics. However, AQ-13 was cleared more rapidly than CQ (respectively, median oral clearance 14.0–14.7 l/h versus 9.5–11.3 l/h; p ≤ 0.03). QTc prolongation was greater with CQ than AQ-13 (CQ: mean increase of 28 ms; 95% confidence interval [CI], 18 to 38 ms, versus AQ-13: mean increase of 10 ms; 95% CI, 2 to 17 ms; p = 0.01). There were no arrhythmias or other cardiac AEs with either AQ-13 or CQ.Conclusions:These studies revealed minimal differences in toxicity between AQ-13 and CQ, and similar linear pharmacokinetics.

For the purpose of better understanding the molecular mechanism of action of sulfonylurea and sulfonamide herbicides, the quantitative relationship between their structure and herbicidal activity against rape, Brassica campestris L, was analysed using physicochemical parameters and regression analysis and comparative molecular field analysis (CoMFA). The results showed that the structure–activity relationships of the two sets of compounds were identical, which suggested that the two different sets of compounds affect a common region of the receptor site. The CoMFA results were consistent with those derived from traditional QSAR analysis. Combining the traditional QSAR analysis with the CoMFA results, we can conclude that the variations in the herbicidal activity of the two sets of ALS inhibitors were governed dominantly by the three‐dimensional steric and electrostatic field parameters of molecules participating in the interaction with the receptor site and there is apparently an optimum electronic property (Σσ or pKa) for the molecules to fit the receptor. © 1999 Society of Chemical Industry

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...

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