4-aminoquinolines active against chloroquine-resistant Plasmodium falciparum: basis of antiparasite activity and quantitative structure-activity relationship analyses.

Simon J Hocart, Huayin Liu, Haiyan Deng, Dibyendu De, Frances M Krogstad, Donald J Krogstad

Peptide Research, Department of Medicine, School of Medicine, Mail Stop SL-12, Tulane University Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112-2699, USA. Simon.Hocart@tulane.edu

Antimicrobial agents and chemotherapy 2011 May

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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 [IC50s], ≤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.

Citation

Simon J Hocart, Huayin Liu, Haiyan Deng, Dibyendu De, Frances M Krogstad, Donald J Krogstad. 4-aminoquinolines active against chloroquine-resistant Plasmodium falciparum: basis of antiparasite activity and quantitative structure-activity relationship analyses. Antimicrobial agents and chemotherapy. 2011 May;55(5):2233-44