- Synthesis, Structure-activity relationship, and mode-of-action studies of antimalarial reversed chloroquine compounds
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We have previously shown that a "reversed chloroquine (RCQ)" molecule, composed of a chloroquine-like moiety and a resistance reversal-like moiety, can overcome chloroquine resistance in P. falciparum (Burgess, S. J.; Selzer, A.; Kelly, J. X.; Smilkstein, M. J.; Riscoe, M. K.; Peyton, D. H. J. Med. Chem. 2006, 49, 5623. Andrews, S.; Burgess, S. J.; Skaalrud, D.; Kelly, J. X.; Peyton, D. H. J. Med. Chem. 2010, 53, 916). Here, we present an investigation into the Structure-activity relationship of the RCQ structures, resulting in an orally active molecule with good in vitro and in vivo antimalarial activity. We also present evidence of the mode of action, indicating that the RCQ molecules inhibit hemozoin formation in the parasite's digestive vacuole in a manner similar to that of chloroquine.
- Burgess, Steven J.,Kelly, Jane X.,Shomloo, Shawheen,Wittlin, Sergio,Brun, Reto,Liebmann, Katherine,Peyton, David H.
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experimental part
p. 6477 - 6489
(2010/11/05)
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- Hybrid approach for the design of highly affine and selective dopamine D3 receptor ligands using privileged scaffolds of biogenic amine GPCR ligands
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A series of compounds containing privileged scaffolds of the known histamine H1 receptor antagonists cetirizine, mianserin, ketotifen, loratadine, and bamipine were synthesized for further optimization as ligands for the related biogenic amine binding dopamine D3 receptor. A pharmacological screening was carried out at dopamine D2 and D3 receptors. In the preliminary testing various ligands have shown moderate to high affinities for dopamine D3receptors, for example, N-(4-{4-[benzyl(phenyl)amino]piperidin-1-yl}butylnaphthalen-2-carboxamide (19a) (hD3 Ki = 0.3 nM; hD2 Ki = 703 nM), leading to a selectivity ratio of 2343.
- Sasse, Britta C.,Mach, Ulrich R.,Leppaenen, Jukka,Calmels, Thierry,Stark, Holger
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p. 7258 - 7273
(2008/03/27)
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- THIAZOLIDINECARBOXYLIC ACID AMIDE DERIVATIVES AND THEIR THERAPEUTIC USES
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Thiazolidinecarboxylic acid amides having combined antiallergic and antiasthmatic activities with an antagonist activity against platelet Activating Factor and having the following general formula (I) STR1
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