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Title: Synthesis and in Vitro Evaluation of 9-Anilino-3,6-diaminoacridines Active Against a Multidrug-Resistant Strain of the Malaria Parasite Plasmodium falciparum
Authors: Swarna A. Gamage
Nisana Tepsiri
Prapon Wilairat
Stanley J. Wojcik
David P. Figgitt
Raymond K. Ralph
William A. Denny
School of Medicine, University of Auckland
Mahidol University
University of Auckland
Keywords: Biochemistry, Genetics and Molecular Biology;Pharmacology, Toxicology and Pharmaceutics
Issue Date: 1-May-1994
Citation: Journal of Medicinal Chemistry. Vol.37, No.10 (1994), 1486-1494
Abstract: A series of 9-anilinoacridines have been prepared and evaluated for their activity against a multidrug-resistant K1 strain of the malaria parasite Plasmodium falciparum in erythrocyte suspensions. 3,6-Diamino substitution on the acridine ring resulted in lower mammalian cell cytotoxicity and higher antiparasitic activity than other substitution patterns, providing compounds with the highest in vitro therapeutic indices. A new synthesis of 3,6-diamino-9-anilinoacridines, via reduction of the corresponding diazides, gives much higher yields than traditional methods. Within the subset of 3,6-diamino-9-anilinoacridines, there was considerable tolerance to substitution at the 1′-anilino position. In a sharp divergence with structure-activity relationships for high mammalian cell toxicity and anticancer effects, derivatives bearing electron-withdrawing 1′-substituents (e.g., SO 2 - NHR and CONHR) showed the most potent antimalarial activity (IC 50 values of 10–20 nM). Representative compounds were shown to be potent inhibitors of the DNA strand-passing activity of human topoisomerase II and of the DNA decatenation activity of the corresponding parasite enzyme. The 1′-SO 2 NH 2 derivative 7n completely inhibited strand passage by Jurkat topoisomerase II at 20 μM, and an increase in linear DNA (indicative of inhibition of religation) was seen at or above 1 μM. It also inhibited the decatenating activity of the parasite topoisomerase II at 6 μM and above. In contrast, the analogous compound without the 3,6-diamino substituent was inactive in both assays up to 100 μM. Overall, there was a positive relationship between the ability of the drugs to inhibit parasite growth in culture and their ability to inhibit parasite topoisomerase II activity in an isolated enzyme assay. The 1′-SO 2 NH 2 derivative 7n showed a high IVTI (1000) and was a potent inhibitor of both P. falciparum in vitro (IC 50 20 nM) and P. falciparum-derived topoisomerase II. However, the compound was inactive against Plasmodium berghei in mice; reasons may include rapid metabolic inactivation (possibly by N-acetylation) and/or poor distribution. © 1994, American Chemical Society. All rights reserved.
ISSN: 15204804
Appears in Collections:Scopus 1991-2000

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