title: Synthesis and in vitro evaluation of 9-anilino-3,6-diaminoacridines active against a multidrug-resistant strain of the malaria parasite Plasmodium falciparum.
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., SO2-NHR and CONHR) showed the most potent antimalarial activity (IC50 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'-SO2NH2derivative 7n completely inhibited strand passage by Jurkat topoisomerase II at 20 microM, and an increase in linear DNA (indicative of inhibition of religation) was seen at or above 1 microM. It also inhibited the decatenating activity of the parasite topoisomerase II at 6 microM and above. In contrast, the analogous compound without the 3,6-diamino substituent was inactive in both assays up to 100 microM. 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'-SO2NH2 derivative 7n showed a high IVTI (1000) and was a potent inhibitor of both P. falciparum in vitro (IC50 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.
authors.affiliation: Cancer Research Laboratory, School of Medicine, University of Auckland, New Zealand.
authors.forename: S A
authors.initials: SA
authors.lastname: Gamage
authors.forename: N
authors.initials: N
authors.lastname: Tepsiri
authors.forename: P
authors.initials: P
authors.lastname: Wilairat
authors.forename: S J
authors.initials: SJ
authors.lastname: Wojcik
authors.forename: D P
authors.initials: DP
authors.lastname: Figgitt
authors.forename: R K
authors.initials: RK
authors.lastname: Ralph
authors.forename: W A
authors.initials: WA
authors.lastname: Denny
mesh_terms: D000609:Aminoacridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004351:Drug Resistance; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D000609:Aminoacridines; D000962:Antimalarials; D059005:Topoisomerase II Inhibitors