Synthesis and in vitro Evaluation of 9-Anilino-3,6-diaminoacridines Active Against a Multidrug-Resistant Strain of the Malaria Parasite Plasmodium falciparum

摘要: A series of 9-anilinoacridines have been prepared and evaluated for their activity against a multidrug-resistant K1 strain the malaria parasite Plasmodium falciparum in erythrocyte suspensions. 3,6-Diamino substitution on acridine ring resulted lower mammalian cell cytotoxicity higher antiparasitic than other patterns, providing compounds with highest vitro therapeutic indices. new synthesis 3,6-diamino-9-anilinoacridines, via reduction corresponding diazides, gives much yields traditional methods. Within subset there was considerable tolerance to at 1'-anilino position. In sharp divergence structure-activity relationships high toxicity anticancer effects, derivatives bearing electron-withdrawing 1'-substituents (e.g., SO2-NHR CONHR) showed most potent antimalarial (IC50 values 10-20 nM). Representative were shown be inhibitors DNA strand-passing human topoisomerase II decatenation enzyme. The 1'-SO2NH2derivative 7n completely inhibited strand passage by Jurkat 20 microM, an increase linear (indicative inhibition religation) seen or above 1 microM. It also decatenating 6 microM above. contrast, analogous compound without 3,6-diamino substituent inactive both assays up 100 Overall, positive relationship between ability drugs inhibit growth culture isolated enzyme assay. 1'-SO2NH2 derivative IVTI (1000) inhibitor P. nM) falciparum-derived II. However, berghei mice; reasons may include rapid metabolic inactivation (possibly N-acetylation) and/or poor distribution.