title: Antimalarial 9-anilinoacridine compounds directed at hematin.
abstract: Antimalarial 9-anilinoacridines are potent inhibitors of parasite DNA topoisomerase II both in vitro and in situ. 3,6-diamino substitution on the acridine ring greatly improves parasiticidal activity against Plasmodium falciparum by targeting DNA topoisomerase II. A series of 9-anilinoacridines were investigated for their abilities to inhibit beta-hematin formation, to form drug-hematin complexes, and to enhance hematin-induced lysis of red blood cells. Inhibition of beta-hematin formation was minimal with 3,6-diamino analogs of 9-anilinoacridine and greatest with analogs with a 3,6-diCl substitution together with an electron-donating group in the 1'-anilino position. On the other hand, the presence of a 1'-N(CH3)2 group in the anilino ring produced compounds that strongly inhibited beta-hematin formation but which did not appear to be sensitive to the nature of the substitutions in the acridine nucleus. The derivatives bound hematin, and Job's plots of UV-visible absorbance changes in drug-hematin complexes at various molar ratios indicated a stoichiometric ratio of 1:2. The drugs enhanced hematin-induced red blood cell lysis at low concentrations (<4 microM). These studies open up the novel possibility of development of 9-anilinoacridine antimalarials that target not only DNA topoisomerase II but also beta-hematin formation, which should help delay the rapid onset of resistance to drugs acting at only a single site.
authors.affiliation: Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Saranya
authors.initials: S
authors.lastname: Auparakkitanon
authors.forename: Wilai
authors.initials: W
authors.lastname: Noonpakdee
authors.forename: Raymond K
authors.initials: RK
authors.lastname: Ralph
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
authors.forename: Prapon
authors.initials: P
authors.lastname: Wilairat
mesh_terms: D000677:Amsacrine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000378:metabolism / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects; D006427:Hemin / Q000096:biosynthesis* / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D010963:Plasmodium falciparum / Q000187:drug effects; D011485:Protein Binding; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
chemical_list: D000962:Antimalarials; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; C022202:9-anilinoacridine; D006427:Hemin; D002738:Chloroquine