Antimalarial 9-Anilinoacridine Compounds Directed at Hematin

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Dec. 2003, p. 3708–3712 0066-4804/03/$08.00⫹0 DOI: 10.1128/AAC.47.12.3708–3712.2003 Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Vol. 47, No. 12

Antimalarial 9-Anilinoacridine Compounds Directed at Hematin Saranya Auparakkitanon,1 Wilai Noonpakdee,1 Raymond K. Ralph,2 William A. Denny,3 and Prapon Wilairat1* Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand,1 and Cancer Research and Developmental Biology, School of Biological Sciences,2 and Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences,3 The University of Auckland, Auckland, New Zealand Received 2 June 2003/Returned for modification 15 July 2003/Accepted 26 August 2003

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 ␤-hematin formation, to form drug-hematin complexes, and to enhance hematin-induced lysis of red blood cells. Inhibition of ␤-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 1ⴕ-anilino position. On the other hand, the presence of a 1ⴕ-N(CH3)2 group in the anilino ring produced compounds that strongly inhibited ␤-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 (