Cleavage of DNA induced by 9-anilinoacridine inhibitors of topoisomerase II in the malaria parasite Plasmodium falciparum.
Due to resistance by Plasmodium falciparum, the most virulent strain of the four species of human malaria parasites, to most currently used antimalarial drugs, development of new effective antimalarials is urgently needed. Derivatives of 9-anilinoacridine, an antitumor drug, have been shown to inhibit P. falciparum growth in culture and to inhibit parasite DNA topoisomerase II activity in vitro. Using KCl-SDS precipitation assay to detect the presence of protein-DNA complexes within parasite cells, an indicator of DNA topoisomerase II inactivation, derivatives containing 3,6-diNH(2) substitutions with 1'-electron donating (NMe(2), CH(2)NMe(2), NHSO(2)Me, OH, OMe), and 1'-electron withdrawing (SO(2)NH(2)) groups produced protein-DNA complexes. However, the antimalarial pyronaridine, 9-anilinoazaacridine, did not generate protein-DNA complexes, although it was capable of inhibiting P. falciparum DNA topoisomerase II activity in vitro. These results should prove useful in future designs of novel antimalarial compounds directed against parasite DNA topoisomerase II.
Auparakkitanon
S
S
Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand.
Wilairat
P
P
D000677:Amsacrine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016054:DNA, Protozoan / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D059005:Topoisomerase II Inhibitors
D016054:DNA, Protozoan; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; C022202:9-anilinoacridine