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.
Members of the class of 9-anilinoacridine topoisomerase II inhibitors bearing lipophilic electron-donating 1'-anilino substituents are active against both the promastigote and amastigote forms of the parasite Leishmania major. A series of analogues of the known 1'-NHhexyl lead compound were prepared and evaluated against L. major in macrophage culture to further develop structure-activity relationships (SAR). Toxicity toward mammalian cells was measured in a human leukemia cell line, and the ratio of the two IC50 values (IC50(J)/IC50(L)) was used as a measure of the in vitro therapeutic index (IVTI). A 3,6-diNMe2 substitution pattern on the acridine greatly increased toxicity to L. major without altering mammalian toxicity, increasing IVTIs over that of the lead compound. The 2-OMe, 6-Cl acridine substitution pattern used in the antimalarial drug mepacrine also resulted in potent antileishmanial activity and high IVTIs. Earlier suggestions of the utility of 2'-OR groups in lowering mammalian cytotoxicity were not borne out in this wider study. A series of very lipophilic 1'-NRR (symmetric dialkylamino)-substituted analogues showed relatively high antileishmanial potency, but no clear trend was apparent across the series, and none were superior to the 1'-NH(CH2)5Me subclass. Subsets of the most active 1'-N(R)(CH2)5Me- and 1'-N(alkyl)2-substituted compounds against L. major were also evaluated against Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei, but no consistent SAR could be discerned in these physiologically diverse test systems. The present study has confirmed earlier conclusions that lipophilic electron-donating groups at the 1'-position of 9-anilinoacridines provide high activity against L. major, but the SAR patterns observed do not carry over to the other parasites studied.
A number of 1'-substituted 9-anilinoacridines were evaluated for their activities against promastigote and amastigote forms of Leishmania major and for their toxicities to human Jurkat leukemia cells. Several compounds possessing l'-NH-alkyl substituents produced more than 80% growth inhibition of macrophageinfected L. major amastigotes at or below a concentration of 1 ,uM. l'-Hexylamino-9-anilinoacridine (compound 14) was the least toxic compound to human Jurkat cells, while it retained strong antileishmanial activity. There was a general trend for the more lipophilic compounds to show the greatest antileishmanial activity, whereas 3,6-di-NH2 substitution of the acridine nucleus reduced or eliminated activity. Some structure-activity relationships of the various compounds are discussed.The widespread occurrence of leishmaniasis (2) and the limited repertoire of drugs currently capable of treating leishmanial infections without undesirable side effects (18) are spurring efforts to find more effective cures for the disease. There is evidence that some drugs active against bacterial and mammalian DNA topoisomerases II have limited activity against Leishmania donovani (7) and Leishmania mexicana (20) and that two other potent antileishmanial drugs, sodium stibogluconate and ureastilbamine, inhibit DNA topoisomerase I of L. donovani (6). Also, it was recently reported that a number of aminoacridines have in vitro activity against Leishmania promastigotes (21). These observations suggested that a more systematic study of DNA topoisomerase inhibitors for their potential activities against trypanosomes, and in particular Leishmania species, would be worthwhile.Anilinoacridines have successfully been used to target isozymes of mammalian DNA topoisomerase II (3,14), and various analogs are clinically effective against some forms of cancer (11,12). Therefore, we tested a wide variety of substituted 9-anilinoacridines for their activities against Trypanosoma lewisi (9) and, on the assumption that protozoal DNA topoisomerases would be closely related, the subset of compounds most active against T. lewisi and additional derivatives were screened against L. major. In the present study we identified a small group of compounds that show in vitro activity against macrophage-infected L. major in the concentration range of <0.1 to 1 ,uM. The structures and properties of the range of compounds tested together with data on their activities against L. major and their toxicities to human Jurkat cells are described. The results confirm that it is possible to modify existing anticancer drugs targeted at DNA topoisomerase II and improve their activities and specificities against other organisms, such as trypanosomes, that cause leishmaniasis. Better knowledge of the structure-activity relationships that increase the potencies of drugs against parasite DNA topoisomerases and that decrease their activities against human cells is now being sought to aid in the design of new drugs that are effective against these and other pathogenic parasi...
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