STRUCTURE-ACTIVITY-RELATIONSHIPS FOR THE ANTILEISHMANIAL AND ANTITRYPANOSOMAL ACTIVITIES OF 1'-SUBSTITUTED 9-ANILINOACRIDINES

Members of the class of 9-anilinoacridine topoisomerase II inhibitors bearing lipophilic electron-donating 1'-anilino substituents are activ e against both the promastigote and amastigote forms of the parasite L eishmania major. A series of analogues of the known 1'-NHhexyl lead co mpound were prepared and evaluated against L. major in macrophage cult ure to further develop structure-activity relationships (SAR). Toxicit y toward mammalian cells was measured in a human leukemia cell line, a nd the ratio of the two IC50 values (IC50(J)/IC50(L)) was used as a me asure of the in vitro therapeutic index (IVTI). A 3,6-diNMe(2) substit ution pattern on the acridine greatly increased toxicity to L. major w ithout altering mammalian toxicity, increasing IVTIs over that of the lead compound. The 2-OMe, 6-Cl acridine substitution pattern used in t he 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 w ider 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 sup erior to the 1'-NH(CH2)(5)Me subclass. Subsets of the most active 1'-N (R)(CH2)(5)Me- and 1'-N(alkyl)(2)-substituted compounds against L. maj or were also evaluated against Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei, but no consistent SAR could be discerned in t hese physiologically diverse test systems. The present study has confi rmed earlier conclusions that lipophilic electron-donating groups at t he 1'-position of 9-anilinoacridines provide high activity against L. major, but the SAR patterns observed do not carry over to the other pa rasites studied.