Gamage S A, Figgitt D P, Wojcik S J, Ralph R K, Ransijn A, Mauel J, Yardley V, Snowdon D, Croft S L, Denny W A
Cancer Research Laboratory, Faculty of Medicine and Health Sciences, University of Auckland, New Zealand.
J Med Chem. 1997 Aug 1;40(16):2634-42. doi: 10.1021/jm970232h.
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.
带有亲脂性供电子1'-苯胺基取代基的9-苯胺基吖啶拓扑异构酶II抑制剂对寄生虫硕大利什曼原虫的前鞭毛体和无鞭毛体形式均有活性。制备了一系列已知的1'-NH己基先导化合物的类似物，并在巨噬细胞培养中针对硕大利什曼原虫进行评估，以进一步建立构效关系（SAR）。在人白血病细胞系中测量对哺乳动物细胞的毒性，并使用两个IC50值的比值（IC50(J)/IC50(L)）作为体外治疗指数（IVTI）的衡量指标。吖啶上的3,6-二NMe2取代模式在不改变哺乳动物毒性的情况下大大增加了对硕大利什曼原虫的毒性，使IVTI比先导化合物有所提高。抗疟药物米帕林中使用的2-OMe、6-Cl吖啶取代模式也产生了强效的抗利什曼活性和高IVTI。在这项更广泛的研究中，早期关于2'-OR基团在降低哺乳动物细胞毒性方面效用的建议并未得到证实。一系列非常亲脂的1'-NRR（对称二烷基氨基）取代类似物显示出相对较高的抗利什曼效力，但整个系列中没有明显的趋势，且没有一个优于1'-NH(CH2)5Me亚类。还针对杜氏利什曼原虫、克氏锥虫和布氏锥虫评估了对硕大利什曼原虫最具活性的1'-N(R)(CH2)5Me-和1'-N(烷基)2-取代化合物的子集，但在这些生理上不同的测试系统中无法辨别出一致的SAR。本研究证实了早期的结论，即9-苯胺基吖啶1'-位的亲脂性供电子基团对硕大利什曼原虫具有高活性，但观察到的SAR模式并未延伸至所研究的其他寄生虫。
