Indoloquinoline (IQ) is an important class of naturally occurring antimalarial alkaloids, mainly represented by cryptolepine, isocryptolepine, and neocryptolepine. The IQ structural framework consists of four isomeric ring systems differing via the linkage of indole with quinoline as [3,2-b], [3,2-c], [2,3-c], and [2,3-b]. Structurally, IQs are planar and thus they bind strongly to the DNA which largely contributes to their biological properties. The structural rigidity and associated nonspecific cellular toxicity is a key shortcoming of the IQ structural framework for preclinical development. Thus, the lead optimization efforts were aimed at improving the therapeutic window and ADME properties of IQs. The structural modifications mainly involved attaching the basic aminoalkyl chains that positively modulates the vital physicochemical and topological parameters, thereby improves biological activity. Our analysis has found that the aminoalkylation consistently improved the selectivity index and provided acceptable in-vivo antimalarial/anticancer activity. Herein, we critically review the role of aminoalkylation in deciphering the antimalarial and cytotoxic activity of IQs.

吲哚喹啉（IQ）是一类重要的天然存在的抗疟生物碱，主要以隐脑平、异隐脑平和新隐脑平为代表。IQ 结构框架由四个异构环系统组成，它们通过以下方式不同：吲哚与喹啉的连接为 [3,2-b]、[3,2-c]、[2,3-c] 和 [2,3-b]。在结构上，智商是平面的，因此它们与 DNA 紧密结合，这在很大程度上有助于它们的生物学特性。结构刚性和相关的非特异性细胞毒性是临床前开发的 IQ 结构框架的主要缺点。因此，先导优化工作旨在改善智商的治疗窗口和 ADME 特性。结构修饰主要涉及连接碱性氨基烷基链，正向调节重要的物理化学和拓扑参数，从而提高生物活性。我们的分析发现，氨基烷基化持续改善选择性指数并提供可接受的体内抗疟疾/抗癌活性。在这里，我们批判性地回顾了氨基烷基化在破译智商的抗疟和细胞毒活性中的作用。