Improvement of Aqueous Solubility of Lapatinib-Derived Analogues: Identification of a Quinolinimine Lead for Human African Trypanosomiasis Drug Development

Lapatinib, an approved epidermal growth factor receptor inhibitor, was explored as a starting point for the synthesis of new hits against Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). Previous work culminated in 1 (NEU-1953), which was part of a series typically associated with poor aqueous solubility. In this report, we present various medicinal chemistry strategies that were used to increase the aqueous solubility and improve the physicochemical profile without sacrificing antitrypanosomal potency. To rank trypanocidal hits, a new assay (summarized in a cytocidal effective concentration (CEC50)) was established, as part of the lead selection process. Increasing the sp3 carbon content of 1 resulted in 10e (0.19 μM EC50 against T. brucei and 990 μM aqueous solubility). Further chemical exploration of 10e yielded 22a, a trypanocidal quinolinimine (EC50: 0.013 μM; aqueous solubility: 880 μM; and CEC50: 0.18 μM). Compound 22a reduced parasitemia 109 fold in trypanosome-infected mice; it is an advanced lead for HAT drug development.拉帕替尼（Lapatinib）是一款已获批上市的表皮生长因子受体抑制剂（epidermal growth factor receptor inhibitor），本研究以其为起始骨架，开发针对布氏锥虫（Trypanosoma brucei）的新型活性命中化合物，而布氏锥虫正是人类非洲锥虫病（human African trypanosomiasis, HAT）的致病病原体。前期研究已得到化合物1（NEU-1953），但该化合物所属的系列普遍存在水溶性不佳的缺陷。本报告详述了多种药物化学修饰策略，可在不削弱抗锥虫活性的前提下，提升化合物的水溶性并优化其理化性质。为对抗锥虫活性命中化合物进行优先级排序，我们建立了全新的检测方法，以细胞杀伤有效浓度（cytocidal effective concentration, CEC50）作为评价指标，该方法被纳入先导化合物筛选流程。对化合物1提升sp3碳含量后得到化合物10e，其对布氏锥虫的半最大效应浓度（half maximal effective concentration, EC50）为0.19 μM，水溶性达990 μM。对化合物10e进行进一步化学修饰后得到22a，该化合物为喹啉亚胺类抗锥虫化合物，其EC50为0.013 μM，水溶性为880 μM，CEC50为0.18 μM。化合物22a可使感染锥虫的小鼠体内虫血症水平降低10^9倍，是一款用于HAT药物开发的优质先导化合物。