Medicinal Chemistry Optimization of a Diaminopurine Chemotype: Toward a Lead for Trypanosoma brucei Inhibitors

Human
African trypanosomiasis (HAT), or sleeping sickness, is caused
by the protozoan parasite Trypanosoma brucei and transmitted through the bite of infected tsetse flies. The disease
is considered fatal if left untreated. To identify new chemotypes
against Trypanosoma brucei, previously
we identified 797 potent kinase-targeting inhibitors grouped into
59 clusters plus 53 singleton compounds with at least 100-fold selectivity
over HepG2 cells. From this set of hits, a cluster of diaminopurine-derived
compounds was identified. Herein, we report our medicinal chemistry
investigation involving the exploration of structure–activity
and structure–property relationships around one of the high-throughput
screening (HTS) hits, N2-(thiophen-3-yl)-N6-(2,2,2-trifluoroethyl)-9H-purine-2,6-diamine (1, NEU-1106). This work led to
the identification of a potent lead compound (4aa, NEU-4854)
with improved in vitro absorption, distribution, metabolism, and excretion
(ADME) properties, which was progressed into proof-of-concept translation
of in vitro antiparasitic activity to in vivo efficacy.

人类非洲锥虫病（Human African Trypanosomiasis, HAT），又称昏睡病，由布氏锥虫（Trypanosoma brucei）这种原生动物寄生虫引发，经受感染的采采蝇叮咬传播。该疾病若不进行治疗则会致命。为筛选针对布氏锥虫的新型化学型药物，我们此前已鉴定出797种强效激酶靶向抑制剂，可划分为59个化合物簇与53个单一化合物，这些抑制剂对HepG2细胞均具有至少100倍的选择性。在该批命中化合物中，研究人员发现了一个二氨基嘌呤衍生化合物簇。本文报道了针对高通量筛选（high-throughput screening, HTS）命中化合物之一——N2-(噻吩-3-基)-N6-(2,2,2-三氟乙基)-9H-嘌呤-2,6-二胺（化合物1，NEU-1106）的药物化学研究，探索了其构效关系与构性质关系。本研究最终鉴定出一款强效先导化合物4aa（NEU-4854），其体外吸收、分布、代谢与排泄（ADME）性质得到改善，并完成了从体外抗寄生虫活性到体内药效的概念验证转化。