Structure–Property Optimization of a Series of Imidazopyridines for Visceral Leishmaniasis

Leishmaniasis is a collection of diseases caused by more
than 20 Leishmania parasite species
that manifest as either
visceral, cutaneous, or mucocutaneous leishmaniasis. Despite the significant
mortality and morbidity associated with leishmaniasis, it remains
a neglected tropical disease. Existing treatments have variable efficacy,
significant toxicity, rising resistance, and limited oral bioavailability,
which necessitates the development of novel and affordable therapeutics.
Here, we report on the continued optimization of a series of imidazopyridines
for visceral leishmaniasis and a scaffold hop to a series of substituted
2-(pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazoles with improved absorption, distribution, metabolism,
and elimination properties.

利什曼病（Leishmaniasis）是一类由20余种利什曼原虫（Leishmania）感染引发的疾病，临床表现分为内脏利什曼病、皮肤利什曼病与黏膜皮肤利什曼病三种类型。尽管利什曼病可造成严重的致死率与致残负担，但其仍属于被忽视的热带病。现有治疗手段存在疗效不稳定、毒性显著、耐药性日益增强以及口服生物利用度有限等问题，因此亟需开发新型且可负担的治疗药物。本研究针对内脏利什曼病，报道了一系列咪唑并吡啶类化合物的持续优化工作，并通过骨架跃迁设计得到一系列取代的2-(吡啶-2-基)-6,7-二氢-5H-吡咯并[1,2-a]咪唑类化合物，其吸收、分布、代谢与排泄性能得到显著改善。