Jandl Bernhard, Zheng Rebecca, Muttenthaler Markus, Baell Jonathan
Institute of Biological Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria.
Vienna Doctoral School in Chemistry, University of Vienna, 1090 Vienna, Austria.
ACS Omega. 2024 Aug 22;9(35):37170-37182. doi: 10.1021/acsomega.4c04517. eCollection 2024 Sep 3.
Visceral leishmaniasis is a neglected tropical disease with the highest mortality among different forms of leishmaniasis manifestation in humans. The disease is caused by the parasitic protists and , and treatments remain unsuitable due to high costs, complicated administration, lack of efficacy, variable patient susceptibility, toxic side effects, and rising parasitic resistance. Herein, we report a structure-activity relationship (SAR) exploration of the diacyl-hydrazide scaffold identified to have antiparasitic activity from a high-throughput screen against , , and . This SAR study revealed new structural insights into this scaffold related to bioactivity resulting in a new series of lead compounds with nanomolar activity against and no toxicity against human THP-1 macrophages. These optimized diacyl-hydrazide compounds set the stage for future drug development and hold promise for a new treatment avenue for visceral leishmaniasis.
内脏利什曼病是一种被忽视的热带疾病，在人类利什曼病的不同表现形式中死亡率最高。该疾病由寄生原生生物和引起，由于成本高、给药复杂、缺乏疗效、患者易感性不同、有毒副作用以及寄生虫耐药性增加，治疗方法仍然不合适。在此，我们报告了对二酰肼支架的构效关系（SAR）探索，该支架在针对、和的高通量筛选中被确定具有抗寄生虫活性。这项SAR研究揭示了该支架与生物活性相关的新结构见解，从而产生了一系列对具有纳摩尔活性且对人THP-1巨噬细胞无毒性的新型先导化合物。这些优化的二酰肼化合物为未来的药物开发奠定了基础，并有望为内脏利什曼病开辟新的治疗途径。
