Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Melbourne, Victoria, 3052, Australia; Key Lab of Biofabrication of Anhui Higher Education, Institution Centre for Advanced Biofabrication, Hefei University, Hefei, 230601, PR China.
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Melbourne, Victoria, 3052, Australia; Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia; State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
Eur J Med Chem. 2020 Mar 15;190:112100. doi: 10.1016/j.ejmech.2020.112100. Epub 2020 Jan 25.
Parasitic roundworms (nematodes) are significant pathogens of humans and animals and cause substantive socioeconomic losses due to the diseases that they cause. The control of nematodes in livestock animals relies heavily on the use of anthelmintic drugs. However, their extensive use has led to a widespread problem of drug resistance in these worms. Thus, the discovery and development of novel chemical entities for the treatment of parasitic worms of humans and animals is needed. Herein, we describe our medicinal chemistry optimization efforts of a phenotypic hit against Haemonchus contortus based on a pyrrolidine-oxadiazole scaffold. This led to the identification of compounds with potent inhibitory activities (IC = 0.78-22.4 μM) on the motility and development of parasitic stages of H. contortus, and which were found to be highly selective in a mammalian cell counter-screen. These compounds could be used as suitable chemical tools for drug target identification or as lead compounds for further optimization.
寄生性圆线虫（线虫）是人类和动物的重要病原体，由于它们引起的疾病，给社会经济造成了重大损失。家畜线虫的防治主要依赖于驱虫药物的使用。然而，这些药物的广泛使用导致了线虫耐药性的广泛问题。因此，需要发现和开发治疗人类和动物寄生性蠕虫的新型化学实体。在此，我们描述了我们对线虫 Haemonchus contortus 的表型命中基于吡咯烷-恶二唑支架的药物化学优化工作。这导致了鉴定出具有强烈抑制活性（IC = 0.78-22.4 μM）的化合物，对 H.contortus 的运动和寄生虫阶段的发育有抑制作用，并且在哺乳动物细胞计数器筛选中具有高度选择性。这些化合物可用作药物靶标鉴定的合适化学工具，或作为进一步优化的先导化合物。
