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Eur J Med Chem. 2020 Mar 15;190:112100. doi: 10.1016/j.ejmech.2020.112100. Epub 2020 Jan 25.

Synthesis and structure-activity relationship study of pyrrolidine-oxadiazoles as anthelmintics against Haemonchus contortus.

Author information

1
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.
2
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.
3
Department of Pharmaceutical Chemistry and Pharmacognosy, School of Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
4
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia; School of Health and Life Sciences, Federation University, Ballarat, Victoria, 3353, Australia.
5
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia.
6
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Melbourne, Victoria, 3052, Australia.
7
State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
8
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Melbourne, Victoria, 3052, Australia; School of Pharmaceutical Sciences, Nanjing Tech University, No. 30, South Puzhu Road, Nanjing, 211816, PR China; ARC Centre for Fragment-Based Design, Monash University, Parkville, VIC, 3052, Australia; Australian Translational Medicinal Chemistry Facility (ATMCF), Monash University, Parkville, Victoria, 3052, Australia. Electronic address: jonathan.baell@monash.edu.

Abstract

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 (IC50 = 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.

KEYWORDS:

Anthelmintic; Drug discovery; Haemonchus contortus; Pyrrolidine-oxadiazoles; Structure-activity relationship

Conflict of interest statement

Declaration of competing interest The authors declare no conflict of interest.

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