Schistosomiasis and hookworm are parasitic diseases responsible for significant mortality and morbidity in developing countries, together infecting more than 1 billion people worldwide. They can cause serious chronic illnesses, resulting in organ damage, cancer, and impaired growth and cognitive development in children. Current standard-of-care therapies for these diseases are not effective in all patients, and there are concerns about developing drug resistance. The purpose of this project is to develop a novel class of drugs with potent anti-parasitic activity.
Scientific Synopsis
Schistosomes and hookworms are parasites responsible for significant mortality and morbidity in developing countries. They can cause serious chronic illnesses resulting in organ damage, cancer, and impaired growth and cognitive development in children. The current standard-of-care therapies for schistosomiasis (praziquantel) and hookworm (albendazole) are effective in most but not all patients. Due to the high infection rate, these drugs must be administered on an annual or semi-annual basis. Additionally, there are concerns about the development of drug resistance due to widespread treatment of very large populations.
A previous collaboration between NIH grantee David Williams, Ph.D., and the NCATS Chemical Genomics Center identified a potential class of drugs for the treatment of schistosomiasis. Researchers screened several libraries for compounds that could inhibit the schistosome redox pathway, which is involved in the defense against free radical damage. They identified several classes of compounds active against this pathway, including phosphinic amides and oxadiazole 2-oxides. Follow-up studies on these compounds showed that oxadiazole 2-oxides effectively killed schistosomes in infected mice at all intramammalian life cycle stages and with little toxicity to the mice.
Lead Collaborator
Rush University Medical Center, Chicago
David Williams, Ph.D.
Public Health Impact
Schistosomiasis and hookworm infection affect more than one billion people worldwide but are generally neglected because they primarily affect developing countries. These infections can cause serious chronic illnesses resulting in organ damage, cancer, and impaired growth and cognitive development in children.
Outcomes
TRND scientists supported additional medicinal chemistry optimization and evaluation of the target anti-parasitic compounds, as well as studies of drug efficacy in animal models of the diseases. Despite considerable effort, milestones of pharmacokinetics and in vivo efficacy were not met, and TRND discontinued this project in November 2011. This project is complete.
Publications
Structure Mechanism Insights and the Role of Nitric Oxide Donation Guide the Development of Oxidiazole-2-Oxides as Therapeutic Agents against Schistosomiasis • Journal of Medicinal Chemistry • Oct. 22, 2009
Synthesis of Oxadiazole-2-oxide Analogues as Potential Antischistosomal Agents • Tetrahedron Letters • April 2009
Identification of Oxadiazoles as New Drug Leads for the Control of Schistosomiasis • Nature Medicine • April 2008
Quantitative High-Throughput Screen Identifies Inhibitors of the Schistosoma mansoni Redox Cascade • PLoS Neglected Tropical Diseases • Jan. 2, 2008
A 1,536-Well-Based Kinetic HTS Assay for Inhibitors of Schistosoma mansoni Thioredoxin Glutathione Reductase • ASSAY and Drug Development Technologies • August 2008
Related Information
News Release: Scientists Identify New Leads for Treating Parasitic Worm Disease (March 2008)
U.S. Patent Application No. 13/057,667 filed 13 Aug 2009: Treatment of Schistosomiasis Using Substituted Oxadiazole 2-Oxides Thomas, C. J.; Maloney, D. J.; Bantukallu, G. R.; Sayed, A. A.; Simeonov, A.; Williams, D. L.