Design, Synthesis, and Characterization of Novel Small Molecules as Broad Range Antischistosomal Agents

Rugel, Anastasia; Tarpley, Reid S.; Lopez, Ambrosio; Menard, Travis; Guzman, Meghan A.; Taylor, Alexander B.; Cao, Xiaohang; Kovalskyy, Dmytro; Chevalier, Frédéric D.; Anderson, Timothy J.  C.; Hart, P. John; LoVerde, Philip T.; McHardy, Stanton F.

doi:10.1021/acsmedchemlett.8b00257

Title: Design, Synthesis, and Characterization of Novel Small Molecules as Broad Range Antischistosomal Agents

Journal Article · Fri Sep 14 00:00:00 EDT 2018 · ACS Medicinal Chemistry Letters

DOI:https://doi.org/10.1021/acsmedchemlett.8b00257· OSTI ID:1481298

Rugel, Anastasia ^[1]; Tarpley, Reid S. ^[2]; Lopez, Ambrosio ^[2]; Menard, Travis ^[2]; Guzman, Meghan A. ^[1]; Taylor, Alexander B. ^[1]; Cao, Xiaohang ^[1]; Kovalskyy, Dmytro ^[1]; Chevalier, Frédéric D. ^[3]; Anderson, Timothy J. C. ^[3]; Hart, P. John ^[4]; LoVerde, Philip T. ^[1];

^[2]

University of Texas Health Science Center at San Antonio, TX (United States)
Univ. of Texas at San Antonio, TX (United States). Center for Innovative Drug Discovery
Texas BioMedical Research Inst., San Antonio, TX (United States)
University of Texas Health Science Center at San Antonio, TX (United States); South Texas Veterans Health Care System, San Antonio, TX (United States)

Schistosomiasis is a major human parasitic disease afflicting more than 250 million people, historically treated with chemotherapies praziquantel or oxamniquine. Since oxamniquine is species-specific, killing Schistosoma mansoni but not other schistosome species (S. haematobium or S. japonicum) and evidence for drug resistant strains is growing, research efforts have focused on identifying novel approaches. Guided by data from X-ray crystallographic studies and Schistosoma worm killing assays on oxamniquine, our structure-based drug design approach produced a robust structure–activity relationship (SAR) program that identified several new lead compounds with effective worm killing. We report these studies culminated in the discovery of compound 12a, which demonstrated broad-species activity in killing S. mansoni (75%), S. haematobium (40%), and S. japonicum (83%).

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID); The Welch Foundation; National Institute of General Medical Sciences (NIGMS); USDOE Office of Science (SC)

Grant/Contract Number:: NIAID R01 AI115691; AC02-06CH11357; HHSN272201000005I

OSTI ID:: 1481298

Journal Information:: ACS Medicinal Chemistry Letters, Vol. 9, Issue 10; ISSN 1948-5875

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 12 works

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Cited By (2)

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
60 APPLIED LIFE SCIENCES
Schistosomiasis
oxamniquine
structure−activity relationships
X-ray crystallographic studies
aminopyrrolidine
aminopiperidine