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

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

doi:10.1021/acsmedchemlett.8b00257

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

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

Department of Biochemistry & Structural Biology

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

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. 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%).

Original language	English (US)
Pages (from-to)	967-973
Number of pages	7
Journal	ACS Medicinal Chemistry Letters
Volume	9
Issue number	10
DOIs	https://doi.org/10.1021/acsmedchemlett.8b00257
State	Published - Oct 11 2018

Keywords

Schistosomiasis
X-ray crystallographic studies
aminopiperidine
aminopyrrolidine
oxamniquine
structure-activity relationships

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/acsmedchemlett.8b00257

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Rugel, A., Tarpley, R. S., Lopez, A., Menard, T., Guzman, M. A., Taylor, A. B., Cao, X., Kovalskyy, D., Chevalier, F. D., Anderson, T. JC., Hart, P. J., Loverde, P. T., & McHardy, S. F. (2018). Design, Synthesis, and Characterization of Novel Small Molecules as Broad Range Antischistosomal Agents. ACS Medicinal Chemistry Letters, 9(10), 967-973. https://doi.org/10.1021/acsmedchemlett.8b00257

Rugel, A, Tarpley, RS, Lopez, A, Menard, T, Guzman, MA, Taylor, AB, Cao, X, Kovalskyy, D, Chevalier, FD, Anderson, TJC, Hart, PJ, Loverde, PT & McHardy, SF 2018, 'Design, Synthesis, and Characterization of Novel Small Molecules as Broad Range Antischistosomal Agents', ACS Medicinal Chemistry Letters, vol. 9, no. 10, pp. 967-973. https://doi.org/10.1021/acsmedchemlett.8b00257

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abstract = "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. 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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AU - Chevalier, Frédéric D.

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

Abstract

Keywords

ASJC Scopus subject areas

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