Activity of diphenyl ether benzyl amines against Human African Trypanosomiasis

James P. Hagen; Grant Darner; Samuel Anderson; Katie Higgins; Derek A. Leas; Ananya Mitra; Victoria Mashinson; Tasloach Wol; Carlos Vera-Esquivel; Bret Belter; Monica Cal; Marcel Kaiser; Alexander Wallick; Rosalie C. Warner; Paul H. Davis

doi:10.1016/j.bioorg.2020.103590

Activity of diphenyl ether benzyl amines against Human African Trypanosomiasis

James P. Hagen, Grant Darner, Samuel Anderson, Katie Higgins, Derek A. Leas, Ananya Mitra, Victoria Mashinson, Tasloach Wol, Carlos Vera-Esquivel, Bret Belter, Monica Cal, Marcel Kaiser, Alexander Wallick, Rosalie C. Warner, Paul H. Davis

Biology

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

2 Scopus citations

Abstract

Insect-borne parasite Trypanosoma brucei plagues humans and other animals, eliciting the disease Human African trypanosomiasis, also known as African sleeping sickness. This disease poses the biggest threat to the people in Sub-Saharan Africa. Given the high toxicity and difficulties with administration of currently available drugs, a novel treatment is needed. Building on known Human African trypanosomiasis structure–activity relationship (SAR), we now describe a number of functionally simple diphenyl ether analogs which give low micromolar activity (IC₅₀ = 0.16–0.96 μM) against T. b. rhodesiense. The best compound shows favorable selectivity against the L6 cell line (SI = 750) and even greater selectivity (SI = 1200) against four human cell lines. The data herein provides direction for the ongoing optimization of antitrypanosomal diphenyl ethers.

Original language	English (US)
Article number	103590
Journal	Bioorganic Chemistry
Volume	97
DOIs	https://doi.org/10.1016/j.bioorg.2020.103590
State	Published - Apr 2020

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Drug Discovery
Organic Chemistry

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Hagen, J. P., Darner, G., Anderson, S., Higgins, K., Leas, D. A., Mitra, A., Mashinson, V., Wol, T., Vera-Esquivel, C., Belter, B., Cal, M., Kaiser, M., Wallick, A., Warner, R. C., & Davis, P. H. (2020). Activity of diphenyl ether benzyl amines against Human African Trypanosomiasis. Bioorganic Chemistry, 97, Article 103590. https://doi.org/10.1016/j.bioorg.2020.103590

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title = "Activity of diphenyl ether benzyl amines against Human African Trypanosomiasis",

abstract = "Insect-borne parasite Trypanosoma brucei plagues humans and other animals, eliciting the disease Human African trypanosomiasis, also known as African sleeping sickness. This disease poses the biggest threat to the people in Sub-Saharan Africa. Given the high toxicity and difficulties with administration of currently available drugs, a novel treatment is needed. Building on known Human African trypanosomiasis structure–activity relationship (SAR), we now describe a number of functionally simple diphenyl ether analogs which give low micromolar activity (IC50 = 0.16–0.96 μM) against T. b. rhodesiense. The best compound shows favorable selectivity against the L6 cell line (SI = 750) and even greater selectivity (SI = 1200) against four human cell lines. The data herein provides direction for the ongoing optimization of antitrypanosomal diphenyl ethers.",

author = "Hagen, {James P.} and Grant Darner and Samuel Anderson and Katie Higgins and Leas, {Derek A.} and Ananya Mitra and Victoria Mashinson and Tasloach Wol and Carlos Vera-Esquivel and Bret Belter and Monica Cal and Marcel Kaiser and Alexander Wallick and Warner, {Rosalie C.} and Davis, {Paul H.}",

note = "Funding Information: This work was supported by the University of Nebraska at Omaha Fund for Undergraduate Scholarly Experiences and the University Committee on Research and Creative Activity and NIH GM103427 . We would like to thank Dr. Jonathan Vennerstrom, Dr. Yuxiang Dong and Dr. Xiaofang Wang without whose advice and assistance this work would not have been accomplished. We thank Ryan Mathiesen, Kokou Kanley, and Matt Schaich for preliminary experiments. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = apr,

doi = "10.1016/j.bioorg.2020.103590",

language = "English (US)",

volume = "97",

journal = "Bioorganic Chemistry",

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T1 - Activity of diphenyl ether benzyl amines against Human African Trypanosomiasis

AU - Hagen, James P.

AU - Darner, Grant

AU - Anderson, Samuel

AU - Higgins, Katie

AU - Leas, Derek A.

AU - Mitra, Ananya

AU - Mashinson, Victoria

AU - Wol, Tasloach

AU - Vera-Esquivel, Carlos

AU - Belter, Bret

AU - Cal, Monica

AU - Kaiser, Marcel

AU - Wallick, Alexander

AU - Warner, Rosalie C.

AU - Davis, Paul H.

N1 - Funding Information: This work was supported by the University of Nebraska at Omaha Fund for Undergraduate Scholarly Experiences and the University Committee on Research and Creative Activity and NIH GM103427 . We would like to thank Dr. Jonathan Vennerstrom, Dr. Yuxiang Dong and Dr. Xiaofang Wang without whose advice and assistance this work would not have been accomplished. We thank Ryan Mathiesen, Kokou Kanley, and Matt Schaich for preliminary experiments. Publisher Copyright: © 2020 Elsevier Inc.

PY - 2020/4

Y1 - 2020/4

N2 - Insect-borne parasite Trypanosoma brucei plagues humans and other animals, eliciting the disease Human African trypanosomiasis, also known as African sleeping sickness. This disease poses the biggest threat to the people in Sub-Saharan Africa. Given the high toxicity and difficulties with administration of currently available drugs, a novel treatment is needed. Building on known Human African trypanosomiasis structure–activity relationship (SAR), we now describe a number of functionally simple diphenyl ether analogs which give low micromolar activity (IC50 = 0.16–0.96 μM) against T. b. rhodesiense. The best compound shows favorable selectivity against the L6 cell line (SI = 750) and even greater selectivity (SI = 1200) against four human cell lines. The data herein provides direction for the ongoing optimization of antitrypanosomal diphenyl ethers.

AB - Insect-borne parasite Trypanosoma brucei plagues humans and other animals, eliciting the disease Human African trypanosomiasis, also known as African sleeping sickness. This disease poses the biggest threat to the people in Sub-Saharan Africa. Given the high toxicity and difficulties with administration of currently available drugs, a novel treatment is needed. Building on known Human African trypanosomiasis structure–activity relationship (SAR), we now describe a number of functionally simple diphenyl ether analogs which give low micromolar activity (IC50 = 0.16–0.96 μM) against T. b. rhodesiense. The best compound shows favorable selectivity against the L6 cell line (SI = 750) and even greater selectivity (SI = 1200) against four human cell lines. The data herein provides direction for the ongoing optimization of antitrypanosomal diphenyl ethers.

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Activity of diphenyl ether benzyl amines against Human African Trypanosomiasis

Abstract

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