Pyridyl benzamides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei

Lori Ferrins, Michelle Gazdik, Raphael Steve Rahmani, Swapna Varghese, Melissa L Sykes, Amy J Jones, Vicky M Avery, Karen Louise White, Eileen Ryan, Susan Ann Charman, Marcel Kaiser, Christel A S Bergstrom, Jonathan Bayldon Baell

Research output: Contribution to journalArticleResearchpeer-review

Abstract

A whole-organism screen of approximately 87000 compounds against Trypanosoma brucei brucei identified a number of promising compounds for medicinal chemistry optimization. One of these classes of compounds we termed the pyridyl benzamides. While the initial hit had an IC50 of 12 ?M, it was small enough to be attractive for further optimization, and we utilized three parallel approaches to develop the structure-activity relationships. We determined that the physicochemical properties for this class are generally favorable with particular positions identified that appear to block metabolism when substituted and others that modulate solubility. Our most active compound is 79, which has an IC50 of 0.045 ?M against the human pathogenic strain Trypanosoma brucei rhodesiense and is more than 4000 times less active against the mammalian L6 cell line.
Original languageEnglish
Pages (from-to)6393 - 6402
Number of pages10
JournalJournal of Medicinal Chemistry
Volume57
Issue number15
DOIs
Publication statusPublished - 2014

Cite this

Ferrins, Lori ; Gazdik, Michelle ; Rahmani, Raphael Steve ; Varghese, Swapna ; Sykes, Melissa L ; Jones, Amy J ; Avery, Vicky M ; White, Karen Louise ; Ryan, Eileen ; Charman, Susan Ann ; Kaiser, Marcel ; Bergstrom, Christel A S ; Baell, Jonathan Bayldon. / Pyridyl benzamides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 15. pp. 6393 - 6402.
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title = "Pyridyl benzamides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei",
abstract = "A whole-organism screen of approximately 87000 compounds against Trypanosoma brucei brucei identified a number of promising compounds for medicinal chemistry optimization. One of these classes of compounds we termed the pyridyl benzamides. While the initial hit had an IC50 of 12 ?M, it was small enough to be attractive for further optimization, and we utilized three parallel approaches to develop the structure-activity relationships. We determined that the physicochemical properties for this class are generally favorable with particular positions identified that appear to block metabolism when substituted and others that modulate solubility. Our most active compound is 79, which has an IC50 of 0.045 ?M against the human pathogenic strain Trypanosoma brucei rhodesiense and is more than 4000 times less active against the mammalian L6 cell line.",
author = "Lori Ferrins and Michelle Gazdik and Rahmani, {Raphael Steve} and Swapna Varghese and Sykes, {Melissa L} and Jones, {Amy J} and Avery, {Vicky M} and White, {Karen Louise} and Eileen Ryan and Charman, {Susan Ann} and Marcel Kaiser and Bergstrom, {Christel A S} and Baell, {Jonathan Bayldon}",
year = "2014",
doi = "10.1021/jm500191u",
language = "English",
volume = "57",
pages = "6393 -- 6402",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "AMER CHEMICAL SOC",
number = "15",

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Ferrins, L, Gazdik, M, Rahmani, RS, Varghese, S, Sykes, ML, Jones, AJ, Avery, VM, White, KL, Ryan, E, Charman, SA, Kaiser, M, Bergstrom, CAS & Baell, JB 2014, 'Pyridyl benzamides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei' Journal of Medicinal Chemistry, vol. 57, no. 15, pp. 6393 - 6402. https://doi.org/10.1021/jm500191u

Pyridyl benzamides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei. / Ferrins, Lori; Gazdik, Michelle; Rahmani, Raphael Steve; Varghese, Swapna; Sykes, Melissa L; Jones, Amy J; Avery, Vicky M; White, Karen Louise; Ryan, Eileen; Charman, Susan Ann; Kaiser, Marcel; Bergstrom, Christel A S; Baell, Jonathan Bayldon.

In: Journal of Medicinal Chemistry, Vol. 57, No. 15, 2014, p. 6393 - 6402.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Pyridyl benzamides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei

AU - Ferrins, Lori

AU - Gazdik, Michelle

AU - Rahmani, Raphael Steve

AU - Varghese, Swapna

AU - Sykes, Melissa L

AU - Jones, Amy J

AU - Avery, Vicky M

AU - White, Karen Louise

AU - Ryan, Eileen

AU - Charman, Susan Ann

AU - Kaiser, Marcel

AU - Bergstrom, Christel A S

AU - Baell, Jonathan Bayldon

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AB - A whole-organism screen of approximately 87000 compounds against Trypanosoma brucei brucei identified a number of promising compounds for medicinal chemistry optimization. One of these classes of compounds we termed the pyridyl benzamides. While the initial hit had an IC50 of 12 ?M, it was small enough to be attractive for further optimization, and we utilized three parallel approaches to develop the structure-activity relationships. We determined that the physicochemical properties for this class are generally favorable with particular positions identified that appear to block metabolism when substituted and others that modulate solubility. Our most active compound is 79, which has an IC50 of 0.045 ?M against the human pathogenic strain Trypanosoma brucei rhodesiense and is more than 4000 times less active against the mammalian L6 cell line.

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