3-(Oxazolo[4,5-b]pyridin-2-yl)anilides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei, the causative agent for human African trypanosomiasis

Lori Ferrins, Raphael Steve Rahmani, Melissa L Sykes, Amy J Jones, Vicky M Avery, Eliott Teston, Basmah Almohaywi, JieXiang Yin, Jason Smith, Hyland Chris, Karen Louise White, Eileen Ryan, Michael Campbell, Susan Ann Charman, Marcel Kaiser, Jonathan Bayldon Baell

Research output: Contribution to journalArticleResearchpeer-review

Abstract

A whole organism high-throughput screen of approximately 87,000 compounds against Trypanosoma brucei brucei led to the recent discovery of several novel compound classes with low micromolar activity against this organism and without appreciable cytotoxicity to mammalian cells. Herein we report a structure activity relationship (SAR) investigation around one of these hit classes, the 3-(oxazolo[4,5-b] pyridin-2-yl)anilides. Sharp SAR is revealed, with our most active compound (5) exhibiting an IC50 of 91 nM against the human pathogenic strain T.b. rhodesiense and being more than 700 times less toxic towards the L6 mammalian cell line. Physicochemical properties are attractive for many compounds in this series. For the most potent representatives, we show that solubility and metabolic stability are key parameters to target during future optimisation.
Original languageEnglish
Pages (from-to)450 - 465
Number of pages16
JournalEuropean Journal of Medicinal Chemistry
Volume66
DOIs
Publication statusPublished - 2013

Cite this

Ferrins, Lori ; Rahmani, Raphael Steve ; Sykes, Melissa L ; Jones, Amy J ; Avery, Vicky M ; Teston, Eliott ; Almohaywi, Basmah ; Yin, JieXiang ; Smith, Jason ; Chris, Hyland ; White, Karen Louise ; Ryan, Eileen ; Campbell, Michael ; Charman, Susan Ann ; Kaiser, Marcel ; Baell, Jonathan Bayldon. / 3-(Oxazolo[4,5-b]pyridin-2-yl)anilides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei, the causative agent for human African trypanosomiasis. In: European Journal of Medicinal Chemistry. 2013 ; Vol. 66. pp. 450 - 465.
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title = "3-(Oxazolo[4,5-b]pyridin-2-yl)anilides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei, the causative agent for human African trypanosomiasis",
abstract = "A whole organism high-throughput screen of approximately 87,000 compounds against Trypanosoma brucei brucei led to the recent discovery of several novel compound classes with low micromolar activity against this organism and without appreciable cytotoxicity to mammalian cells. Herein we report a structure activity relationship (SAR) investigation around one of these hit classes, the 3-(oxazolo[4,5-b] pyridin-2-yl)anilides. Sharp SAR is revealed, with our most active compound (5) exhibiting an IC50 of 91 nM against the human pathogenic strain T.b. rhodesiense and being more than 700 times less toxic towards the L6 mammalian cell line. Physicochemical properties are attractive for many compounds in this series. For the most potent representatives, we show that solubility and metabolic stability are key parameters to target during future optimisation.",
author = "Lori Ferrins and Rahmani, {Raphael Steve} and Sykes, {Melissa L} and Jones, {Amy J} and Avery, {Vicky M} and Eliott Teston and Basmah Almohaywi and JieXiang Yin and Jason Smith and Hyland Chris and White, {Karen Louise} and Eileen Ryan and Michael Campbell and Charman, {Susan Ann} and Marcel Kaiser and Baell, {Jonathan Bayldon}",
year = "2013",
doi = "10.1016/j.ejmech.2013.05.007",
language = "English",
volume = "66",
pages = "450 -- 465",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier",

}

Ferrins, L, Rahmani, RS, Sykes, ML, Jones, AJ, Avery, VM, Teston, E, Almohaywi, B, Yin, J, Smith, J, Chris, H, White, KL, Ryan, E, Campbell, M, Charman, SA, Kaiser, M & Baell, JB 2013, '3-(Oxazolo[4,5-b]pyridin-2-yl)anilides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei, the causative agent for human African trypanosomiasis', European Journal of Medicinal Chemistry, vol. 66, pp. 450 - 465. https://doi.org/10.1016/j.ejmech.2013.05.007

3-(Oxazolo[4,5-b]pyridin-2-yl)anilides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei, the causative agent for human African trypanosomiasis. / Ferrins, Lori; Rahmani, Raphael Steve; Sykes, Melissa L; Jones, Amy J; Avery, Vicky M; Teston, Eliott; Almohaywi, Basmah; Yin, JieXiang; Smith, Jason; Chris, Hyland; White, Karen Louise; Ryan, Eileen; Campbell, Michael; Charman, Susan Ann; Kaiser, Marcel; Baell, Jonathan Bayldon.

In: European Journal of Medicinal Chemistry, Vol. 66, 2013, p. 450 - 465.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - 3-(Oxazolo[4,5-b]pyridin-2-yl)anilides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei, the causative agent for human African trypanosomiasis

AU - Ferrins, Lori

AU - Rahmani, Raphael Steve

AU - Sykes, Melissa L

AU - Jones, Amy J

AU - Avery, Vicky M

AU - Teston, Eliott

AU - Almohaywi, Basmah

AU - Yin, JieXiang

AU - Smith, Jason

AU - Chris, Hyland

AU - White, Karen Louise

AU - Ryan, Eileen

AU - Campbell, Michael

AU - Charman, Susan Ann

AU - Kaiser, Marcel

AU - Baell, Jonathan Bayldon

PY - 2013

Y1 - 2013

N2 - A whole organism high-throughput screen of approximately 87,000 compounds against Trypanosoma brucei brucei led to the recent discovery of several novel compound classes with low micromolar activity against this organism and without appreciable cytotoxicity to mammalian cells. Herein we report a structure activity relationship (SAR) investigation around one of these hit classes, the 3-(oxazolo[4,5-b] pyridin-2-yl)anilides. Sharp SAR is revealed, with our most active compound (5) exhibiting an IC50 of 91 nM against the human pathogenic strain T.b. rhodesiense and being more than 700 times less toxic towards the L6 mammalian cell line. Physicochemical properties are attractive for many compounds in this series. For the most potent representatives, we show that solubility and metabolic stability are key parameters to target during future optimisation.

AB - A whole organism high-throughput screen of approximately 87,000 compounds against Trypanosoma brucei brucei led to the recent discovery of several novel compound classes with low micromolar activity against this organism and without appreciable cytotoxicity to mammalian cells. Herein we report a structure activity relationship (SAR) investigation around one of these hit classes, the 3-(oxazolo[4,5-b] pyridin-2-yl)anilides. Sharp SAR is revealed, with our most active compound (5) exhibiting an IC50 of 91 nM against the human pathogenic strain T.b. rhodesiense and being more than 700 times less toxic towards the L6 mammalian cell line. Physicochemical properties are attractive for many compounds in this series. For the most potent representatives, we show that solubility and metabolic stability are key parameters to target during future optimisation.

UR - http://www.sciencedirect.com.ezproxy.lib.monash.edu.au/science/article/pii/S0223523413003073

U2 - 10.1016/j.ejmech.2013.05.007

DO - 10.1016/j.ejmech.2013.05.007

M3 - Article

VL - 66

SP - 450

EP - 465

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -