Quinol derivatives as potential trypanocidal agents. / Capes, Amy; Patterson, Stephen; Wyllie, Susan; Hallyburton, Irene; Collie, Iain T.; McCarroll, Andrew J.; Stevens, Malcolm F. G.; Frearson, Julie A.; Wyatt, Paul G.; Fairlamb, Alan H.; Gilbert, Ian H.
In: Bioorganic & Medicinal Chemistry, Vol. 20, No. 4, 15.02.2012, p. 1607-1615.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Quinol derivatives as potential trypanocidal agents
A1 - Capes,Amy
A1 - Patterson,Stephen
A1 - Wyllie,Susan
A1 - Hallyburton,Irene
A1 - Collie,Iain T.
A1 - McCarroll,Andrew J.
A1 - Stevens,Malcolm F. G.
A1 - Frearson,Julie A.
A1 - Wyatt,Paul G.
A1 - Fairlamb,Alan H.
A1 - Gilbert,Ian H.
AU - Capes,Amy
AU - Patterson,Stephen
AU - Wyllie,Susan
AU - Hallyburton,Irene
AU - Collie,Iain T.
AU - McCarroll,Andrew J.
AU - Stevens,Malcolm F. G.
AU - Frearson,Julie A.
AU - Wyatt,Paul G.
AU - Fairlamb,Alan H.
AU - Gilbert,Ian H.
PY - 2012/2/15
Y1 - 2012/2/15
N2 - <p>Quinols have been developed as a class of potential anti-cancer compounds. They are thought to act as double Michael acceptors, forming two covalent bonds to their target protein(s). Quinols have also been shown to have activity against the parasite Trypanosoma brucei, the causative organism of human African trypanosomiasis, but they demonstrated little selectivity over mammalian MRC5 cells in a counter-screen. In this paper, we report screening of further examples of quinols against T. brucei. We were able to derive an SAR, but the compounds demonstrated little selectivity over MRC5 cells. In an approach to increase selectivity, we attached melamine and benzamidine motifs to the quinols, because these moieties are known to be selectively concentrated in the parasite by transporter proteins. In general these transporter motif-containing analogues showed increased selectivity; however they also showed reduced levels of potency against T. brucei. (C) 2011 Elsevier Ltd. All rights reserved.</p>
AB - <p>Quinols have been developed as a class of potential anti-cancer compounds. They are thought to act as double Michael acceptors, forming two covalent bonds to their target protein(s). Quinols have also been shown to have activity against the parasite Trypanosoma brucei, the causative organism of human African trypanosomiasis, but they demonstrated little selectivity over mammalian MRC5 cells in a counter-screen. In this paper, we report screening of further examples of quinols against T. brucei. We were able to derive an SAR, but the compounds demonstrated little selectivity over MRC5 cells. In an approach to increase selectivity, we attached melamine and benzamidine motifs to the quinols, because these moieties are known to be selectively concentrated in the parasite by transporter proteins. In general these transporter motif-containing analogues showed increased selectivity; however they also showed reduced levels of potency against T. brucei. (C) 2011 Elsevier Ltd. All rights reserved.</p>
KW - Inhibitors
KW - Medicinal chemistry
KW - Trypanosoma brucei
KW - P2 transporter
KW - Quinols
KW - HUMAN AFRICAN TRYPANOSOMIASIS
KW - CANCER CELL-LINES
KW - THERAPEUTIC AGENTS
KW - ANTITUMOR QUINOLS
KW - BRUCEI
KW - THIOREDOXIN
KW - BENZOTHIAZOLE
KW - APOPTOSIS
KW - TARGET
KW - CYCLOADDITIONS
UR - http://ukpmc.ac.uk/articles/PMC3281193
U2 - 10.1016/j.bmc.2011.12.018
DO - 10.1016/j.bmc.2011.12.018
M1 - Article
JO - Bioorganic & Medicinal Chemistry
JF - Bioorganic & Medicinal Chemistry
SN - 0968-0896
IS - 4
VL - 20
SP - 1607
EP - 1615
ER -