Final published version
Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
}
TY - JOUR
T1 - Simplifying nature
T2 - Towards the design of broad spectrum kinetoplastid inhibitors, inspired by acetogenins
AU - Gould, Eoin R.
AU - King, Elizabeth F.B.
AU - Menzies, Stefanie K.
AU - Fraser, Andrew L.
AU - Tulloch, Lindsay B.
AU - Zacharova, Marija K.
AU - Smith, Terry K.
AU - Florence, Gordon J.
PY - 2017/11/15
Y1 - 2017/11/15
N2 - The need for new treatments for the neglected tropical diseases African sleeping sickness, Chagas disease and Leishmaniasis remains urgent with the diseases widespread in tropical regions, affecting the world's very poorest. We have previously reported bis-tetrahydropyran 1,4-triazole analogues designed as mimics of the annonaceous acetogenin natural product chamuvarinin, which maintained trypanocidal activity. Building upon these studies, we here report related triazole compounds with pendant heterocycles, mimicking the original butenolide of the natural product. Analogues were active against T. brucei, with a nitrofuran compound displaying nanomolar trypanocidal activity. Several analogues also showed strong activity against T. cruzi and L. major. Importantly, select compounds gave excellent selectivity over mammalian cells with a furan-based analogue highly selective while remaining active against all three cell lines, thus representing a potential lead for a new broad spectrum kinetoplastid inhibitor.
AB - The need for new treatments for the neglected tropical diseases African sleeping sickness, Chagas disease and Leishmaniasis remains urgent with the diseases widespread in tropical regions, affecting the world's very poorest. We have previously reported bis-tetrahydropyran 1,4-triazole analogues designed as mimics of the annonaceous acetogenin natural product chamuvarinin, which maintained trypanocidal activity. Building upon these studies, we here report related triazole compounds with pendant heterocycles, mimicking the original butenolide of the natural product. Analogues were active against T. brucei, with a nitrofuran compound displaying nanomolar trypanocidal activity. Several analogues also showed strong activity against T. cruzi and L. major. Importantly, select compounds gave excellent selectivity over mammalian cells with a furan-based analogue highly selective while remaining active against all three cell lines, thus representing a potential lead for a new broad spectrum kinetoplastid inhibitor.
KW - Acetogenins
KW - Natural products
KW - Neglected tropical diseases
KW - Tetrahydropyran
U2 - 10.1016/j.bmc.2017.01.021
DO - 10.1016/j.bmc.2017.01.021
M3 - Journal article
C2 - 28185724
AN - SCOPUS:85011592200
VL - 25
SP - 6126
EP - 6136
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 22
ER -