title: Simplifying nature: Towards the design of broad spectrum kinetoplastid inhibitors, inspired by acetogenins.
abstract: 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.
authors.affiliation: EaStChem School of Chemistry, Biomedical Science Research Complex, University of St Andrews, North Haugh, St Andrews, Fife KY16 9ST, UK.
authors.forename: Eoin R
authors.initials: ER
authors.lastname: Gould
authors.affiliation: EaStChem School of Chemistry, Biomedical Science Research Complex, University of St Andrews, North Haugh, St Andrews, Fife KY16 9ST, UK.
authors.forename: Elizabeth F B
authors.initials: EFB
authors.lastname: King
authors.affiliation: EaStChem School of Chemistry, Biomedical Science Research Complex, University of St Andrews, North Haugh, St Andrews, Fife KY16 9ST, UK.
authors.forename: Stefanie K
authors.initials: SK
authors.lastname: Menzies
authors.affiliation: EaStChem School of Chemistry, Biomedical Science Research Complex, University of St Andrews, North Haugh, St Andrews, Fife KY16 9ST, UK.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Fraser
authors.affiliation: EaStChem School of Chemistry, Biomedical Science Research Complex, University of St Andrews, North Haugh, St Andrews, Fife KY16 9ST, UK.
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Tulloch
authors.affiliation: EaStChem School of Chemistry, Biomedical Science Research Complex, University of St Andrews, North Haugh, St Andrews, Fife KY16 9ST, UK.
authors.forename: Marija K
authors.initials: MK
authors.lastname: Zacharova
authors.affiliation: EaStChem School of Chemistry, Biomedical Science Research Complex, University of St Andrews, North Haugh, St Andrews, Fife KY16 9ST, UK. Electronic address: tks1@st-andrews.ac.uk.
authors.forename: Terry K
authors.initials: TK
authors.lastname: Smith
authors.affiliation: EaStChem School of Chemistry, Biomedical Science Research Complex, University of St Andrews, North Haugh, St Andrews, Fife KY16 9ST, UK. Electronic address: gjf1@st-andrews.ac.uk.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Florence
mesh_terms: D054378:Acetogenins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D005663:Furans / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D018320:Leishmania major / Q000187:drug effects; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: D054378:Acetogenins; D005663:Furans; D014230:Triazoles; D014344:Trypanocidal Agents; C488316:chamuvarinin; C039281:furan
keywords: Acetogenins; Natural products; Neglected tropical diseases; Tetrahydropyran