title: Non-natural acetogenin analogues as potent Trypanosoma brucei inhibitors.
abstract: Neglected tropical diseases remain a serious global health concern. Here, a series of novel bis-tetrahydropyran 1,4-triazole analogues based on the framework of chamuvarinin, a polyketide natural product isolated from the annonaceae plant species are detailed. The analogues synthesized display low micromolar trypanocidal activities towards both bloodstream and insect forms of Trypanosoma brucei, the causative agent of African sleeping sickness, also known as Human African Trypanosomiasis (HAT). A divergent synthetic strategy was adopted for the synthesis of the key tetrahydropyran intermediates to enable rapid access to diastereochemical variation either side of the 1,4-triazole core. The resulting diastereomeric analogues displayed varying degrees of trypanocidal activity and selectivity in structure-activity relationship studies. Together, the biological potency and calculated lipophilicity values indicate that while there is room for improvement, these derivatives may represent a promising novel class of anti-HAT agents.
authors.affiliation: EaStCHEM School of Chemistry, Biomedical Sciences Research Complex, University of St Andrews, North Haugh, St Andrews, KY16 9ST (UK). gjf1@st-andrews.ac.uk.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Florence
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Fraser
authors.forename: Eoin R
authors.initials: ER
authors.lastname: Gould
authors.forename: Elizabeth F B
authors.initials: EF
authors.lastname: King
authors.forename: Stefanie K
authors.initials: SK
authors.lastname: Menzies
authors.forename: Joanne C
authors.initials: JC
authors.lastname: Morris
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Tulloch
authors.forename: Terry K
authors.initials: TK
authors.lastname: Smith
mesh_terms: D054378:Acetogenins / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D014346:Trypanosoma brucei brucei / Q000187:drug effects*
chemical_list: D054378:Acetogenins; D014230:Triazoles; D014344:Trypanocidal Agents; C488316:chamuvarinin
keywords: Human African Trypanosomiasis (HAT); Trypanosoma brucei; acetogenin; natural product analogues; neglected diseases; stereochemistry