Development of Simplified Heterocyclic Acetogenin Analogues as Potent and Selective Trypanosoma brucei Inhibitors.
Neglected tropical diseases caused by parasitic infections are an ongoing and increasing concern. They are a burden to human and animal health, having the most devastating effect on the world's poorest countries. Building upon our previously reported triazole analogues, in this study we describe the synthesis and biological testing of other novel heterocyclic acetogenin-inspired derivatives, namely 3,5-isoxazoles, furoxans, and furazans. Several of these compounds maintain low-micromolar levels of inhibition against Trypanosoma brucei, whilst having no observable inhibitory effect on mammalian cells, leading to the possibility of novel lead compounds for selective treatment.
EaStCHEM School of Chemistry and School of Biology, Biomedical Sciences Research Complex, University of St. Andrews, North Haugh, St. Andrews, KY16 9ST, UK. gjf1@st-andrews.ac.uk.
Gordon J
GJ
Florence
EaStCHEM School of Chemistry and School of Biology, Biomedical Sciences Research Complex, University of St. Andrews, North Haugh, St. Andrews, KY16 9ST, UK.
Andrew L
AL
Fraser
EaStCHEM School of Chemistry and School of Biology, Biomedical Sciences Research Complex, University of St. Andrews, North Haugh, St. Andrews, KY16 9ST, UK.
Eoin R
ER
Gould
EaStCHEM School of Chemistry and School of Biology, Biomedical Sciences Research Complex, University of St. Andrews, North Haugh, St. Andrews, KY16 9ST, UK.
Elizabeth F
EF
King
EaStCHEM School of Chemistry and School of Biology, Biomedical Sciences Research Complex, University of St. Andrews, North Haugh, St. Andrews, KY16 9ST, UK.
Stefanie K
SK
Menzies
EaStCHEM School of Chemistry and School of Biology, Biomedical Sciences Research Complex, University of St. Andrews, North Haugh, St. Andrews, KY16 9ST, UK.
Joanne C
JC
Morris
EaStCHEM School of Chemistry and School of Biology, Biomedical Sciences Research Complex, University of St. Andrews, North Haugh, St. Andrews, KY16 9ST, UK.
Marie I
MI
Thomson
EaStCHEM School of Chemistry and School of Biology, Biomedical Sciences Research Complex, University of St. Andrews, North Haugh, St. Andrews, KY16 9ST, UK.
Lindsay B
LB
Tulloch
EaStCHEM School of Chemistry and School of Biology, Biomedical Sciences Research Complex, University of St. Andrews, North Haugh, St. Andrews, KY16 9ST, UK.
Marija K
MK
Zacharova
EaStCHEM School of Chemistry and School of Biology, Biomedical Sciences Research Complex, University of St. Andrews, North Haugh, St. Andrews, KY16 9ST, UK.
Terry K
TK
Smith
D054378:Acetogenins / Q000138:chemical synthesis / Q000494:pharmacology*; D061565:Cycloaddition Reaction; D006367:HeLa Cells; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000494:pharmacology; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000494:pharmacology; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects*
D054378:Acetogenins; D007555:Isoxazoles; D010069:Oxadiazoles; D010091:Oximes; D014344:Trypanocidal Agents
[3+2] cycloaddition; drug discovery; natural product analogues; trypanosomatids