DOI: 10.1002/cmdc.201600210
Communications
Development of Simplified Heterocyclic Acetogenin
Analogues as Potent and Selective Trypanosoma brucei
Inhibitors
Gordon J. Florence,* Andrew L. Fraser, Eoin R. Gould, Elizabeth F. King, Stefanie K. Menzies,
Joanne C. Morris, Marie I. Thomson, Lindsay B. Tulloch, Marija K. Zacharova, and
Terry K. Smith[a]
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 syn-
thesis and biological testing of other novel heterocyclic aceto-
genin-inspired derivatives, namely 3,5-isoxazoles, furoxans, and
furazans. Several of these compounds maintain low-micromo-
lar levels of inhibition against Trypanosoma brucei, whilst
having no observable inhibitory effect on mammalian cells,
leading to the possibility of novel lead compounds for selec-
tive treatment.
and the onset of drug resistance highlights the urgent need
for the development of novel small molecule inhibitors of
T. brucei as potential lead compounds in the quest for new and
effective treatments for HAT.[6]
Acetogenins are a class of polyketide secondary metabolites
isolated from medicinal plants of the Annonaceae species, typi-
cally found in tropical regions of West Africa and South Ameri-
ca.[7,8] Isolated in 2004 by Laurens et al. from the roots of bush
banana plant Uvaria chamae, chamuvarinin 1, displayed high
levels of cytotoxicity toward the KB3-1 cell line (IC50 =0.8 nm).[9]
In 2011, our research group reported the first total synthesis of
this unique tetrahydopyran-containing acetogenin and found
1 to exhibit unexpected trypanocidal activity in both the
bloodstream and procyclic forms of T. brucei (Figure 1).[10,11] In-
spired by chamuvarinin, we sought to design a series of simpli-
fied acetogenin-like analogues retaining key structural and ste-
reochemical features of the parent natural product. These sim-
plified analogues were assembled from a pool of readily acces-
sible chiral tetrahydropyran (THP) building blocks via copper-
mediated click chemistry.[12] These 1,4-triazole linked analogues,
including 2, maintained high trypanocidal activity with modest
selectivity profiles when compared against the human HeLa
cell line.
Neglected tropical diseases remain one of the largest concerns
in the developing countries of Africa and the South Americas,
both in terms of healthcare provision and financial impact on
the economies of the world’s poorest countries. This ongoing
threat has arisen from a lack of effective prevention methods
and minimal financial incentive to develop new therapeutic
agents.[1] One of these prevalent neglected tropical diseases
which has attracted attention in recent years is African sleep-
ing sickness or human African trypanosomiasis (HAT), caused
by the protozoan parasite Trypanosoma brucei. HAT is a serious
health concern in sub-Saharan Africa with >65 million people
at risk and with an annual mortality rate of approximately
9000 per annum.[2] The World Health Organization (WHO) esti-
mates 20000 new cases of HAT per year based on reported
cases, and has set an ambitious target to eradicate HAT by
2020.[3] Current drug treatments depend on the stage of HAT
and are difficult to administer to patients, requiring lengthy in-
fusion rates, and have varying degrees of human toxicity, while
showing low efficacy toward the parasite.[4] The combination
eflornithine/nifurtimox therapy (NECT) for stage 2 HAT has
proven successful, but resistance to this combination therapy
is emerging.[5] The lack of new effective therapeutic agents
Following on from this success we sought to explore alter-
native heterocyclic linkers, in particular those that would di-
rectly attach the heterocycle spacer to the flanking THP rings,
in close analogy to the acetogenins. This direct linkage serves
to decrease the molecules’ available degrees of freedom and
so potentially improve binding efficiency. Moreover, we wished
to expand the toolbox of available reactions employing our
chiral THP building blocks as a source of molecular diversity.
This paper describes the expansion of our methodology to
new heterocycles: 3,5-isoxazoles, furoxans and furazans, as
well as their assessment as potential trypanocidal agents.
Despite their prevalence in natural products and their pres-
ence in several important drug compounds (e.g., valdecoxib,
leflunomide, cloxacillin),[13] synthetic routes to aliphatic isoxa-
zoles remain extremely limited.[14] In particular, there are only
limited examples of a-oxygenated 3,5-isoxazoles and none of
these, to our knowledge, have been prepared in enantio-en-
riched form. Our approach employs the coupling of chiral a-
oxygenated alkynes with in situ prepared nitrile oxides, derived
from the corresponding oximes, in a [3+2] cycloaddition.
Oximes 3–5 were rapidly accessed from the corresponding
THP alcohols by Swern oxidation and condensation with hy-
[a] Dr. G. J. Florence, A. L. Fraser, Dr. E. R. Gould, E. F. King, S. K. Menzies,
Dr. J. C. Morris, M. I. Thomson, Dr. L. B. Tulloch, M. K. Zacharova,
Prof. Dr. T. K. Smith
EaStCHEM School of Chemistry and School of Biology,
Biomedical Sciences Research Complex,
University of St. Andrews, North Haugh, St. Andrews, KY16 9ST, (UK)
Supporting information for this article can be found under http://
ChemMedChem 2016, 11, 1 – 5
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