Total synthesis of thiaplakortone A: Derivatives as metabolically stable leads for the treatment of malaria

Article abstract of DOI:10.1021/ml400447v

Thiaplakortone A (3a), an antimalarial natural product, was prepared by an operationally simple and scalable synthesis. In our efforts to deliver a lead compound with improved potency, metabolic stability, and selectivity, the synthesis was diverted to access a series of analogues. Compounds 3a-d showed nanomolar activity against the chloroquine-sensitive (3D7) Plasmodium falciparum line and were more active against the chloroquine- and mefloquine-resistant (Dd2) P. falciparum line. All compounds are "Rule-of-5" compliant, and we show that metabolic stability can be enhanced via modification at either the primary or pyrrole nitrogen. These promising results lay the foundation for the development of this structurally unprecedented natural product.

Full text of DOI:10.1021/ml400447v

Letter
pubs.acs.org/acsmedchemlett
Total Synthesis of Thiaplakortone A: Derivatives as Metabolically
Stable Leads for the Treatment of Malaria
Rebecca H. Pouwer,† Sophie M. Deydier,† Phuc Van Le,† Brett D. Schwartz,† Nicole C. Franken,†
Rohan A. Davis,† Mark J. Coster,† Susan A. Charman,‡ Michael D. Edstein,§ Tina S. Skinner-Adams,†
Katherine T. Andrews,† Ian D. Jenkins,† and Ronald J. Quinn*,†
†Eskitis Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia
‡Centre for Drug Candidate Optimisation, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia
§Australian Army Malaria Institute, Brisbane, QLD 4051, Australia
S
* Supporting Information
ABSTRACT: Thiaplakortone A (3a), an antimalarial natural
product, was prepared by an operationally simple and scalable
synthesis. In our efforts to deliver a lead compound with improved
potency, metabolic stability, and selectivity, the synthesis was
diverted to access a series of analogues. Compounds 3a−d showed
nanomolar activity against the chloroquine-sensitive (3D7)
Plasmodium falciparum line and were more active against the
chloroquine- and mefloquine-resistant (Dd2) P. falciparum line.
All compounds are “Rule-of-5” compliant, and we show that metabolic stability can be enhanced via modification at either the
primary or pyrrole nitrogen. These promising results lay the foundation for the development of this structurally unprecedented
natural product.
KEYWORDS: Malaria, natural products, total synthesis
pproximately 3.3 billion people, almost half the world’s
annua), respectively,14 are well-known natural products, which
Apopulation, including the populations of Africa, Asia, Latin have served as a structural basis for numerous antimalarial
drugs, such as artesunate, artemether, chloroquine, mefloquine,
and halofantrine.15 Many other drugs are also derived from
Nature, with natural product drugs representing ∼50% of small
molecule approved drugs.13 The basis for the wide-ranging
biological activity of natural products is explained by the
concept of protein fold topology (PFT),16 where molecular
recognition during biosynthesis (the biosynthetic imprint) has
been shown to translate to a similar binding mode with
therapeutic targets. The cavity recognition points described by
PFT may be unrelated to fold and sequence similarity and
define a natural product’s ability to interact with biological
space.17−19
We have developed a lead-like enhanced natural product
fraction screening library, in which fractions are selected for
drug-like properties including logP.20 Active natural products
from our malaria drug discovery program include tsitsikamm-
amine C (1) and makaluvamine G (2) from the marine sponge,
Zyzzya sp.,21 and more recently thiaplakortone A from the
sponge, Plakortis lita (Figure 1).22 Thiaplakortone A (3a)
contains a unique tricyclic alkaloid skeleton that is without
precedent among natural products.22 The thiazine dioxide-
fused pyrroloquinone moiety shares some structural similarity
America, the Middle East, and South East Asia, are at risk of
developing malaria.1 In 2010, approximately 655,000 people
died due to this disease.1 Of these deaths, an estimated 91%
occurred in sub-Saharan Africa, with children under the age of
five being most at risk. The World Health Organization
(WHO) recommends interventions for the prevention and
treatment of malaria that include (1) the use of insecticide-
treated nets; (2) drug prophylaxis in vulnerable populations;
(3) rapid diagnosis; and (4) treatment with antimalarial drugs.1
Current drug therapy for Plasmodium falciparum malaria,
recommended by the WHO, uses artemisinin in combination
with other antimalarials. The problem of parasite resistance to
artemisinin-based combination therapy (ACT) is of growing
and immense concern, with the presence of artemisinin
resistance having been confirmed in western Cambodia and
western Thailand.2−6 In addition to the threat of parasite
resistance, the poor safety profiles and undesirable side-effects
associated with many of the current antimalarials are also
driving the need for new small molecule therapies. New
antimalarial drugs with unique mechanisms of action are
urgently needed in order to combat the global problem of
parasite drug resistance.7−9
Natural products have played a key role in antimalarial drug
discovery and therapy.10−13 Quinine and artemisinin, first
isolated from the South American “quinine bark” (Cinchona
succirubra) and the Chinese “sweet wormwood” (Artemisia
Received: November 5, 2013
Accepted: December 27, 2013
Published: December 27, 2013
© 2013 American Chemical Society
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ACS Medicinal Chemistry Letters
Letter
a
Scheme 1
Figure 1. Antimalarial pyrroloquinone natural products.
with the antimalarial natural products tsitsikammamine C (1)
and makaluvamine G (2). Previous studies of the tsitsikamm-
amine and makaluvamine series indicated that methylation
affected antimalarial activity and metabolic stability. In
comparing the structural features of 1, 2, and 3a, the right
hemisphere of 3a has the intact pyrrolo moiety; however, the
iminoquinone present in 1 and 2 is ring opened to the quinone
with a free primary amine side chain in 3a. Tsitsikammamine C
(1) displayed potent in vitro activity (IC50 = 13 nM [3D7], 18
nM [Dd2]), had selectivity indices of >200, and inhibited both
ring and trophozoite stages of the parasite life cycle.
Makaluvamine G (2) (IC50 = 36 nM [3D7], 39 nM [Dd2])
had selectivity indices of >50 and primarily inhibited the
trophozoite stage. Thiaplakortone A (3a) was found to have
IC50 values of 51 and 6.6 nM against the chloroquine-sensitive
3D7 and the chloroquine- and mefloquine-resistant Dd2
Plasmodium falciparum lines in an imaging-based growth
inhibition assay, respectively.22 These data led us to further
explore the antimalarial properties of pyrroloquinone scaffolds
through a diverted total synthesis of thiaplakortone A (3a).
Herein we report the first total synthesis of 3a, along with
several thiaplakortone-based analogues (3b−d, 17). The in
vitro antimalarial activity and mammalian cell toxicity studies
for all compounds is also reported as well as metabolic profiling
and in vivo studies with lead compounds in mice.
a
Reagents and conditions: (a) BnBr, K2CO3, acetone, reflux, 36 h; (b)
POCl3, DMF, rt, 1 h, then KOH, H2O, reflux, 3 h; (c) CH3NO2,
NH4OAc, reflux, 1 h; (d) LiAlH4, THF, reflux, 6 h; (e) Boc2O, Et3N,
THF, rt, 16 h; (f) MeI, KOH, DMSO, rt, 19 h; (g) MeI, LiHMDS,
THF, rt, 2 h; (h) TsCl, Bu4NHSO4, KOH, toluene, H2O, rt, 24 h; (i)
MeI, LiHMDS, THF, rt, 2 h; (j) Mg, MeOH, sonicate, 30 min.
A,25,26 and it is anticipated that our synthetic strategy would
equally serve to access compounds of type 1 and 2.
The tryptamine derivatives 7−9 and 12 were then subjected
to a general procedure for the synthesis of the thiazine dioxide
pyrroloquinones (Scheme 2). Initial hydrogenolysis of the
benzyl protecting group was followed by immediate oxidation
of the unstable intermediate with Fremy’s salt. The resulting
a
Scheme 2
In developing a synthetic strategy toward 3a as an early lead
compound for the treatment of malaria, we were mindful of
expense and the need for the synthesis to be operationally
simple. Furthermore, the ability to access monomethyl and
dimethyl analogues (3b−d) for structure−activity relationship
development was of central importance in our synthetic design.
Synthesis of the common intermediate 7 from commercially
available 4-hydroxyindole (4)23 commenced with protection of
the phenol as its benzyl ether,24 followed by Vilsmeier−Haack
formylation to produce aldehyde 6 (Scheme 1). This
compound was subsequently subjected to Henry reaction
with nitromethane, where the resulting nitroalkene was reduced
by LiAlH4, and the primary amine was protected as its t-
butylcarbamate (7). Thus, 7 was synthesized in five facile
synthetic steps from 4, requiring only two chromatographic
separations. Selective methylation of 7 (MeI, KOH) yielded 8,
thus allowing access to derivatives of the natural product in
which the pyrrole nitrogen is methylated. Compound 8, which
upon subsequent treatment with LiHMDS and MeI provided 9,
also served as a precursor to a dimethylated analogue of 3a. To
selectively access an analogue in which only the side-chain
amine was alkylated, it was necessary to protect the indole
nitrogen of 7. Consequently, 7 was protected as its tosylate
(10), and subsequent methylation (LiHMDS, MeI) and
deprotection (Mg, MeOH) gave rise to the monomethylated
derivative 12. It is worth noting that 10 resembles a synthetic
intermediate used in the total synthesis of tsitsikammamine
a
Reagents and conditions: (a) H2, Pd/C, MeOH, rt, 24 h; (b) Fremy’s
salt, NaH2PO4, CH3CN, H2O, rt, 4 h; (c) 2-aminoethanesulfinic acid,
EtOH, CH3CN, H2O, rt, 16 h; (d) O2, KOH, MeOH, H2O, 60 °C; (e)
HCl, MeOH, H2O, rt, 18 h, or HCl 1,4-dioxane, rt, 30 min.
179
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ACS Medicinal Chemistry Letters
Letter
quinones participated in a double conjugate addition/oxidation
sequence upon treatment with 2-aminoethanesulfinic acid to
yield dihydrothiazine dioxides 13a−d as separable mixtures
with their corresponding regioisomers. Dihydrothiazine diox-
ides 13a−d were then oxidized (O2, KOH) and deprotected
under acidic conditions to produce the natural product 3a and
thiazine dioxides 3b−d as their hydrochloride salts. Compound
15, the regioisomer of 13b, was subjected to an equivalent
sequence to deliver 17 (Scheme 3). From tryptamine
methylation of the pyrrole nitrogen appears not to affect the
bioactivity.21 With respect to the thiaplakortone scaffold, our
results demonstrate that alkylation of both the pyrrole and side-
chain nitrogens is well tolerated, with analogues 3b−d
demonstrating low nM potency in both the 3D7 (3b IC50
=
128 nM, 3c IC50 = 137 nM, 3d IC50 = 160 nM) and Dd2 (3b
IC50 = 57 nM, 3c IC50 = 79 nM, 3d IC50 = 47 nM) P.
falciparum lines. When compared with 3b, regioisomer 17
showed decreased activity against both malaria parasite lines
(IC50 = 416 nM [3D7], 162 nM [Dd2]), suggesting that the
orientation of the thiazine dioxide moiety plays an important
role in biological activity. These observations open avenues for
the further manipulation of these moieties in future structure−
activity relationship investigations.
a
Scheme 3
Selectivity between host and parasite is of paramount
concern, as quinones have been associated with toxic effects.30
All compounds were found to have greater than 9-fold
selectivity for the 3D7 P. falciparum line over NFF cells,
providing a reasonable therapeutic window for the development
of an early lead compound. Interestingly, regioisomer 17
showed the highest levels of selectivity (32-fold in 3D7 and 81-
fold in Dd2), demonstrating that minor manipulation of the
core may result in an improved toxicity profile.
a
Reagents and conditions: (a) O2, KOH, MeOH, H2O, 60 °C; (b)
HCl, MeOH, H2O, rt, 18 h.
derivatives 7−9 and 12, this synthetic sequence required only
one chromatographic separation and was used to rapidly
produce the thiazinedioxides on multigram scale. The NMR
spectroscopic data for synthetic 3a (HCl salt) was essentially
identical to that previously reported for the natural product,
thiaplakortone A, which was isolated as a TFA salt.22
Compounds were evaluated for in vitro antimalarial activity
using the [3H]-hypoxanthine incorporation assay27,28 against
the chloroquine-sensitive 3D7 and the chloroquine- and
mefloquine-resistant Dd2 Plasmodium falciparum lines. To
compare the selectivity of the compounds for malaria parasites
versus normal mammalian cells, cytotoxicity tests were carried
out using human neonatal foreskin fibroblast (NFF) cells. All
biological data, including selectivity indices and calculated
physicochemical properties, are detailed in Table 1.
All compounds complied with Lipinski’s rule-of-five31 (logP
< 5, hydrogen bond acceptors (HBA) < 10, hydrogen bond
donors (HBD) < 5, MW < 500), and Hann−Oprea’s guidelines
for lead-likeness32 (logP < 4, HBA < 9, HBD < 5, MW < 460,
rotatable bonds < 10). Compounds 3a−d displayed good
solubility in phosphate buffered saline under both neutral and
acidic conditions. These physicochemical properties support
the drug-likeness of compounds 3a−d.
In vitro studies in hepatic microsomes were conducted to
assess the extent of metabolic degradation (Table 2).
Table 2. In Vitro Metabolism of Compounds 3a−d in
Human and Mouse Liver Microsomes
The synthetic natural product 3a had an IC50 of 104 nM
against the 3D7 P. falciparum line and was found to be 4.3-fold
more potent against the multidrug resistant P. falciparum line
Dd2 (IC50 = 24 nM). This interesting observation held true for
analogues 3b−d, with selectivity for the P. falciparum line Dd2
ranging between 1.7- to 3.4-fold. This effect was not observed
for compounds 1 and 2 and is in fact opposite to that for
chloroquine, which has more than 8-fold less potency against
the Dd2 P. falciparum line. For the makaluvamine series (e.g.,
2), we previously reported that the presence of an N-methyl
iminium moiety increased antimalarial activity by ∼10- to 30-
fold compared to a secondary imine skeleton, while
half-life
(min)
in vitro CLint
a
compd species
(μL/min/mg protein)
EH
3a
3b
3c
3d
human
mouse
human
mouse
human
mouse
human
mouse
37
46
68
<7
<7
<7
<7
17
11
0.64
25
0.75
>250
>250
>250
>250
100
<0.23
<0.23
<0.23
<0.23
0.40
151
0.33
a
EH: predicted in vivo hepatic extraction ratio, calculated according to
published methods.
Table 1. Physicochemical Parameters and Biological Profiles of Compounds 3a−d and 17
a
b
c
physicochemical parameters
IC50 SD (nM)
Dd2
SI
compd
MW
cLogP
HBA
HBD
3D7
NFF
3D7
Dd2
3a
3b
3c
3d
17
293
307
321
307
307
319
−2.06
−1.84
−1.40
−1.77
−1.84
3.93
6
6
6
6
6
4
3
2
2
3
2
1
104 22
128 20
137 29
160 11
416 90
24
2
1500 500
14
18
17
9
60
40
29
31
81
353
57 14
79 0.2
47 10
162 87
130 22
2309 1037
2309 1229
1477 607
13197 3236
45900 19300
32
3060
chloroquine
15
4
a
In silico calculations performed using Instant JChem software.29 MW = molecular weight (Da) of free base, HBA = H-bond acceptors, and HBD =
b
H-bond donors. 50% inhibitory concentration in vitro against P. falciparum chloroquine-sensitive (3D7) and drug-resistant (Dd2) lines, and human
neonatal foreskin fibroblast cells (NFF). SI = mammalian cell IC50/P. falciparum IC50.
c
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ACS Medicinal Chemistry Letters
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Compounds 3a−d were found to be stable in the microsomal
matrix in the absence of cofactors, suggesting that there was no
major contribution of cofactor-independent metabolism to the
rate of metabolism. In the presence of NADPH in both human
and mouse liver microsomes, the synthetic natural product 3a
was rapidly degraded, with half-lives of 37 and 25 min,
respectively. Analogues 3b and 3c, which both feature a
methylated pyrrole, were minimally degraded in both species,
and were found to have significantly increased half-lives (>250
min) and low predicted hepatic extraction ratios (<0.23) in
comparison to 3a and 3d (Table 2). Monomethylation of the
primary amine side-chain (i.e., 3d) resulted in an increased half-
life of 100 min in human microsomes. These results highlight
an opportunity to improve metabolic stability through a simple
modification of either the primary or pyrrole nitrogen of the
natural product.
the ARC for support toward NMR and MS equipment (Grant
LE0668477 and LE0237908) and the National Health and
Medical Research Council (NHMRC) for funding support
(APP1024314).
Notes
The opinions expressed herein are those of the authors and do
not necessarily reflect those of the Australian Defence Force,
Joint Health Command or any extant policy.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Australian Red Cross Blood Service for the
provision of human blood and sera. We are grateful for the
animal work carried out by Stephen McLeod-Robertson and
Donna McKenzie.
The tolerability of 3a−c was assessed in healthy mice. A
slight whole body tremor lasting about 1−2 h after each dose
and slightly ruffled coat were observed in mice administered 3a
at a daily dose of 8 mg/kg for 4 d. However, at 16 mg/kg the
mice exhibited marked whole body tremors, lethargy, and
ruffled coat within 2 h after the first dose. Mice administered 3b
at a dose of 4 and 8 mg/kg exhibited panting and whole body
tremors within 10 to 15 min of the first dose, with adverse
events more noticeable with the higher dose. Compound 3c, at
a dose of 8 mg/kg, led to marked physical distress in all
animals, with whole body tremors, difficulty in moving about,
orange urine, and swollen conjunctiva of the eyes. Overall, 3a−
c were not well tolerated in mice at relatively low doses of
compound. Investigations to address in vivo tolerability of this
compound series are underway.
In conclusion, from 3a, an antimalarial natural product, we
have developed potent antimalarial compounds with favorable
physicochemical and ADME properties. We have designed and
completed the rapid and operationally simple total synthesis of
3a and have diverted this synthesis to access analogues 3b−d.
Methylation of the thiaplakortone scaffold was well tolerated,
and analogues 3b−d showed low nM in vitro activity against
drug-sensitive and drug-resistant P. falciparum lines. Methyl-
ation of the pyrrole nitrogen was found to dramatically increase
the metabolic stability of analogues, without significant loss of
antimalarial activity. These studies pave the way for the
development of structurally unprecedented lead compounds for
the treatment of malaria.
ABBREVIATIONS
■
PFT, protein fold topology; ACT, artemisinin-based combina-
tion therapy; NFF, neonatal foreskin fibroblast cells; 3D7,
chloroquine-sensitive P. falciparum line; Dd2, chloroquine-
resistant P. falciparum line
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ASSOCIATED CONTENT
* Supporting Information
■
S
Details regarding compound synthesis and characterization and
biological assays. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
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*(R.J.Q.) Tel: +61-7-3735-6000. Fax: +61-7-3735-6001. E-
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