3-(Phenethylamino)demethyl(oxy)aaptamine as an anti-dormant mycobacterial substance: Isolation, evaluation and total synthesis

Article abstract of DOI:10.1016/j.tetlet.2020.151924

3-(Phenethylamino)demethyl(oxy)aaptamine (1) was re-discovered from the marine sponge of Aaptos sp. as an anti-dormant mycobacterial substance through the bioassay-guided separation. Compound 1 showed potent anti-microbial activity against Mycobacterium bovis BCG with a minimum inhibitory concentration of 0.75 μg/mL under both aerobic conditions and hypoxic conditions inducing dormant state. Compound 1 was also effective against pathogenic M. tuberculosis strains including clinical multidrug-resistant strains. Furthermore, the successful total syntheses of 1 and its analog 3-aminodemethyl(oxy)aaptamine (2) afford sufficient quantities for further biological studies.

Full text of DOI:10.1016/j.tetlet.2020.151924

Journal Pre-proofs
3-(Phenethylamino)demethyl(oxy)aaptamine as an anti-dormant mycobacteri‐
al substance: Isolation, evaluation and total synthesis
Yuji Sumii, Naoyuki Kotoku, Chisu Han, Kentaro Kamiya, Andi Setiawan,
Catherine Vilchèze, William R. Jacobs Jr, Masayoshi Arai
PII:
S0040-4039(20)30367-1
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151924
TETL 151924
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
28 February 2020
2 April 2020
7 April 2020
Please cite this article as: Sumii, Y., Kotoku, N., Han, C., Kamiya, K., Setiawan, A., Vilchèze, C., Jacobs, W.R.
Jr, Arai, M., 3-(Phenethylamino)demethyl(oxy)aaptamine as an anti-dormant mycobacterial substance: Isolation,
evaluation and total synthesis, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151924
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3-(Phenethylamino)demethyl(oxy)aaptamine
as an anti-dormant mycobacterial substance:
Isolation, evaluation and total synthesis
Leave this area blank for abstract info.
Yuji Sumii, Naoyuki Kotoku*, Chisu Han, Kentaro Kamiya, Andi Setiawan, Catherine Vilchèze, William R.
Jacobs Jr. and Masayoshi Arai *
MeO
MeO
MeO
NH2
N
O
N
Ph
N
H
Marine sponge Aaptos sp.
Anti-dormant mycobacterial substance

1
Tetrahedron Letters
journal homepage: www.elsevier.com
3-(Phenethylamino)demethyl(oxy)aaptamine as an anti-dormant mycobacterial
substance: Isolation, evaluation and total synthesis
Yuji Sumii a,†, Naoyuki Kotoku a,‡,*, Chisu Han a, Kentaro Kamiya a, Andi Setiawan b, Catherine Vilchèze
c, William R. Jacobs Jr. c, and Masayoshi Arai a,*
a Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
b Department of Chemistry, Faculty of Science, Lampung University, Jl. Prof. Dr. Sumantri Brodjonegoro No. 1, Bandar Lampung 35145, Indonesia
c Albert Einstein College of Medicine; 1301 Morris Park Avenue, Bronx, New York 10461, U.S.A.
†Present affiliation: Graduate School of Engineering, Nagoya Institute of Technology, Nagoya 466-8555, Japan
‡Present affiliation: College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-higashi, Kusatsu, Shiga, 525-8577, Japan
*Correspondence to Naoyuki Kotoku and Masayoshi Arai. Email: kotoku@fc.ritsumei.ac.jp; araim@phs.osaka-u.ac.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
3-(Phenethylamino)demethyl(oxy)aaptamine (1) was re-discovered from the marine sponge of
Aaptos sp. as an anti-dormant mycobacterial substance through the bioassay-guided separation.
Compound 1 showed potent anti-microbial activity against Mycobacterium bovis BCG with a
minimum inhibitory concentration of 0.75 µg/mL under both aerobic conditions and hypoxic
conditions inducing dormant state. Compound 1 was also effective against pathogenic M.
tuberculosis strains including clinical multidrug-resistant strains. Furthermore, the successful
total syntheses of 1 and its analog 3-aminodemethyl(oxy)aaptamine (2) afford sufficient
quantities for further biological studies.
Available online
Keywords:
Aaptamine derivative
Antimicrobial
Tuberculosis
Dormant
2009 Elsevier Ltd. All rights reserved.
Tuberculosis (TB) is one of the most common causes of
morbidity and mortality in HIV-positive adults living in poverty
[1]. There are an estimated 10 million new TB cases and 1.5
million deaths from TB each year [2]. It is now generally accepted
that a minimum of 6 months of TB treatment is required owing to
the difficulty of eradicating the non-replicating persistent
Mycobacterium tuberculosis. One of the major reasons for the
extended chemotherapeutic regimens and wide epidemicity of TB
is the ability of its causative agent, namely M. tuberculosis, to
become dormant. Therefore, new anti-mycobacterial lead
compounds effective against M. tuberculosis in both active and
dormant states are urgently required. Hypoxic conditions induce
the dormant state of Mycobacterium sp., which has a drug
susceptibility profile resembling that of the latent M. tuberculosis
infection, although the physiology of the latent M. tuberculosis
infection remains unclear [3-5]. Based on this background, we
previously established a screening system to isolate anti-dormant
mycobacterial substances from marine organisms on the basis of a
bioassay-guided separation [6-8]. Furthermore, we have also
conducted target analyses of the isolated substances to identify
novel drug targets against M. tuberculosis [9-12].
discovered as a promising anti-dormant mycobacterial substance,
from an Indonesian marine sponge of Aaptos sp. In this
manuscript, we present the isolation, the anti-mycobacterial
evaluation against M. bovis BCG and pathogenic strains of M.
tuberculosis,
and
the
total
synthesis
of
3-
(phenethylamino)demethyl(oxy)aaptamine (1).
Previously, we isolated a new aaptamine class alkaloid,
named 2-methoxy-3-oxoaaptamine (8), together with seven
known aaptamines (2-7,9), as anti-dormant mycobacterial
substances from the marine sponge of Aaptos sp. 09C21, which
had been collected in 2009 at Kupang, Indonesia (Fig. 1) [8].
Further exploration of the MeOH extract of the same sponge
resulted in discovering another active constituent exhibiting
potent anti-dormant mycobacterial activity. Bioassay-guided
separation using the saprophyte, fast-growing Mycobacterium
smegmatis
provided
3-
(phenethylamino)demethyl(oxy)aaptamine (1) [13] as a potent
anti-microbial substance. Compound 1 was identified by MS and
NMR analyses. As shown in Table 1, compound 1 showed a
moderate activity against M. smegmatis under aerobic and
hypoxic conditions, with minimum inhibitory concentrations
(MICs) of 12.5 µg/mL and 6.25 µg/mL, respectively.
In the continuous screening from marine organisms and
marine-derived
microorganisms,
3-
We have previously reported that compounds 2-9 showed
potent anti-mycobacterial activities against M. smegmatis under
(phenethylamino)demethyl(oxy)aaptamine (1) [13,14] was re-

2
Tetrahedron
both actively growing and dormancy-inducing hypoxic
aaptaminoids have yet to be synthesized. To access the synthesis
of 1, the introduction of a nitrogen substituent into the C-3 position
and aromatization of the triamine moiety could be considered a
potential route. Based on previous synthetic studies and a brief
exploration of some of our preliminary studies, we envisioned that
adapting the Pelletier and Cava method (AB → C) [19] to the
synthesis of 1 would be a scalable synthetic methodology. Next,
we disclose a concise synthesis of 1 that allows sufficient amount
to be synthesized for further biological studies.
conditions, with MIC values of 1.5-25 µg/mL [8]. However, the
anti-microbial activity of these compounds on pathogenic
mycobacterial species was not investigated. Thus, we examined
the anti-mycobacterial activities of compounds 2–9, together with
that of the newly identified compound 1, against the vaccine strain
M. bovis BCG, a strain with high homology to M. tuberculosis. As
a result, compound 9 retained a moderate anti-microbial activity
against M. bovis BCG under both aerobic and hypoxic conditions
with MIC values of 25 µg/mL, whereas the activity of most of the
other compounds was markedly reduced against M. bovis BCG
(Table 1). In contrast, compound 1 showed a potent anti-microbial
activity against M. bovis BCG with MIC value of 0.75 µg/mL (2
M) under both aerobic and hypoxic conditions (Table 1). As a
comparison, the first-line anti-TB drug isoniazid has an MIC of
0.05 µg/mL (0.4 M) under both aerobic but is inactive under
hypoxic conditions.
H3CO
PGO
H3CO
O
N
N
PG
NH2
11
N
N
Ph
PG
N
H
O
1
ref. 16
H3CO
HO
H3CO
O
3-(phenethylamino)demethyl(oxy)aaptamine (1): R = NHCH2CH2Ph
3-aminodemethyl(oxy)aaptamine (2): R = NH2
H3CO
HO
A
B
NH
N
R
A
B
N
3-(methylamino)demethyl(oxy)aaptamine (3): R = NHCH3
demethyl(oxy)aaptamine (4): R = H
C
O
N
HN
13
12
H3CO
H3CO
H3CO
H3CO
H3CO
N
N
N
Fig. 2. Retrosynthetic analysis of 1. PG: protecting groups.
N
H3CO
HN
N
N
aaptamine (5)
6
7
Initially, the tricyclic lactam 19 was prepared from
commercially available homoveratrylamine (14) according to a
previously reported method with some modifications (Scheme 1)
[19]. The condensation of 14 with formic acid and the following
Bischler−Napieralski cyclization gave 6,7-dimethoxy-3,4-
dihydroisoquinoline (15) in a quantitative yield [20]. The selective
demethylation of 15 by HBr aq. then gave the compound 13 in a
moderated yield (46%), and the subsequent nitration by 40% nitric
acid and a catalytic amount of NaNO2 gave 16 in 59% yield.
Compound 16 was then treated with monoethyl malonate at 125
°C to afford 17 (89% yield), which was subjected to the catalytic
hydrogenation in AcOH providing the lactam 12 in a good yield.
The secondary amino group of 12 was selectively protected by the
Boc group, using Boc2O in CHCl3 at 75 °C, and then treated with
NaOMe in MeOH to give 18. Finally, 18 was benzylated with
BnBr and K2CO3 to afford the tricyclic lactam 19.
H3CO
H3CO
H3CO
H3CO
HO
N
O
N
O
H3CO
N
N
HN
N
H3C
isoaaptamine (10)
OCH3
O
2-methoxy-3-oxoaaptamine (8)
2,3-dihydro-2,3-dioxoaaptamine (9)
Fig. 1. Chemical structures of 3-(phenethylamino)demethyl(oxy)aaptamine (1)
and related compounds.
Table 1. MICs of aaptamines against M. smegmatis and M. bovis BCG under
aerobic and hypoxic conditions.
MICs (µg/mL)
M. smegmatis
M. bovis BCG
Compounds
Aerobic
12.5
6.25*
6.25*
25*
Hypoxic
6.25
1.5*
12.5*
6.25*
200*
6.25*
12.5*
1.5*
Aerobic
0.75
200
100
200
200
>200
100
50
Hypoxic
0.75
100
1
2
3
4
5
6
7
8
9
MeO
NH2
MeO
MeO
c,d
e
a,b
100
200
200
N
N
MeO
MeO
HO
R
14
100*
15
13 : R = H
16 : R = NO2
25*
25*
6.25*
25*
2.5
>200
100
MeO
HO
MeO
HO
25
25
MeO
BnO
f-h
6.25*
25
25
0.05
i
NH
CO2Et
N
N
R
Boc
Isoniazid
>200
NO2
HN
HN
*MICs of compounds 2-9 against M. smegmatis cited from reference 8.
17
O
O
12 : R = H
18 : R = Boc
19
The intriguing anti-mycobacterial properties of 1 against M.
bovis BCG suggested that compound 1 would be a potential novel
anti-TB drug lead. However, its scarce supply from natural sources
hampered further biological evaluations and mechanistic studies.
To address this issue, we engaged in the total synthesis of 1 to
supply a sufficient amount of compound for further investigations.
Scheme 1. Reagents and conditions: (a) HCO2H, 175 °C; (b) POCl3, toluene,
95 °C; (c) 48% HBr, 95 °C, 46% (3 steps); (d) 40% HNO3, NaNO2, EtOH, –
15 °C to 0 °C, 59%; (e) monoethyl malonate, reflux, 89%; (f) H2, Pd-C,
AcOH, 71%; (g) Boc2O, CHCl3, reflux; (h) NaOMe, MeOH-CH2Cl2, 88% (2
steps); (i) BnBr, K2CO3, quant.
To date, many synthetic approaches to natural aaptamines
[15] and the related analogs of isoaaptamine (10, Fig. 1) [16-18]
have been published due to their interesting fused heterocyclic
structures and their biological activities. In general, the third ring
of the benzo[de][1,6]-naphthyridine ring is constructed using
either the isoquinoline (AB) or the quinoline (AC) structure as a
starting component (Fig. 2). Although tremendous synthetic
studies of aaptaminoids have been conducted, 3-substituted
With the tricyclic lactam 19 in hand, we then examined the
introduction of the amino group at the C-3 position of 19 (Scheme
2). Compound 19 was converted to the bis N-Boc derivative 20 in
89% yield using Boc2O, Et3N, and DMAP at 75 °C. Fortunately,
treatment of 20 with KHMDS and trisyl azide [21] resulted in the
successful introduction of the azide moiety to provide 21 in a
moderate yield. However, selective reduction of the azide group to
the corresponding amine was problematic. Specifically, the

3
catalytic hydrogenation of azide 21 gave a complex mixture, while
the Staudinger reaction of 21 gave a stable N-ylide compound
which could not be hydrolyzed to the corresponding amine under
any conditions examined. After screening various reduction
conditions, we found that the reduction of 21 was successful when
using zinc in an acidic medium. The optimized condition, using
zinc powder (2 equiv.) in the presence of HCO2NH4 (6 equiv.) as
a hydrogen donor [22]in CH2Cl2-MeOH (3:1), provided the amine
22 with good reactivity and selectivity, in a moderate yield on the
gram scale. The primary amine of 22 was then acylated with
phenylacetyl chloride to give the amide 23. Subsequent
deprotection with TFA provided the amino lactam 24 in 46% yield
in three steps. Next, the reduction of the two amide moieties of 24
and the oxidative aromatization to provide the desired compound
1 were examined. Reduction of the diamide proceeded smoothly
using BH3•THF complex (10 equiv) under heating condition (45
°C) to give the amine-borane complex, which was hydrolyzed in a
one-pot reaction by 6N HCl at 80 °C under air to obtain the crude
triamine (Scheme 3). Interestingly, we found that another product
with red color, the desired target compound 1, was formed during
the hydrolysis reaction, albeit in a low yield (~20%). We assumed
that this unexpected oxidation might be induced by the presence
of oxygen and acid. As expected, a higher yield (~30%) of 1 was
obtained when carrying out the hydrolysis-oxidation reaction
under an O2 atmosphere, and no trace of 1 was observed under an
argon atmosphere. In addition, longer reaction time (>15 h) or
higher temperature (>90 °C) gave 1 in poor yield, and the
oxidation did not proceed under lower temperatures (< 60 °C) or
under basic condition (under O2, 80 °C).
effective as an acid and aqueous medium could significantly
promote the oxidation reaction. Finally, the optimized condition
(20% TFA, 85 °C) provided 1 in 69% yield from 25. Furthermore,
this reaction could be scaled up to 100 mg to give 1 with slightly
lower yield (45%). All physical properties (1H and 13C NMR
spectra and MS) of the synthesized 1 were in accordance to those
reported for the natural substance. In addition, the prepared 1
exhibited a comparable anti-mycobacterial activity to the natural 1
against M. smegmatis and M. bovis BCG under both aerobic and
hypoxic conditions.
To evaluate the validity of compound 1 as a candidate new
lead for an anti-TB drug, we further investigated its anti-microbial
activity against various pathogenic strains of M. tuberculosis
(Table 2). As a result, compound 1 was found to exhibit a potent
anti-mycobacterial activity (MIC values ranging from 0.5 to 2.0
µg/mL) against the drug sensitive M. tuberculosis H37Rv, Erdman
and Beijing strains grown under aerobic conditions. In addition,
compound 1 exhibited similar anti-microbial activity against drug-
resistant, multidrug-resistant and extensively drug-resistant M.
tuberculosis strains, with MIC values of 0.5–2.0 µg/mL. These
results imply that the mechanism of action of compound 1 differs
from those of existing anti-TB drugs. To date, a few semi-synthetic
derivatives of aaptamine (5) and isoaaptamine (10) [16] have been
reported to exhibit anti-microbial activity against M. tuberculosis
H37Rv or M. intracellulare under actively growing conditions,
while no anti-microbial activity against pathogenic mycobacterial
species has been reported for aaptamine (5) and other natural
related compounds [17,18]. In addition, the structure-activity
relationships and the target molecule of this class of alkaloids as
an anti-mycobacterial remain to be investigated.
MeO
BnO
Boc
MeO
BnO
Boc
N
R
a
b
c,d,e
Table 2. MICs of compound 1 against M. tuberculosis strains
N
Boc
19
Boc
N
N
Strains
Drug Resistance
MIC (µg/mL)
O
O
H37Rv
Erdman
Beijing
mc24977
mc24986
mc25886
mc25858
CI5071
CI5483
CI12081
KZN11
TF275
-
-
-
0.5~1.0
1.0
2.0
1.0
1.0
0.5
1.0
2.0
0.5~1.0
0.5
21: R = N3
22: R = NH2
20
INHa
MeO
BnO
MeO
HO
MeO
O
RIFb
N
NH
N
f
g
R
O
OFc
N
HN
Ph
N
Ph
R
NH
N
N
INH, RIF
H
H
INH, SMd
O
Ph
O
O
25
1
EMBe, SM
23: R = Boc
24: R = H
INH, RIF, SM, EMB, ETHf
INH, RIF, SM, EMB
INH, RIF, SM, EMB, ETH, KMg, PZAh
0.5
0.5
Scheme 2. Reagents and conditions: (a) Boc2O, Et3N, DMAP, CHCl3, reflux,
(89%); (b) KHMDS, trisylazide, –78 °C, then AcOH, 0 °C, 70%; (c) Zn,
NH4HCO2, CH2Cl2-MeOH; (d) PhCH2COCl, pyridine; (e) TFA, CH2Cl2, 46%
(3 steps); (f) H2, Pd-C, THF-MeOH, 80%; (g) (i) BH3•THF, THF, 45 °C, (ii)
5% HCl, THF; (iii) O2, 20% TFA, 85 °C, 45%.
a: isoniazid, b: rifampicin, c: ofloxacin, d: streptomycin,
e: ethambutol f: ethionamide, g: kanamycin, h: pyrazinamide.
Considering
that
the
synthesis
of
3-(N-
substituted)demethyl(oxy)aaptamine analogues could lead to
potential novel antimycobacterial compounds, we hypothesized
that 3-aminodemethyl(oxy)aaptamine (2) may be a useful building
block and therefore attempted its synthesis. We envisioned that the
BH3-reduction–hydrolysis–aromatization reaction of a 3-azide
compound would give 2. Thus, removal of bis Boc groups of the
3-azide 21 by treatment with TFA in CH2Cl2 was carried out to
give the 3-azide-amino lactam 26 in a quantitative yield (Scheme
4). We then examined the one-pot BH3 reduction–hydrolysis–
oxidation reaction. After treatment of the azide amino lactam 26
by BH3, the reaction mixture was hydrolyzed with 6N HCl and
heated at 85 °C under oxygen atmosphere. As expected, removal
of Bn group, hydrolysis reaction and aromatization afforded the
desired product 2 in a low yield (Scheme 4). All of the spectral
data of the synthetic 2 were identical with those of the naturally
occurring 2.
MeO
RO
H3B
MeO
RO
MeO
NH
NH
N
O
O
N
Ph
HN
Ph
N
Ph
N
N
N
H
H
BH3
O
1
24: R = Bn
25: R = H
Scheme 3. Conversion of 24 or 25 to 1.
From these results, we estimated that the phenol 25 might be
more reactive in the hydrolysis–oxidation reaction since removal
of the Bn group is necessary to the oxidation reaction providing
the oxyaaptamine skeleton. Thus, the Bn group of diamide 24 was
removed by hydrogenation to give 25 in 80% yield, and the
reduction–hydrolysis–oxidation reaction sequence against the
phenol 25 was attempted. As expected, phenol 25 was smoothly
converted to 1 in moderate yield (42%) under the same reaction
condition ((i) BH3, 45 °C, (ii) O2, 6N HCl, 85 °C). Upon further
screening of the reaction conditions, we found that using TFA was

4
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O
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NH
N3
N
a
b
21
HN
N
NH2
O
2
26
Scheme 4. Reagents and conditions: (a) TFA, CH2Cl2, quant.; (b) BH3•THF,
THF, 45 °C, then O2, 6N HCl, 85 °C, 33%.
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In
summary,
we
re-discovered
3-
(phenethylamino)demethyl(oxy)aaptamine (1) as a potent anti-
dormant mycobacterial substance against M. bovis BCG and M.
tuberculosis under aerobic and hypoxic conditions. We also
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accomplished the total syntheses of
1
and 3-
aminodemethyl(oxy)aaptamine (2), through the introduction of
nitrogen into the α-position of the lactam, and subsequent oxygen-
mediated aromatization. Although the elegant total syntheses of
demethyl(oxy)aaptamine and its 3-alkylamino derivatives were
reported recently [22], our method provides a more diversified
library of analogs with various oxidation states in the core
structure and/or substituents. We expect that structure-activity
relationship studies of the analogs could lead to the development
of more promising anti-dormant mycobacterial drug candidates.
Further validation of the feasibility of the above compounds as
anti-TB drugs are now underway, along with target identification
study.
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This research was funded by the Platform Project for Supporting
Drug Discovery and Life Science Research (Basis for Supporting
Innovative Drug Discovery and Life Science Research [BINDS])
from AMED (grant no. JP19am0101084), the Kobayashi
International Scholarship Foundation, and a Grant-in-Aid for
Scientific Research B (grant nos. 18H02096 and 17H04645) from
JSPS to MA. This work was also supported by the National
Institutes of Health Grant AI26170 to WRJ.
22. Y. Gao, F. Yang, F. Sun, L. Liu, B. Liu, S.P. Wang, C.W. Cheng,
H. Liao, H.W. Lin, Org. Lett. 21 (5) (2019) 1430-1433.
Supplementary Material
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References and notes
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1.
2.
V. Idemyor, J. Natl. Med. Assoc. 99 (12) (2007) 1414-1419.
Global Tuberculosis report 2019 World Health Organization:
Geneva, Switzerland. Available online:

5
Highlights
1) 3-(Phenethylamino)demethyl(oxy)aaptamine (1)
was isolated from marine sponge of Aaptos sp.
2) Compound 1 was a potent antimicrobial agent
against dormant state of Mycobacterial bacilli.
3) Compound 1 was effective against M.
tuberculosis including drug resistant strains.
4) The total syntheses of 1 and 3-
aminodemethyl(oxy)aaptamine were successfully
accomplished.