New orally active amino- and hydroxy-functionalized 11-azaartemisinins and their derivatives with high order of antimalarial activity against multidrug-resistant Plasmodium yoelii in swiss mice1

Article abstract of DOI:10.1021/jm401774f

By use of artemisinin 1 as the starting material, two new amino- and hydroxy-functionalized 11-azaartemisinins 9 and 11 and their derivatives 12a-g, 13a-g, 14a-g, and 15a-c have been prepared and screened for antimalarial activity by oral route against mu

Full text of DOI:10.1021/jm401774f

Article
pubs.acs.org/jmc
New Orally Active Amino- and Hydroxy-Functionalized 11-
Azaartemisinins and Their Derivatives with High Order of
Antimalarial Activity against Multidrug-Resistant Plasmodium yoelii
in Swiss Mice1
Chandan Singh,*,† Ved Prakash Verma,† Mohammad Hassam,† Ajit Shankar Singh,† Niraj K. Naikade,†
and Sunil K. Puri‡
‡
†Division of Medicinal and Process Chemistry and Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow
226001, India
S
* Supporting Information
ABSTRACT: By use of artemisinin 1 as the starting material, two new amino-
and hydroxy-functionalized 11-azaartemisinins 9 and 11 and their derivatives
12a−g, 13a−g, 14a−g, and 15a−c have been prepared and screened for
antimalarial activity by oral route against multidrug-resistant Plasmodium yoelii
in Swiss mice. While azaartemisinins 9 and 11 showed only modest activity,
several of their derivatives showed high order of antimalarial activity. Biphenyl-
based compound 13f, the most active compound of the series, provided 100%
and 80% protection to the infected mice at 12 mg/kg × 4 days and 6 mg/kg ×
4 days, respectively. Compounds 12f, 13b, 13e, 13g, and 14f showed 100%
protection at 12 mg/kg × 4 days, while compounds 12a−c, 14a, 14c−e, 14g,
and 15a−c showed similar levels of protection at 24 mg/kg × 4 days.
Clinically useful drug β-arteether provided 100% protection at 48 mg/kg × 4 days and 20% protection at 24 mg/kg × 4 days in
this model.
complicated malaria caused by multidrug-resistant Plasmodium
falciparum.4 While these drugs show excellent activity by
parenteral routes, they are poorly absorbed when administered
orally.5 Therefore, the search for artemisinin derivatives with
acceptable activity profile by oral route has been a major
objective of several recent studies.6 Particularly relevant to the
present studies is the conversion of artemisinin to its aza
derivatives, e.g., 5−8 (Figure 2), which are significantly more
INTRODUCTION
■
Malaria, a vector-borne infectious disease caused by protozoan
parasites of the genus Plasmodium, affects around 40% of the
world population residing in tropical and subtropical regions of
America, Asia, and Africa. Around 300−500 million clinical
cases of malaria are reported every year. More than a million
cases, mostly involving children, result in death due to
complicated malaria.2 The malaria situation is getting worse
with the rapid spread of multidrug-resistant Plasmodium
falciparum. Against this background, discovery of artemisinin
1 as the active principle of the Chinese traditional drug against
malaria, Artemisia annua, and its conversion to clinically useful
derivatives artemether 2, arteether 3, and artesunic acid 4
(Figure 1) were major breakthroughs in malaria chemo-
therapy.3 These artemisinin derivatives are fast acting and are
currently the drugs of choice for the treatment of cerebral/
Figure 2. 11-Azaartemisinin and its derivative.
active than artemisinin.7,8 In these aza derivatives nitrogen is in
the form of an amide group, and only a limited number of
derivatives have been made. Herein, we report an efficient
conversion of artemisinin 1 into two new 11-azaartemisinin
prototypes 9 and 11 with either a free amino or a free hydroxyl
group and their subsequent derivatives, several of which
Received: November 15, 2013
Published: February 13, 2014
Figure 1. Artemisinin and its derivatives.
© 2014 American Chemical Society
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a
Scheme 1
a
Reagents and conditions: (i) N2H4.H2O, MeOH, rt, 1 h; (ii) SiO2/20% H2SO4, 2,6-di-tert-butylphenol, CHCl3, 0 °C to rt, 12 h; (iii) RCOCl, Et3N,
C6H6, 0 °C, 2 h; (iv) RCHO, Amberlyst-15, C6H6, rt, 2 h; (v) NaBH4, C6H6, 0 °C, 4 h.
showed high order of antimalarial activity against multidrug-
chloride, 9H-fluorene-9-carbonyl chloride, p-phenylbenzoyl
chloride, and adamantan-1-yl-acetyl chloride furnished the
corresponding hydrazides 12b−g in 60−93% yields. Hydra-
zones 13a−g were prepared (76−94% yields) by reacting 9
with benzaldehyde, p-methylbenzaldehyde, p-chlorobenzalde-
hyde, p-fluorobenzaldehyde, p-trifluoromethylbenzaldehyde, p-
phenylbenzaldehyde, and 9H-fluorene-2-carbaldehyde in the
presence of Amberlyst-15 in dry benzene at room temperature.
Sodium borohydride reduction of hydrazones 13a−g in dry
benzene at 0 °C provided the hydrazines 14a−g in 62−74%
yields. N-Hydroxy-11-azaartemisinin 11 and its derivatives
15a−c were prepared according to Scheme 2. Thus, the
reaction of artemisinin 1 with hydroxylamine in MeOH−
CHCl3 for 1 h at 0 °C followed by the treatment with SiO2/
20% H2SO4 in the presence of 2,6-di-tert-butylphenol in CHCl3
furnished N-hydroxy-11-azaartemisinin 11 in 45% yield.
Compound 11, when reacted with benzyl bromide/NaH in
dry THF, provided ether derivative 15a in 72% yield. Similar
reaction of 11 with o-fluorobenzyl bromide and p-phenylbenzyl
resistant P. yoelii in Swiss mice by oral route.9
CHEMISTRY
■
N-Amino-11-azaartemisinin 9 and its derivatives 12a−g, 13a−
g, and 14a−g were prepared according to the Scheme 1. Thus,
artemisinin 1 on reaction with hydrazine hydrate in MeOH at
room temperature for 1 h followed by the treatment with silica
gel and 20% H2SO4 in the presence of 2,6-di-tert-butylphenol in
CHCl3 furnished a mixture of N-amino-11-azaartemisinin 9 and
its deoxy analogue 10 in a combined yield of 59% and in a ratio
1
of 3:7, as indicated by H NMR spectrum of the mixture. The
yield of 9 improved to 70% when the first step of the reaction
sequence was conducted in MeOH−CHCl3 (7:3) for 1 h at 0
°C; no deoxy analogue was formed under these conditions. The
reaction of 9 with benzoyl chloride in dry benzene in the
presence of Et3N at 0 °C furnished hydrazide derivative 12a in
93% yield. Similar reaction of 9 with p-bromobenzoyl chloride,
p-trifluoromethylbenzoyl chloride, adamantane-1-carbonyl
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a
mg/kg × 4 days, while hydrazides 12d, 12e, 12g showed only
partial protection at 24 mg/kg × 4 days. Among the
hydrazones, biphenyl-based derivative 13f was the most active
compound of the series. It showed 100% and 80% protection at
12 mg/kg × 4 days and 6 mg/kg × 4 days, respectively.
Hydrazones 13b, 13e, and 13g also provided 100% protection
at 12 mg/kg × 4 days. Among hydrazines 14a−g, biphenyl-
based derivative 14f, the most active compound of this series,
showed 100% and 20% protection at 12 mg/kg × 4 days and 6
mg/kg × 4 days, respectively. Hydrazine 14c showed 100% and
80% protection at 24 mg/kg × 4 days and 12 mg/kg × 4 days,
respectively. Hydrazines 14a, 14d, 14e, and 14g were another
four compounds of this series that showed promising activity;
these compounds provided 100% protection at 24 mg/kg × 4
days.
All the ether derivatives (15a−c) prepared from hydroxy-
functionalized azaartemisinin 11 showed 100% protection at 24
mg/kg × 4 days. Ether 15a was the most active derivative of 11.
It showed 100% and 80% protection at 24 mg/kg × 4 days and
12 mg/kg × 4 days, respectively.
It is clear from this discussion that the compounds derived
from amino-functionalized azaartemisinin 9 in general showed
better activity profile than the compounds derived from
hydroxy-functionalized azaartemisinin 11. Six of the derivatives
of 9 (12f, 13b, 13e−g, and 14f) showed 100% protection at
dose of 12 mg/kg × 4 days. These compounds are thus 4-fold
more potent than β-arteether, which showed 100% protection
at 48 mg/kg × 4 days.
Scheme 2
a
Reagents and conditions: (i) NH2OH, MeOH−CHCl3, 0 °C, 1 h;
(ii) SiO2/20% H2SO4, 2,6-di-tert-butylphenol, CHCl3, 0 °C to rt, 12 h;
(iii) NaH, RBr, THF, 0 °C to rt, 12 h.
bromide furnished the corresponding ethers 15b and 15c in
65% and 74% yields, respectively.
All the new azaartemisinin derivatives were stable at room
temperature and under standard conditions of purification such
as column chromatography and crystallization.
ANTIMALARIAL ACTIVITY
■
Azaartemisinins 9 and 11 and their derivatives 12a−g, 13a−g,
14a−g, and 15a−c were evaluated for antimalarial activity
against multidrug-resistant Plasmodium yoelii in Swiss mice by
oral route.10 In this model β-arteether provided 100%
protection at a dose of 48 mg/kg × 4 days and 20% protection
at 24 mg/kg × 4 days. Since the objective of this study was to
discover compounds with better activity profile than that of
arteether, all the compounds were initially screened at a dose of
24 mg/kg × 4 days. Compounds that provided 100%
protection at 24 mg/kg × 4 days were further screened at 12
mg/kg × 4 days and 6 mg/kg × 4 days. The results are
summarized in Table 1.
It is instructive to note that log P values of the six most active
compounds of the series lie in the range 5.40−6.65. These
activity results reinforce our earlier observation that increased
lipophilicity generally leads to improved activity by oral route.
CONCLUSION
■
We have prepared a new series of azaartemisinins, several of
which showed excellent antimalarial activity by oral route.
Hydrazone 13f, the most active compound of the series,
showed 100% and 80% protection at 12 mg/kg × 4 days and 6
mg/kg × 4 days, respectively. Compounds 12f, 13b, 13e, 13g,
and 14f, which showed 100% protection at 12 mg/kg × 4 days,
are the other promising compounds of this series. All six of
these compounds are 4-fold more potent than β-arteether by
oral route.
RESULTS AND DISCUSSION
■
Artemisinin derivatives such as artemether 2, arteether 3, and
artesunic acid 4 are active against both chloroquine-sensitive
and chloroquine-resistant malaria and are currently the drugs of
choice for the treatment of malaria caused by chloroquine-
resistant P. falciparum.4 These drugs, however, have serious
limitations such as short half-life and poor bioavailability when
given by oral route.5 Therefore the main objective of the recent
studies on artemisinin has been to produce compound with
improved bioavailability by oral route.6
We had recently reported the synthesis of several lipophilic
ethers and esters of dihydroartemisinin that showed high order
of antimalarial activity by oral route.11 We have observed a
similar relationship between lipophilicity and antimalarial
activity in our work on synthetic 1,2,4-trioxanes.12 Therefore,
it was heartening to note that several of the lipophilic
azaartemisinins reported in this paper showed high order of
antimalarial activity against multidrug-resistant P. yoelii by oral
route.
EXPERIMENTAL SECTION
■
General Comments on Experimental Data. All glass apparatus
were oven-dried prior to use. Melting points were taken in open
capillaries on Complab melting point apparatus and are presented
uncorrected. Infrared spectra were recorded on a Perkin-Elmer FT-IR
RXI spectrophotometer. 1H NMR and 13C NMR spectra were
recorded using a Bruker Supercon Magnet DPX-200 and DRX-300
spectrometers (respectively operating at 200 and 300 MHz for 1H and
at 50 and 75 MHz for 13C) using CDCl3 as solvent. Tetramethylsilane
1
(δ 0.00 ppm) served as an internal standard in H NMR, and CDCl3
(δ 77.23 ppm) was the internal standard in 13C NMR. Chemical shifts
are reported in parts per million (ppm). Fast atom bombardment mass
spectrometry (FAB-MS) results were obtained on a JEOL SX-102/
DA-6000 mass spectrometer using argon/xenon (6 kV, 10 mA) as the
FAB gas. Glycerol or m-nitrobenzyl alcohol was used as matrix.
Electrospray mass spectrometry (ES-MS) results were recorded on a
Micromass Quattro II triple quadruple mass spectrometer. High-
resolution electron impact mass spectrometry (EI-HRMS) results were
obtained on JEOL MS route 600H instrument. Column chromatog-
raphy was performed over silica gel (particle size, 60−120 mesh)
As can be seen from Table 1, both the parent azaartemisinins
9 and 11 showed poor activity but several of their derivatives,
particularly hydrazides, hydrazones, and hydrazine derivatives
of 9, showed very promising antimalarial activity. Among the
hydrazides, biphenyl-based derivative 12f was the most active
compound of the series. It provided 100% protection at 12 mg/
kg × 4 days. Hydrazides 12a−c provided 100% protection at 24
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Table 1. Blood Schizontocidal Activity of Compounds 9, 11, 12a−g, 13a−g, 14a−g, and 15a−c against Multidrug-Resistant P.
yoelii in Swiss Mice via Oral Route
a
b
Percent suppression = [(C − T)/C] × 100; where C is parasitemia in control group and T is parasitaemia in treated group. 100% suppression of
parasitemia means no parasites were detected in 50 oil immersion fields during microscopic observation.13
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procured from Qualigens (India). All chemicals and reagents were
obtained from Aldrich (Milwaukee, WI), Lancaster (England), or
Spectrochem (India) and were used without further purification.
Nomenclature and log P values of the compounds were assigned using
ChemBio Draw Ultra 13.0 software. Elemental analysis results of all
the new compounds were recorded on Vario EL-III CHNS analyzer
(Germany), and values were within 0.5% of the calculated values for all
compounds; therefore, these compounds meet the criteria of ≥95%
purity.
(CH3), 19.88 (CH3), 22.74 (CH2), 25.26 (CH2), 25.49 (CH3), 33.71
(CH), 34.05 (CH2), 36.72 (CH2), 37.58 (CH), 46.28 (CH), 51.51
(CH), 80.25 (C), 81.29 (CH), 105.19 (C), 127.68 (2 × CH), 128.50
(2 × CH), 131.66 (C), 132.04 (CH), 165.94 (C), 172.51 (C); ESI-MS
(m/z) 401 [M + H]+. Anal. Calcd for C22H28N2O5: C, 65.98%, H,
7.05%, N, 7.00%. Found: C, 66.06%, H, 7.39%, N, 7.01%.
Compounds 12b−g were prepared by the above procedure by
replacing benzoyl chloride with p-bromobenzoyl chloride, p-trifluor-
omethylbenzoyl chloride, adamantane-1-carbonyl chloride, 9H-fluo-
rene-9-carbonyl chloride, p-phenylbenzoyl chloride, and adamantan-1-
ylacetyl chloride, respectively.
Preparation of N-Amino-11-azaartemisnin (9). To a stirred
solution of N2H4·H2O (21.3 mL, 425 mmol, 20 equiv) in a mixture of
MeOH−CHCl3 (7:3, 120 mL) at 0 °C was added a solution of
artemisinin 1 (6.00 g, 21.3 mmol) in CHCl3 (30.0 mL) gradually over
5 min, and the reaction mixture was allowed to stir for 1 h at the same
temperature. The reaction mixture was diluted with water (300 mL)
and extracted with CHCl3 (3 × 100 mL). To the combined organic
layer, 2,6-di-tert-butylphenol (400 mg), 20% H2SO4 (40.0 mL) and
silica gel (40.0 g) were added, and the mixture was stirred for 12 h at
room temperature. The reaction mixture was filtered, and the residue
was washed with CHCl3 (2 × 100 mL). The combined filtrate was
washed with water (2 × 100 mL), dried over anhydrous Na2SO4, and
concentrated under reduced pressure at room temperature. The crude
product was purified by column chromatography over silica gel using
50% EtOAc/hexane as eluent to furnish pure N-amino-11-
azaartemisinin 9 (4.40 g, yield 70%) as a white solid, mp 122−125
4-Bromo-N-((3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-trimethyl-10-ox-
odecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-
yl)benzamide (12b). Yield 60%, white solid, mp 230−232 °C; FT-IR
1
(KBr cm−1) 1692, 1727, 3450; H NMR (300 MHz, CDCl3) δ 0.97−
1.01 (m, 1H), 0.98 (d, 3H, J = 6.0 Hz), 1.21 (d, 3H, J = 7.3 Hz), 1.39−
2.04 (m, 9H), 1.48 (s, 3H), 2.39−2.49 (m, 1H), 3.42−3.46 (m, 1H),
5.59 (s, 1H), 7.38 (d, 2H, Ar, J = 8.4 Hz), 7.62 (d, 2H, Ar, J = 8.4 Hz),
9.87 (brs, 1H, NH); 13C NMR (75 MHz, CDCl3) δ 12.79 (CH3),
19.90 (CH3), 22.87 (CH2), 25.29 (CH2), 25.47 (CH3), 33.71 (CH),
34.07 (CH2), 36.70 (CH2), 37.64 (CH), 46.14 (CH), 51.48 (CH),
80.03 (C), 81.26 (CH), 105.24 (C), 127.09 (C), 129.27 (2 × CH),
130.22 (C), 131.68 (2 × CH), 164.66 (C), 172.99 (C); ESI-MS (m/z)
479 [M + H]+. Anal. Calcd for C22H27N2O5Br: C, 55.12%, H, 5.68%,
N, 5.84%. Found: C, 54.80%, H, 6.06%, N, 5.80%.
1
°C. FT-IR (KBr cm−1) 1653, 3315; H NMR (300 MHz, CDCl3) δ
4-(Trifluoromethyl)-N-((3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-tri-
methyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]-
isoquinolin-11(12H)-yl)benzamide (12c). Yield 85%, white solid, mp
0.86−1.00 (m, 2H), 0.94 (d, 3H, J = 6.2 Hz), 1.10 (d, 3H, J = 7.3 Hz),
1.29−1.44 (m, 3H), 1.33 (s, 3H), 1.59−1.75 (m, 3H), 1.92−2.03 (m,
2H), 2.30−2.41 (m, 1H), 3.24−3.33 (m, 1H), 4.63 (brs, 2H, NH2),
5.26 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 12.64 (CH3), 19.80
(CH3), 22.77 (CH2), 25.06 (CH2), 25.51 (CH3), 32.85 (CH), 33.65
(CH2), 36.56 (CH2), 37.38 (CH), 46.01 (CH), 51.35 (CH), 80.66
(C), 80.99 (CH), 104.92 (C), 169.68 (C); ESI-MS (m/z) 297 [M +
H]+. EI-HRMS calcd for C15H24N2O4 [M]+: 296.1736. Found:
296.1742. Anal. Calcd for C15H24N2O4: C, 60.79%, H, 8.16%, N,
9.45%. Found: C, 60.92%, H, 8.65%, N, 9.75%.
Preparation of N-Hydroxy-11-azaartemisinin (11). Com-
pound 11 was prepared by the above procedure by replacing
hydrazine hydrate with hydroxylamine. Yield 45%, white solid, mp
165−167 °C; IR (KBr, cm−1) 1649, 3418; 1H NMR (300 MHz,
CDCl3) δ 0.89−1.02 (m, 2H), 0.97 (d, 3H, J = 5.9 Hz), 1.10 (d, 3H, J
= 7.3 Hz), 1.31−1.52 (m, 3H), 1.43 (s, 3H), 1.63−1.77 (m, 3H),
1.94−2.07 (m, 2H), 2.35−2.46 (m, 1H), 3.35−3.44 (m, 1H), 5.40 (s,
1H), 8.81 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 12.11 (CH3), 19.88
(CH3), 22.94 (CH2), 25.18 (CH2), 25.47 (CH3), 32.98 (CH), 33.75
(CH2), 36.70 (CH2), 37.52 (CH), 46.64 (CH), 51.49 (CH), 81.22
(CH), 81.52 (C), 105.27 (C), 170.08 (C); ESIMS (m/z) 298 [M +
H]+. HRMS [ESI] calcd for C15H24NO5 [M + H]+: 298.1654. Found:
298.1631. Anal. Calcd for C15H23NO5: C, 60.59%, H, 7.80%, N, 4.71%.
Found: C, 60.64%, H, 7.89%, N, 4.53%.
1
217−220 °C; FT-IR (KBr cm−1) 1653, 1702, 3422; H NMR (300
MHz, CDCl3) δ 0.99 (d, 3H, J = 6.1 Hz), 1.03−1.12 (m, 1H), 1.23 (d,
3H, J = 7.3 Hz), 1.37−2.05 (m, 9H), 1.50 (s, 3H), 2.40−2.49 (m, 1H),
3.42−3.51 (m, 1H), 5.60 (s, 1H), 7.43 (d, 2H, Ar, J = 8.2 Hz), 7.84 (d,
2H, Ar, J = 8.2 Hz), 10.35 (brs, 1H, NH); 13C NMR (75 MHz,
CDCl3) δ 12.83 (CH3), 19.90 (CH3), 22.95 (CH2), 25.28 (CH2),
25.40 (CH3), 33.71 (CH), 34.05 (CH2), 36.64 (CH2), 37.66 (CH),
46.02 (CH), 51.42 (CH), 79.87 (C), 81.23 (CH), 105.29 (C), 125.48
(q, C, JC−F = 3.8 Hz), 128.09 (4 × CH), 133.14 (C), 134.34 (CH),
163.81 (C), 173.26 (C); ESI-MS (m/z) 469 [M + H]+. EI-HRMS
calcd for C23H27N2O5F3 [M]+: 468.1872. Found: 468.1843. Anal.
Calcd for C23H27N2O5F3: C, 58.97%, H, 5.81%, N, 5.98%. Found: C,
58.82%, H, 5.96%, N, 6.00%.
(1R,3R)-N-((3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-Trimethyl-10-oxo-
decahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)-
adamantane-2-carboxamide (12d). Yield 89%, white solid, mp 168−
1
170 °C; FT-IR (KBr cm−1) 1672, 1702, 3018, 3334; H NMR (300
MHz, CDCl3); δ 0.63−0.68 (m, 3H), 0.77 (d, 3H, J = 6.3 Hz), 0.97 (d,
3H, J = 7.3 Hz), 1.32−1.87 (m, 22H), 1.19 (s, 3H), 2.18−2.28 (m,
1H), 3.15−3.23 (m, 1H), 5.26 (s, 1H), 7.16 (brs, 1H, NH); 13C NMR
(75 MHz, CDCl3) δ 12.55 (CH3), 19.86 (CH3), 22.58 (CH2), 25.20
(CH2), 25.73 (CH3), 28.16 (3 × CH), 33.72 (CH), 33.99 (CH2),
36.61 (3 × CH2), 36.76 (CH2), 37.48 (CH), 39.03 (3 × CH2), 40.69
(C), 46.48 (CH), 51.51 (CH), 80.76 (CH), 81.35 (C), 104.98 (C),
171.68 (C), 177.23 (C); ESI-MS (m/z) 459 [M + H]+. EI-HRMS
calcd for C26H39N2O5 [M + H]+: 459.2859. Found: 459.2843. Anal.
Calcd for C26H38N2O5: C, 68.10%, H, 8.35%, N, 6.11%. Found: C,
68.45%, H, 8.70%, N, 5.88%.
N-((3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-Trimethyl-10-oxodecahy-
dro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)-9H-fluo-
rene-9-carboxamide (12e). Yield 85%, white solid, mp 217−219 °C;
FT-IR (KBr cm−1) 1664, 1706, 3264; 1H NMR (300 MHz, CDCl3); δ
0.87−1.03 (m, 2H), 0.97 (d, 3H, J = 6.2 Hz), 1.16 (d, 3H, J = 7.3 Hz),
1.25 (s, 3H), 1.28−2.01 (m, 8H), 2.35−2.44 (m, 1H), 3.33−3.37 (m,
1H), 4.88 (s, 1H), 5.49 (s, 1H), 7.34−7.85 (m, 9H including NH);
13C NMR (75 MHz, CDCl3) δ 12.54 (CH3), 19.86 (CH3), 22.70
General Procedure for Preparation of Hydrazide Derivatives
(12a−g) of N-Amino-11-azaartemisnin (9). Preparation of N-
((3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-Trimethyl-10-oxodecahydro-
3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)benzamide
(12a). To a stirred solution of compound 9 (500 mg, 1.69 mmol) and
Et3N (1.17 mL, 8.39 mmol) in dry benzene (5.00 mL) at 0 °C was
added a solution of benzoyl chloride (0.970 mL, 8.34 mmol) in dry
benzene (5.00 mL), and the reaction mixture was allowed to stir at the
same temperature for 2 h. The reaction mixture was quenched with
water (10.0 mL) and extracted with ether (3 × 25 mL). The combined
organic layer was washed with saturated NaHCO3 (3 × 10 mL), dried
over anhydrous Na2SO4, and concentrated under reduced pressure at
room temperature. The crude product was purified by column
chromatography over silica gel using 20% EtOAc/hexane as eluent to
furnish compound 12a (628 mg, 93% yield) as a white solid, mp 218−
(CH2), 25.17 (CH2), 25.47 (CH3), 33.75 (CH), 33.96 (CH2), 36.69
(CH2), 37.52 (CH), 46.34 (CH), 51.45 (CH), 54.46 (CH), 80.35
(CH), 81.20 (C), 104.97 (C), 120.46 (2 × CH), 125.63 (CH), 125.68
(CH), 127.80 (CH), 128.10 (CH), 128.59 (CH), 128.64 (CH),
140.78 (C), 140.88 (C), 141.63 (C), 141.82 (C), 169.71 (C), 171.43
(C); ESI-MS (m/z) 489 [M + H]+. EI-HRMS Calcd for C29H32N2O5
1
220 °C. FT-IR (KBr cm−1) 1654, 1701, 3246; H NMR (300 MHz,
CDCl3) δ 1.04 (d, 3H, J = 6.3 Hz), 1.05−1.09 (m, 1H), 1.22 (d, 3H, J
= 7.3 Hz), 1.32−1.52 (m, 3H), 1.47 (s, 3H), 1.70−2.05 (m, 6H),
2.39−2.50 (m, 1H), 3.41−3.48 (m, 1H), 5.62 (s, 1H), 7.24−7.77 (m,
5H, Ar), 9.33 (s, 1H, NH); 13C NMR (75 MHz, CDCl3) δ 12.73
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[M]+: 488.2311. Found: 488.2312. Anal. Calcd for C29H32N2O5: C,
71.29%, H, 6.60%, N, 5.73%. Found: C, 71.49%, H, 6.34%, N, 5.96%.
N-((3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-Trimethyl-10-oxodecahy-
dro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)-[1,1′-bi-
phenyl]-4-carboxamide (12f). Yield 93%, white solid, mp 205−207
°C; FT-IR (KBr cm−1) 1614, 1675, 3396; 1H NMR (300 MHz,
CDCl3) δ 0.99 (d, 3H, J = 6.1 Hz), 1.07−1.11 (m, 1H), 1.25 (d, 3H, J
= 7.3 Hz), 1.38−2.06 (m, 9H), 1.51 (s, 3H), 2.41−2.51 (m, 1H),
3.47−3.50 (m, 1H), 5.66 (s, 1H), 7.37−7.88 (m, 9H, Ar), 9.59 (brs,
1H, NH); 13C NMR (75 MHz, CDCl3) δ 12.81 (CH3), 19.91 (CH3),
22.85 (CH2), 25.29 (CH2), 25.55 (CH3), 33.74 (CH), 34.09 (CH2),
36.74 (CH2), 37.61 (CH), 46.26 (CH), 51.52 (CH), 80.22 (CH),
81.32 (C), 105.20 (C), 127.03 (2 × CH), 127.30 (2 × CH), 128.07
(CH), 128.20 (2 × CH), 128.98 (2 × CH), 130.23 (C), 140.16 (C),
144.55 (C), 165.56 (C), 172.78 (C); ESI-MS (m/z) 477 [M + H]+.
EI-HRMS calcd for C28H32N2O5 [M]+: 476.2311. Found: 476.2310
Anal. Calcd for C28H32N2O5: C, 70.57%, H, 6.77%, N, 5.88%. Found:
C, 70.89%, H, 7.00%, N, 6.15%.
37.56 (CH), 46.57 (CH), 51.72 (CH), 81.22 (C), 81.65 (CH), 105.14
(C), 128.47 (2 × CH), 129.49 (2 × CH), 131.19 (C), 141.72 (C),
165.18 (C), 169.02 (C); ESI-MS (m/z) 399 [M + H]+. Anal. Calcd for
C23H30N2O4: C, 69.32%, H, 7.59%, N, 7.03%. Found: C, 69.55%, H,
7.77%, N, 7.08%.
(3R,5aS,6R,8aS,9R,12R,12aR)-11-(((E)-4-Chlorobenzylidene)-
amino)-3,6,9-trimethyldecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]-
isoquinolin-10(3H)-one (13c). Yield 76%, white solid, mp 170−172
°C; FT-IR (KBr cm−1) 1654, 2931, 3020; 1H NMR (300 MHz,
CDCl3) δ 1.04 (d, 3H, J = 6.2 Hz), 1.09−1.13 (m, 2H), 1.19 (d, 3H, J
= 7.2 Hz), 1.33 (s, 3H), 1.41−2.07 (m, 8H), 2.45−2.49 (m, 1H),
3.50−3.59 (m, 1H), 5.76 (s, 1H), 7.40 (d, 2H, J = 8.5 Hz), 7.74 (d,
2H, J = 8.5 Hz), 8.61 (s, 1H, imine H); 13C NMR (75 MHz, CDCl3) δ
12.64 (CH3), 19.96 (CH3), 23.01 (CH2), 25.22 (CH2), 25.64 (CH3),
33.88 (CH2), 34.41 (CH), 36.71 (CH2), 37.61 (CH), 46.53 (CH),
51.68 (CH), 81.20 (C), 81.91 (CH), 105.25 (C), 129.09 (2 × CH),
129.58 (2 × CH), 132.56 (C), 137.21 (C), 162.48 (CH), 169.26 (C);
ESI-MS (m/z) 419 [M + H]+. Anal. Calcd for C22H27N2O4Cl: C,
63.08%, H, 6.50%, N, 6.69%. Found: C, 62.95%, H, 6.66%, N, 6.50%.
(3R,5aS,6R,8aS,9R,12R,12aR)-11-(((E)-4-Fluorobenzylidene)-
amino)-3,6,9-trimethyldecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]-
isoquinolin-10(3H)-one (13d). Yield 92%, white solid, mp 115−120
°C; FT-IR (KBr cm−1) 1652, 2931, 3017; 1H NMR (300 MHz,
CDCl3) δ 1.03 (d, 3H, J = 6.2 Hz), 1.07−1.14 (m, 2H), 1.19 (d, 3H, J
= 7.2 Hz), 1.33 (s, 3H), 1.40−2.06 (m, 8H), 2.40−2.49 (m, 1H),
3.50−3.58 (m, 1H), 5.75 (s, 1H), 7.07−7.83 (m, 4H, Ar), 8.58 (s, 1H,
imine H); 13C NMR (75 MHz, CDCl3) δ 12.61 (CH3), 19.94 (CH3),
22.98 (CH2), 25.19 (CH2), 25.62 (CH3), 33.86 (CH2), 34.32 (CH),
36.69 (CH2), 37.58 (CH), 46.54 (CH), 51.66 (CH), 81.18 (C), 81.80
(CH), 105.21 (C), 115.93 (d, 2 × CH, JC−F = 22 Hz), 130.19 (d, C,
JC−F = 3.0 Hz), 130.42 (d, 2 × CH, JC−F = 9.0 Hz), 163.26 (CH),
164.77 (d, C, JC−F = 250 Hz), 169.20 (C); ESI-MS (m/z) 403 [M +
H]+, 425 [M + Na]+. EI-HRMS calcd for C22H27N2O4F [M]+:
402.1955. Found: 402.1982. Anal. Calcd for C22H27N2O4F: C, 65.66%,
H, 6.76%, N, 6.96%. Found: C, 65.79%, H, 6.83%, N, 6.82%.
(3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-Trimethyl-11-(((E)-4-
(trifluoromethyl)benzylidene)amino)decahydro-3,12-epoxy[1,2]-
dioxepino[4,3-i]isoquinolin-10(3H)-one (13e). Yield 82%, white solid,
2-((1R,3R)-Adamantan-2-yl)-N-((3R,5aS,6R,8aS,9R,12R,12aR)-
3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]-
isoquinolin-11(12H)-yl)acetamide (12g). Yield 88%, white solid, mp
1
166−168 °C; FT-IR (KBr cm−1), 1646, 1702, 3201; H NMR (300
MHz, CDCl3); δ 0.97−1.05 (m, 1H), 0.98 (d, 3H, J = 6.1 Hz), 1.17 (d,
3H, J = 7.2 Hz), 1.30−2.07 (m, 26H), 1.38 (s, 3H), 2.37−2.48 (m,
1H), 3.33−3.41 (m, 1H), 5.49 (s, 1H), 7.43 (brs, 1H, NH); 13C NMR
(75 MHz, CDCl3) δ 12.65 (CH3), 19.87 (CH3), 22.65 (CH2), 25.28
(CH2), 25.59 (CH3), 28.84 (3 × CH), 33.15 (CH), 33.71 (C), 33.98
(CH2), 36.75 (CH2), 36.91 (3 × CH2), 37.59 (CH), 42.55 (3 × CH2),
46.44 (CH), 49.35 (CH2), 51.48 (CH), 80.47 (CH), 81.25 (C),
105.08 (C), 169.75 (C), 171.60 (C); ESI-MS (m/z) 473 [M + H]+.
Anal. Calcd for C27H40N2O5: C, 68.62%, H, 8.53%, N, 5.93%. Found:
C, 68.99%, H, 8.66%, N, 5.67%.
General Procedure for Preparation of Hydrazone Deriva-
tives (13a−g) of N-Amino-11-azaartemisnin (9). Preparation of
(3R,5aS,6R,8aS,9R,12R,12aR)-11-(((E)-Benzylidene)amino)-3,6,9-tri-
methyldecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-
10(3H)-one (13a). To a stirred solution of 9 (500 mg, 1.69 mmol) in
dry benzene (5.00 mL) at room temperature were added
benzaldehyde (0.700 mL, 6.86 mmol) and Amberlyst-15 (50.0 mg),
and the reaction mixture was allowed to stir for 2 h at the same
temperature. The reaction mixture was filtered, and the residue was
washed with ether (2 × 50 mL). The combined organic layer was
concentrated under reduced pressure at room temperature and the
crude product was purified by column chromatography over silica gel
using 5% EtOAc/hexane as eluent to furnish compound 13a (610 mg,
94% yield) as a white solid, mp 178−181 °C. FT-IR (KBr cm−1) 1662,
1603; 1H NMR (300 MHz, CDCl3) δ 1.04 (d, 3H, J = 6.3 Hz), 1.09−
1.16 (m, 2H), 1.20 (d, 3H, J = 7.2 Hz), 1.34 (s, 3H), 1.41−2.07 (m,
8H), 2.40−2.49 (m, 1H), 3.50−3.59 (m, 1H), 5.77 (s, 1H), 7.39−7.83
(m, 5H, Ar), 8.61 (s, 1H, imine H); 13C NMR (75 MHz, CDCl3) δ
12.67 (CH3), 19.99 (CH3), 23.02 (CH2), 25.23 (CH2), 25.66 (CH3),
33.91 (CH2), 34.36 (CH), 36.74 (CH2), 37.59 (CH), 46.59 (CH),
51.72 (CH), 81.24 (C), 81.80 (CH), 105.20 (C), 128.48 (2 × CH),
128.78 (2 × CH), 131.30 (C), 133.96 (C), 164.67 (CH), 169.12 (C);
ESI-MS (m/z) 385 [M + H]+. EI-HRMS calcd for C22H28N2O4 [M]+:
384.2049. Found: 384.2024. Anal. Calcd for C22H28N2O4: C, 68.73%,
H, 7.34%, N, 7.29%. Found: C, 68.80%, H, 7.16%, N, 7.25%.
1
mp 170−173 °C; FT-IR (KBr cm−1) 1672; H NMR (300 MHz,
CDCl3) δ 1.04 (d, 3H, J = 6.2 Hz), 1.09−1.13 (m, 2H), 1.21 (d, 3H, J
= 7.2 Hz), 1.33 (s, 3H), 1.41−2.06 (m, 8H), 2.40−2.51 (m, 1H),
3.51−3.60 (m, 1H), 5.79 (s, 1H), 7.67 (d, 2H, Ar, J = 8.1 Hz), 7.91 (d,
2H, Ar, J = 8.1 Hz), 8.74 (s, 1H, imine H); 13C NMR (75 MHz,
CDCl3) δ 12.62 (CH3), 19.92 (CH3), 22.99 (CH2), 25.19 (CH2),
25.60 (CH3), 33.83 (CH2), 34.51 (CH), 36.67 (CH2), 37.59 (CH),
46.46 (CH), 51.64 (CH), 81.15 (C), 82.05 (CH), 105.27 (C), 125.71
(q, C, JC−F = 4.0 Hz, CF3), 128.45 (4 × CH), 137.56 (2 × C), 160.75
(CH), 169.38 (C); ESI-MS (m/z) 453 [M + H]+. EI-HRMS calcd for
C23H27N2O4F3 [M]+: 452.1923. Found: 452.1922. Anal. Calcd for
C23H27N2O4F3: C, 61.05%, H, 6.01%, N, 6.19%. Found: C, 61.15%, H,
6.20%, N, 6.14%.
(3R,5aS,6R,8aS,9R,12R,12aR)-11-(((E)-[1,1′-Biphenyl]-4-
ylmethylene)amino)-3,6,9-trimethyldecahydro-3,12-epoxy[1,2]-
dioxepino[4,3-i]isoquinolin-10(3H)-one (13f). Yield 94%, white solid,
mp 118−120 °C; FT-IR (KBr cm−1) 1601, 1687; 1H NMR (300 MHz,
CDCl3) δ 0.85−1.13 (m, 2H), 1.05 (d, 3H, J = 6.3 Hz), 1.22 (d, 3H, J
= 7.3 Hz), 1.35 (s, 3H), 1.42−1.81 (m, 6H), 2.02−2.08 (m, 2H),
2.41−2.52 (m, 1H), 3.52−3.61 (m, 1H), 5.80 (s, 1H), 7.36−7.91 (m,
9H, Ar), 8.66 (s, 1H, imine H); 13C NMR (75 MHz, CDCl3) δ 12.67
(CH3), 19.97 (CH3), 23.01 (CH2), 25.22 (CH2), 25.66 (CH3), 33.90
(CH2), 34.38 (CH), 36.73 (CH2), 37.58 (CH), 46.58 (CH), 51.72
(CH), 81.23 (C), 81.81 (CH), 105.20 (C), 127.33 (2 × CH), 127.46
(2 × CH), 127.99 (CH), 128.91 (2 × CH), 129.05 (2 × CH), 132.92
(C), 140.55 (C), 143.99 (C), 164.10 (CH), 169.14 (C); ESI-MS (m/
z) 461 [M + H]+. Anal. Calcd for C28H32N2O4: C, 73.02%, H, 7.00%,
N, 6.08%. Found: C, 72.95%, H, 6.91%, N, 6.00%.
Compounds 13b−g were prepared by the above procedure by
replacing benzaldehyde with p-methylbenzaldehyde, p-chlorobenzal-
dehyde, p-fluorobenzaldehyde, p-trifluoromethylbenzaldehyde, p-phe-
nylbenzaldehyde, and 9H-fluorene-2-carbaldehyde, respectively.
(3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-Trimethyl-11-(((E)-4-
methylbenzylidene)amino)decahydro-3,12-epoxy[1,2]dioxepino-
[4,3-i]isoquinolin-10(3H)-one (13b). Yield 94%, white solid, mp 138−
1
140 °C; FT-IR (KBr cm−1) 1667, 2864, 2936; H NMR (300 MHz,
CDCl3) δ 1.03 (d, 3H, J = 6.0 Hz), 1.08−1.16 (m, 2H), 1.19 (d, 3H, J
= 7.2 Hz), 1.33 (s, 3H), 1.40−2.04 (m, 8H), 2.39 (s, 3H), 2.39−2.45
(m, 1H), 3.51−3.55 (m, 1H), 5.75 (s, 1H), 7.23 (d, 2H, J = 7.8 Hz),
7.70 (d, 2H, J = 7.8 Hz), 8.54 (s, 1H, imine H); 13C NMR (75 MHz,
CDCl3) δ 12.64 (CH3), 19.96 (CH3), 21.77 (CH3), 22.99 (CH2),
25.20 (CH2), 25.62 (CH3), 33.90 (CH2), 34.29 (CH), 36.72 (CH2),
(3R,5aS,6R,8aS,9R,12R,12aR)-11-(((E)-(9H-Fluoren-2-yl)-
methylene)amino)-3,6,9-trimethyldecahydro-3,12-epoxy[1,2]-
dioxepino[4,3-i]isoquinolin-10(3H)-one (13g). Yield 92%, white solid,
mp 205−207 °C; FT-IR (KBr cm−1) 1659, 2930; 1H NMR (300 MHz,
CDCl3) δ 0.88−1.36 (m, 2H), 1.05 (d, 3H, J = 6.2 Hz), 1.21 (d, 3H, J
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1
= 7.2 Hz), 1.36 (s, 3H), 1.44−1.88 (m, 6H), 2.02−2.07 (m, 2H),
2.41−2.51 (m, 1H), 3.55−3.59 (m, 1H), 3.94 (s, 2H), 5.80 (s, 1H),
7.33−7.85 (m, 6H), 8.09 (s, 1H), 8.66 (s, 1H, imine H); 13C NMR
(75 MHz, CDCl3) δ 12.68 (CH3), 19.99 (CH3), 23.02 (CH2), 25.23
(CH2), 25.68 (CH3), 33.92 (CH2), 34.34 (CH), 36.74 (CH2), 36.99
(CH2), 37.61 (CH), 46.60 (CH), 51.73 (CH), 81.25 (C), 81.77 (CH),
105.22 (C), 120.07 (CH), 120.67 (CH), 124.39 (CH), 125.36 (CH),
127.13 (CH), 127.68 (CH), 128.31 (CH), 132.37 (C), 141.21 (C),
143.68 (C), 144.27 (C), 144.97 (C), 165.31 (CH), 169.14 (C); ESI-
MS (m/z) 473 [M + H]+. Anal. Calcd for C29H32N2O4: C 73.70%, H
6.83%, N 5.93%. Found: C 73.99%, H 6.95%, N 5.89%.
General Procedure for Preparation of Hydrazine Derivatives
(14a−g) of N-Amino-11-azaartemisnin (9). Preparation of
(3R,5aS,6R,8aS,9R,12R,12aR)-11-(Benzylamino)-3,6,9-trimethyl-
decahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-10(3H)-one
(14a). To a stirred solution of compound 13a (500 mg, 1.30 mmol) in
benzene (15.0 mL) at 0 °C was added NaBH4 (247 mg, 6.52 mmol),
and the reaction mixture was allowed to stir at the same temperature
for 4 h. The reaction mixture was quenched with glacial AcOH (3.00
mL), neutralized with saturated NaHCO3 (10.0 mL), and extracted
with ether (3 × 25 mL). The combined organic layer was concentrated
under reduced pressure at room temperature and the crude product
was purified by column chromatography over silica gel using 5%
EtOAc/hexane as eluent to furnish compound 14a (336 mg, 67%
yield) as an oil. FT-IR (neat cm−1) 1659; 1H NMR (300 MHz,
CDCl3) δ 0.77−1.00 (m, 2H), 0.99 (d, 3H, J = 5.7 Hz), 1.17 (d, 3H, J
= 7.3 Hz), 1.27−2.11 (m, 8H), 1.49 (s, 3H), 2.41−2.51 (m, 1H),
3.43−3.47 (m, 1H), 4.04 (d, 1H, J = 10.9 Hz, benzylic H), 4.15 (d, 1H,
J = 10.9 Hz, benzylic H), 5.28 (brs, 1H, NH), 5.36 (s, 1H), 7.28−7.49
(m, 5H, Ar); 13C NMR (75 MHz, CDCl3) δ 12.59 (CH3), 19.93
(CH3), 22.88 (CH2), 25.12 (CH2), 25.71 (CH3), 33.59 (CH), 33.78
(CH2), 36.95 (CH2), 37.48 (CH), 46.63 (CH), 51.61 (CH), 56.81
(CH2), 81.11 (C), 82.50 (CH), 105.13 (C), 127.76 (C), 128.67 (2 ×
CH), 129.43 (2 × CH), 137.69 (C), 172.18 (C); ESI-MS (m/z) 387
[M + H]+, 409 [M + Na]+. Anal. Calcd for C22H30N2O4: C, 68.37%,
H, 7.82%, N, 7.25%. Found: C, 68.59%, H 7.96%, N 7.24%.
3271; H NMR (300 MHz, CDCl3) δ 0.77−1.07 (m, 2H), 0.99 (d,
3H, J = 5.9 Hz), 1.16 (d, 3H, J = 7.3 Hz), 1.27−2.12 (m, 9H), 1.48 (s,
3H), 2.41−2.51 (m, 1H), 3.43−3.47 (m, 1H), 4.02 (d, 1H, J = 11.0
Hz, benzylic H), 4.11 (d, 1H, J = 11.0 Hz, benzylic H), 5.36 (s, 1H),
6.99−7.05 (m, 2H), 7.42−7.47 (m, 2H); 13C NMR (75 MHz, CDCl3)
δ 12.57 (CH3), 19.94 (CH3), 22.91 (CH2), 25.13 (CH2), 25.71
(CH3), 33.59 (CH), 33.77 (CH2), 36.93 (CH2), 37.52 (CH), 46.63
(CH), 51.59 (CH), 56.06 (CH2), 81.13 (C), 82.55 (CH), 105.17 (C),
115.51 (d, 2 × CH, JC−F = 22 Hz), 131.11 (d, 2 × CH, JC−F = 8.0 Hz),
133.48 (d, C, JC−F = 3.0 Hz), 162.56 (d, C, JC−F = 245 Hz), 172.28
(C); ESI-MS (m/z) 405 [M + H]+, 427 [M + Na]+. EI-HRMS calcd
for C22H29N2O4F [M]+: 404.2111. Found: 404.2117. Anal. Calcd for
C22H29N2O4F: C, 65.33%, H, 7.23%, N, 6.93%. Found: C, 65.38%, H,
7.29%, N, 6.91%.
(3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-Trimethyl-11-((4-
(trifluoromethyl)benzyl)amino)decahydro-3,12-epoxy[1,2]-
dioxepino[4,3-i]isoquinolin-10(3H)-one (14e). Yield 68%, white solid,
mp 137−140 °C; FT-IR (KBr cm−1) 1660; H NMR (300 MHz,
1
CDCl3) δ 0.80−1.03 (m, 2H), 1.00 (d, 3H, J = 5.7 Hz), 1.16 (d, 3H, J
= 7.2 Hz), 1.32−2.11 (m, 8H), 1.46 (s, 3H), 2.41−2.51 (m, 1H),
3.40−3.49 (m, 1H), 4.06−4.25 (m, 2H, benzylic H), 5.29 (d, 1H, NH,
J = 5.6 Hz), 5.35 (s, 1H), 7.59 (s, 4H, Ar); 13C NMR (75 MHz,
CDCl3) δ 12.55 (CH3), 19.90 (CH3), 22.93 (CH2), 25.13 (CH2),
25.69 (CH3), 33.62 (CH), 33.75 (CH2), 36.92 (CH2), 37.54 (CH),
46.63 (CH), 51.59 (CH), 56.17 (CH2), 81.13 (C), 82.64 (CH),
105.18 (C), 125.58 (q, C, JC−F = 3.8 Hz, CF3), 129.63 (4 × CH),
141.83 (C), 141.85 (C), 172.42 (C); ESI-MS (m/z) 455 [M + H]+.
EI-HRMS calcd for C23H29N2O4F3 [M]+: 454.2079. Found: 454.2078..
Anal. Calcd for C23H29N2O4F3: C, 60.78%, H, 6.43%, N, 6.16%.
Found: C, 60.74%, H, 6.46%, N, 6.20%.
(3R,5aS,6R,8aS,9R,12R,12aR)-11-(([1,1′-Biphenyl]-4-ylmethyl)-
amino)-3,6,9-trimethyldecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]-
isoquinolin-10(3H)-one (14f). Yield 62%, white solid, mp 68−70 °C;
FT-IR (KBr cm−1) 1652; H NMR (300 MHz, CDCl3) δ 0.82−1.04
1
(m, 2H), 1.00 (d, 3H, J = 5.8 Hz), 1.19 (d, 3H, J = 7.3 Hz), 1.28−1.80
(m, 6H), 1.51 (s, 3H), 1.99−2.14 (m, 2H), 2.42−2.53 (m, 1H), 3.46−
3.49 (m, 1H), 4.12 (d, 1H, J = 11.1 Hz, benzylic H), 4.21 (d, 1H, J =
11.1 Hz, benzylic H), 5.32 (brs, 1H, NH), 5.38 (s, 1H), 7.33−7.62 (m,
9H, Ar); 13C NMR (75 MHz, CDCl3) δ 12.61 (CH3), 19.94 (CH3),
22.89 (CH2), 25.13 (CH2), 25.73 (CH3), 33.61 (CH), 33.77 (CH2),
36.94 (CH2), 37.49 (CH), 46.61 (CH), 51.60 (CH), 56.41 (CH2),
81.12 (C), 82.51 (CH), 105.14 (C), 127.27 (2 × CH), 127.43 (3 ×
CH), 128.91 (2 × CH), 129.87 (2 × CH), 136.77 (C), 140.71 (C),
141.14 (C), 172.22 (C); ESI-MS (m/z) 463 [M + H]+. EI-HRMS
calcd for C28H34N2O4 [M]+: 462.2519. Found: 462.2511. Anal. Calcd
for C28H34N2O4: C, 72.70%, H, 7.41%, N, 6.06%. Found: C, 72.99%,
H, 7.02%, N, 5.95%.
Hydrazines 14b−g were prepared by the above procedure from
hydrazones 13b−g.
(3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-Trimethyl-11-((4-
methylbenzyl)amino)decahydro-3,12-epoxy[1,2]dioxepino[4,3-i]-
isoquinolin-10(3H)-one (14b). Yield 62%, white solid, mp 125−127
°C; FT-IR (KBr cm−1) 1652, 2928, 3398; 1H NMR (300 MHz,
CDCl3) δ 0.77−1.04 (m, 2H), 0.99 (d, 3H, J = 5.8 Hz), 1.17 (d, 3H, J
= 7.2 Hz), 1.28−2.12 (m, 8H), 1.49 (s, 3H), 2.34 (s, 3H), 2.40−2.51
(m, 1H), 3.43−3.47 (m, 1H), 4.01−4.12 (m, 2H), 5.23 (brs, 1H, NH),
5.35 (s, 1H), 7.15 (d, 2H, J = 7.8 Hz), 7.37 (d, 2H, J = 7.8 Hz); 13C
NMR (75 MHz, CDCl3) δ 12.61 (CH3), 19.94 (CH3), 21.34 (CH3),
22.89 (CH2), 25.14 (CH2), 25.71 (CH3), 33.59 (CH), 33.80 (CH2),
36.96 (CH2), 37.49 (CH), 46.64 (CH), 51.63 (CH), 56.55 (CH2),
81.12 (C), 82.48 (CH), 105.12 (C), 129.34 (2 × CH), 129.39 (2 ×
CH), 134.66 (C), 137.38 (C), 172.12 (C); ESI-MS (m/z) 401 [M +
H]+. Anal. Calcd for C23H32N2O4: C, 68.97%, H, 8.05%, N, 6.99%.
Found: C, 69.15%, H, 8.39%, N, 6.77%.
(3R,5aS,6R,8aS,9R,12R,12aR)-11-(((9H-Fluoren-2-yl)methyl)-
amino)-3,6,9-trimethyldecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]-
isoquinolin-10(3H)-one (14g). Yield 74%, white solid, mp 78−80 °C;
FT-IR (KBr cm−1) 1659, 2930, 3456; 1H NMR (300 MHz, CDCl3) δ
0.87−1.05 (m, 2H), 0.98 (d, 3H, J = 5.7 Hz), 1.19 (d, 3H, J = 7.3 Hz),
1.28−1.74 (m, 6H), 1.53 (s, 3H), 1.99−2.53 (m, 3H), 3.46−3.50 (m,
1H), 3.91 (s, 2H), 4.15 (d, 1H, J = 10.9 Hz, benzylic H), 4.21 (d, 1H, J
= 10.7 Hz, benzylic H), 5.31 (brs, 1H, NH), 5.39 (s, 1H), 7.28−7.80
(m, 7H); 13C NMR (75 MHz, CDCl3) δ 12.61 (CH3), 19.92 (CH3),
22.89 (CH2), 25.13 (CH2), 25.76 (CH3), 33.62 (CH), 33.77 (CH2),
36.96 (CH2), 37.00 (CH2), 37.49 (CH), 46.63 (CH), 51.60 (CH),
57.06 (CH), 81.13 (C), 82.50 (CH), 105.16 (C), 120.04 (CH),
120.06 (CH), 125.21 (CH), 126.21 (CH), 126.81 (CH), 126.88
(CH), 128.21 (CH), 136.17 (C), 141.40 (C), 141.69 (C), 143.59 (C),
143.78 (C), 172.21 (C); ESI-MS (m/z) 475 [M + H]+, 497 [M +
Na]+. Anal. Calcd for C29H34N2O4: C, 73.39%, H, 7.22%, N, 5.90%.
Found: C, 73.55%, H, 6.99%, N, 5.95%.
(3R,5aS,6R,8aS,9R,12R,12aR)-11-((4-Chlorobenzyl)amino)-3,6,9-
trimethyldecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-
10(3H)-one (14c). Yield 74%, white solid, mp 118−120 °C; FT-IR
(KBr cm−1) 1667, 2923, 3402; 1H NMR (300 MHz, CDCl3) δ 0.77−
1.07 (m, 2H), 1.00 (d, 3H, J = 5.9 Hz), 1.16 (d, 3H, J = 7.2 Hz), 1.28−
1.80 (m, 6H), 1.47 (s, 3H), 1.98−2.12 (m, 2H), 2.42−2.51 (m, 1H),
3.42−3.46 (m, 1H), 4.01−4.13 (m, 2H), 5.22 (d, 1H, J = 5.4 Hz), 5.35
(s, 1H), 7.31 (d, 2H, J = 8.4 Hz), 7.40 (d, 2H, J = 8.4 Hz); 13C NMR
(75 MHz, CDCl3) δ 12.57 (CH3), 19.94 (CH3), 22.92 (CH2), 25.13
(CH2), 25.71 (CH3), 33.59 (CH), 33.76 (CH2), 36.93 (CH2), 37.53
(CH), 46.63 (CH), 51.59 (CH), 56.07 (CH2), 81.12 (C), 82.58 (CH),
105.16 (C), 128.81 (2 × CH), 130.79 (2 × CH), 133.60 (C), 136.24
(C), 172.30 (C); ESI-MS (m/z) 421 [M + H]+. Anal. Calcd for
C22H29N2O4Cl: C, 62.77%, H, 6.94%, N, 6.66%. Found: C, 62.80%, H,
6.59%, N, 6.60%.
General Procedure for Preparation of Ether Derivatives of
N-Hydroxy-11-azaartemisnin (11). Preparation of (3R,5aS,6-
R,8aS,9R,12R,12aR)-11-(Benzyloxy)-3,6,9-trimethyldecahydro-3,12-
epoxy[1,2]dioxepino[4,3-i]isoquinolin-10(3H)-one (15a). To a stirred
slurry of NaH (60% dispersion in mineral oil, 0.323 g, 13.4 mmol) in
dry THF (10.0 mL) at 0 °C was added N-hydroxy-11-azaartemisnin
11 (0.40 g, 1.34 mmol) dissolved in dry THF (10 mL), and the
(3R,5aS,6R,8aS,9R,12R,12aR)-11-((4-Fluorobenzyl)amino)-3,6,9-
trimethyldecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-
10(3H)-one (14d). Yield 72%, oil; FT-IR (neat cm−1) 1655, 2926,
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reaction mixture was stirred at 0 °C for 2 h. To this reaction mixture
was added benzyl bromide (0.960 mL, 8.07 mmol), and the mixture
was further stirred at room temperature for 12 h. The reaction mixture
was quenched with water (10.0 mL) and extracted with ether (3 × 10
mL). The organic layer was dried over anhydrous Na2SO4,
concentrated under reduced pressure at room temperature, and the
crude product was purified by column chromatography over silica gel
(60−120 mesh) using 5% EtOAc/hexane as eluent to furnish (0.375 g,
72% yield) of pure 15a as a white solid, mp 120−122 °C. IR (KBr,
cm−1) 1731; 1H NMR (300 MHz, CDCl3) δ 0.86−1.02 (m, 2H), 0.98
(d, 3H, J = 5.4 Hz), 1.15 (d, 3H, J = 7.2 Hz), 1.34−1.57 (m, 3H), 1.50
(s, 3H), 1.64−1.80 (m, 3H), 1.98−2.12 (m, 2H), 2.42−2.53 (m, 1H),
3.43−3.52 (m, 1H), 5.01 (d, 1H, J = 9.1 Hz, benzylic H), 5.20 (d, 1H,
J = 9.1 Hz, benzylic H), 5.46 (s, 1H), 7.32−7.39 (m, 3H, Ar), 7.54−
7.56 (m, 2H, Ar); 13C NMR (50 MHz, CDCl3) δ 12.00 (CH3), 19.87
(CH3), 22.86 (CH2), 25.06 (CH2), 25.67 (CH3), 33.69 (CH2), 34.07
(CH), 36.77 (CH2), 37.48 (CH), 46.82 (CH), 51.48 (CH), 79.13
(CH2), 81.90 (C), 82.65 (CH), 105.05 (C), 128.53 (2 × CH), 128.67
(CH), 129.68 (2 × CH), 135.63 (C), 171.27 (C); ESIMS (m/z) 388
[M + H]+. EI-HRMS calcd For C22H30NO5 [M + H]+: 388.2124.
Found: 388.2116. Anal. Calcd for C22H29NO5: C, 68.20%, H, 7.54%,
N, 3.61%. Found: C, 67.84%, H, 7.52%, N, 3.31%.
AUTHOR INFORMATION
Corresponding Author
*Phone: +91 0522 2624273. Fax: +91 0522 2623405. E-mail:
chandancdri@yahoo.com.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
V.P.V., M.H., A.S.S., and N.K.N. are thankful to the CSIR and
UGC, New Delhi, India, for the award of Senior Research
Fellowship.
DEDICATION
■
This manuscript is dedicated to Dr. Sukh Dev on the occasion
of his 90th birthday.
ABBREVIATIONS USED
N2H4·H2O, hydrazine hydrate; NaH, sodium hydride; NaBH4,
sodium borohydride; NH2OH, hydroxylamine
■
Compounds 15b,c were prepared from 11 by the above procedure
by replacing benzyl bromide with o-fluorobenzyl bromide and p-
phenylbenzyl bromide, respectively.
REFERENCES
(1) CSIR-CDRI Communication No. 7597.
■
(3R,5aS,6R,8aS,9R,12R,12aR)-11-((2-Fluorobenzyl)oxy)-3,6,9-
(2) (a) World Health Organization. 10 Facts on Malaria. www.who.
int/features/factfiles/malaria. (b) Murray, C. J. L.; Rosenfeld, L. C.;
Lim, S. S.; Andrews, K. G.; Foreman, K. J.; Haring, D.; Fullman, N.;
Naghavi, M.; Lozano, R.; Lopez, A. D. Global malaria mortality
between 1980 and 2010: a systematic analysis. Lancet 2012, 379, 413−
431.
trimethyldecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-
1
10(3H)-one (15b). Yield 65%, oil. IR (neat, cm−1) 1720; H NMR
(300 MHz, CDCl3) δ 0.88−1.00 (m, 2H), 0.96 (d, 3H, J = 5.2 Hz),
1.13 (d, 3H, J = 7.2 Hz), 1.18−1.42 (m, 3H), 1.47 (s, 3H), 1.67−1.78
(m, 3H), 1.95−2.09 (m, 2H), 2.39−2.50 (m, 1H), 3.43−3.47 (m, 1H),
5.18 (s, 2H), 5.44 (s, 1H), 7.00−7.68 (m, 4H, Ar); 13C NMR (50
MHz, CDCl3) δ 11.74 (CH3), 19.60 (CH3), 22.66 (CH2), 24.81
(CH2), 25.32 (CH3), 33.47 (CH2), 33.87 (CH), 36.55 (CH2), 37.23
(CH), 46.58 (CH), 51.25 (CH), 71.43 (d, CH2, JC−F = 3.9 Hz), 81.65
(C), 82.45 (CH), 104.85 (C), 115.18 (d, CH, JC−F = 21.3 Hz), 122.66
(d, C, JC−F = 15.1 Hz), 124.04 (d, CH, JC−F = 3.7 Hz), 130.22 (d, CH,
(3) For reviews on artemisinin and its analogues see the following:
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JC−F = 8.2 Hz), 131.91 (d, CH, JC−F = 3.7 Hz), 160.97 (d, C, JC−F
=
248.1 Hz), 171.15 (C); ESIMS (m/z) 406 [M + H]+. HRMS [ESI]
calcd for C22H29NO5F: 406.2030 [M + H]+. Found: 406.2020. Anal.
Calcd for C22H28NO5F: C, 65.17%, H, 6.96%, N, 3.45%. Found: C,
65.28%, H, 7.00%, N, 3.40%.
(3R,5aS,6R,8aS,9R,12R,12aR)-11-([1,1′-Biphenyl]-4-ylmethoxy)-
3,6,9-trimethyldecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]-
isoquinolin-10(3H)-one (15c). Yield 74%, white solid, mp 65−66 °C.
IR (KBr, cm−1) 1728; 1H NMR (300 MHz, CDCl3) δ 0.89−1.01 (m,
2H), 1.00 (d, 3H, J = 5.3 Hz), 1.16 (d, 3H, J = 7.2 Hz), 1.33−1.42 (m,
3H), 1.52 (s, 3H), 1.64−1.80 (m, 3H), 1.98−2.12 (m, 2H), 2.43−2.53
(m, 1H), 3.44−3.53 (m, 1H), 5.04 (d, 1H, J = 9.1 Hz, benzylic H),
5.24 (d, 1H, J = 9.1 Hz, benzylic H), 5.47 (s, 1H), 7.32−7.46 (m, 3H,
Ar), 7.57−7.64 (m, 6H, Ar); 13C NMR (50 MHz, CDCl3) δ 12.06
(CH3), 19.92 (CH3), 22.93 (CH2), 25.13 (CH2), 25.75 (CH3), 33.76
(CH2), 34.15 (CH), 36.84 (CH2), 37.55 (CH), 46.91 (CH), 51.55
(CH), 78.89 (CH2), 81.98 (C), 82.75 (CH), 105.14 (C), 127.35 (2 ×
CH), 127.40 (2 × CH), 127.52 (CH), 128.94 (2 × CH), 130.19 (2 ×
CH), 134.73 (C), 141.13 (C), 141.69 (C), 171.39 (C); ESIMS (m/z)
464 [M + H]+. HRMS [ESI] calcd for C28H34NO5: 464.2437 [M +
H]+. Found: 464.2461. Anal. Calcd for C28H33NO5: C, 72.55%, H,
7.18%, N, 3.02%. Found: C, 72.48%, H, 7.34%, N, 2.81%.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra of compounds 9, 11, 12a−g,
13a−g, 14a−g, and 15a−c; table showing degree of purity
(elemental analysis) for compounds; and table showng HRMS
results. This material is available free of charge via the Internet
at http://pubs.acs.org.
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Plasmodium falciparum field isolates to in-vitro artemether and point
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the detection limit could multiply and eventually could be detected
during observation on subsequent days. In such cases though the drug
was providing near 100% suppression of the parasitemia on day 4, it
would not provide full protection to the treated mice in the 28-day
survival assay. Multidrug-resistant Plasmodium yoelii nigeriensis used in
this study is resistant to chloroquine, mefloquine, and halofantrine.
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28. Similarly 60% protection means three out of five treated mice
survived till day 28.
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inoculated intraperitoneally with 1 × 106 parasitized RBCs on day 0,
and treatment was administered to a group of five mice at each dose
from day 0 to day 3, once daily. The drug dilutions of compounds 9,
11, 12a−g, 13a−g, 14a−g, and 15a−c were prepared in groundnut oil
to contain the required amount of the drug (0.3 mg for a dose of 24
mg/kg, 0.15 mg for a dose of 12 mg/kg, 0.075 mg for a dose of 6 mg/
kg, and 0.0375 mg) in 0.1 mL and administered orally and
intramuscularly for each required dose. Parasitemia levels were
recorded from thin blood smears on day 4 and subsequently twice a
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