New functionalized 1,2,4-trioxepanes: Synthesis and antimalarial activity against multi-drug resistant P. yoelii in mice

Article abstract of DOI:10.1016/j.bmcl.2008.08.096

A series of new amino functionalized 1,2,4-trioxepanes 8-16 and ester functionalized 1,2,4-trioxepanes 17-19 have been synthesized and evaluated against multi-drug resistant Plasmodium yoelii in Swiss mice. Amino functionalized trioxepanes 14, the most active compound of the series, showed 100% clearance of parasitaemia by oral route on day 4 and 75% protection to the treated mice beyond day 28.

Full text of DOI:10.1016/j.bmcl.2008.08.096

Bioorganic & Medicinal Chemistry Letters 18 (2008) 5190–5193
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
New functionalized 1,2,4-trioxepanes: Synthesis and antimalarial activity
against multi-drug resistant P. yoelii in mice q
a
b
b
Chandan Singh a, , Shilpi Pandey , Ambuj K. Kushwaha , Sunil K. Puri
*
a Division of Medicinal & Process Chemistry, Central Drug Research Institute, Lucknow 226001, India
b Division of Parasitology, Central Drug Research Institute, Lucknow 226001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new amino functionalized 1,2,4-trioxepanes 8–16 and ester functionalized 1,2,4-trioxepanes
17–19 have been synthesized and evaluated against multi-drug resistant Plasmodium yoelii in Swiss mice.
Amino functionalized trioxepanes 14, the most active compound of the series, showed 100% clearance of
parasitaemia by oral route on day 4 and 75% protection to the treated mice beyond day 28.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 22 May 2008
Revised 7 August 2008
Accepted 26 August 2008
Available online 29 August 2008
Keywords:
Antimalarial
Artemisinin
1,2,4-Trioxane
1,2,4-Trioxepane
Amino functionalized trioxepane
Ester functionalized trioxepane
Artemisinin 1, the antimalarial principle of the Chinese tradi-
tional herb, Artemisia annua, and its semi-synthetic derivatives,
for example, artemether 2, arteether 3, and artesunic acid 4 are po-
tent antimalarials and are currently being used clinically to treat
multi-drug resistant malaria (Fig. 1).1 The endoperoxide linkage,
present as 1,2,4-trioxane, is the active pharmacophore responsible
for the antimalarial activity and currently the focus is on synthesis
and antimalarial assessment of structurally simple peroxides,
including 1,2,4-trioxanes,2 1,2,4-trioxepanes,3 1,2,4,5-tetraoxanes4
and ozonides.5
H
H
H
O
O
O
O
O
O
O
O
O
H
H
H
O
O
O
OR
OCOCH2CH2COOH
O
4
1
2 R = Me
3 R = Et
Recently, we have reported a photooxygenation route for the
preparation 1,2,4-trioxepanes.3j Some of the trioxepanes prepared
using this method have shown significant suppression of parasita-
emia but did not provide any long term survival advantage to the
treated animals.3k In our search for trioxepanes showing better
activity profile, we have prepared a series of new amino function-
alized trioxepanes 8–16 and ester functionalized trioxepanes 17–
19 and assessed them for antimalarial activity against multi-drug
resistant Plasmodium yoelii in mice. Some of the amino functional-
ized trioxepanes have shown promising antimalarial activity.
Herein, we report the results of this study.
Figure 1. Artemisinin and its derivatives.
cyclohexane-1,4-dione6 in the presence of conc. HCl (Scheme 1).
c
-Hydroxyhydroperoxides 6a–c were prepared by the photooxy-
genation of homoallylic alcohols 5a–c.3k
Reductive amination of keto-trioxepane 7a with aniline, 4-fluo-
roaniline and 4-trifluoromethylaniline in the presence of NaB-
H(OAc)3 furnished amino functionalized trioxepane 8, 9 and 10
as inseparable mixture of diastereomers in 84%, 85% and 62% yield,
respectively. Similarly, keto-trioxepane 7b on reductive amination
with aniline, 4-fluoroaniline and 4-trifluoromethylaniline fur-
nished trioxepanes 11, 12 and 13 as inseparable mixture of diaste-
reomers in 82%, 77% and 60% yields, respectively. Similar reductive
amination of 7c with aniline, 4-fluoroaniline and 4-trifluorometh-
ylaniline furnished trioxepanes 14, 15 and 16 as mixture of
diastereomers in 83%, 86% and 67% yields, respectively
Keto trioxepanes 7a–c were prepared by the published proce-
dure, via condensation of
c-hydroxyhydroperoxides 6a–c with
q
CDRI Communication No.: 7496.
* Corresponding author. Tel.: +91 522 2624273; fax: +91 522 2623405.
E-mail address: chandancdri@yahoo.com (C. Singh).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.08.096

C. Singh et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5190–5193
5191
1O2
O
O
O
OH
OH
O
Ar
Ar
Ar
H+
O
OOH
6a-c
O
5a-c
7a-c
Scheme 1.
Table 1
Functionalized 1,2,4-trioxepanes
Compound
Ar
R
Time (h)
Yield (%)
8
9
Phenyl
Phenyl
Phenyl
4-Chloro phenyl
4-Chloro phenyl
4-Chloro phenyl
4-Biphenyl
4-Biphenyl
4-Biphenyl
Phenyl
4-Chloro phenyl
4-Biphenyl
Phenyl
4-Fluorophenyl
4-Trifluoro methyl phenyl
Phenyl
4-Fluorophenyl
4-Trifluoro methyl phenyl
Phenyl
4-Fluorophenyl
2.5
2.5
2
2.5
2.5
2.5
3
2.5
3
5
84
85
62
82
77
60
83
86
67
58
57
55
10
11
12
13
14
15
16
17
18
19
4-Trifluoro methyl phenyl
—
—
—
5
6
(Scheme 2, Table 1). Only amino trioxepane 16 could be separated
into pure diastereomers 16a (less polar) and 16b (more polar).7
Horner wordsworth emmons wittig reaction of keto-trioxe-
panes 7a–c furnished inseparable diastereomeric mixtures of ester
functionalized trioxepanes 17–19 in 55–58% overall yields
(Scheme 3).8
exhibited 98% suppression of parasitaemia by oral route on day
4. Trioxepane 19 exhibited 95% clearance of parasitaemia on day
4 by oral route. Compound 13 showed 87% suppression of parasita-
emia by oral route and 73% suppression of parasitaemia by im
route. While, the remaining compounds showed only moderate
activity.
All the trioxepanes 8–19 were screened for antimalarial activity
against multi-drug resistant P. yoelii nigeriensis in Swiss mice at a
dose of 96 mg/kg by oral and intramuscular (im) routes. 9a The re-
sults are shown in Table 2.
As can be seen from Table 2, several of these trioxepanes exhib-
ited significant suppression of parasitaemia on day 4. Amino func-
tionalized trioxepanes 14 was the most active compound of the
series. It showed 100% clearance of parasitaemia by oral route on
day 4 and provided 75% protection to the treated mice beyond
day 28.9b It also showed 99% clearance of parasitaemia on day 4
by i.m. route. Next in order of activity is compound 10 which
showed 100% suppression of parasitaemia on day 4 and 40% of
the treated mice survived beyond day 28. Trioxepanes 11 and 15
In conclusion we have prepared a series of functionalized tri-
oxepanes 8–19, several of which exhibited significant antimalarial
activity by oral route. However, these functionalized trioxepanes
show only moderate activity by im route. Amino functionalized tri-
oxepane 14 is the most active compound of the series. It showed
100% clearance of parasitaemia by oral route on day 4 and provided
75% protection to the treated mice.
Acknowledgments
Shilpi Pandey is thankful to the Council of Scientific and Indus-
trial Research, New Delhi, for the award of Senior Research
Fellowship.
a
O
O
O
O
Ar
Ar
O
NHR
O
O
8-16
7a-c
Ar = Phenyl, 4-Cl-phenyl, 4-Biphenyl
Scheme 2. Reagents and condition: (a) ArNH2,[NaBH4 + AcOH = NaBH(OAc)3], benzene, rt.
a
O
O
O
O
Ar
Ar
O
CHCOOCH2CH3
O
O
7a-c
17-19
Ar = Phenyl, 4-Cl-phenyl, 4-Biphenyl
Scheme 3. Reagents and conditions: (a) (OEt)2P(O) CH2 CO2 Et/NaH, THF, 0 °C-rt.

5192
C. Singh et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5190–5193
Table 2
In vivo antimalarial activity against P. yoelii in Swiss mice
Structure
R
Compound
Dose
(mg/kg/day)
Route
% Suppression
on day 4
Mice survived
on day 28
Phenyl
8
9
96
96
96
96
96
96
96
96
96
96
96
96
96
96
96
96
Oral
im
Oral
im
Oral
im
Oral
im
Oral
im
Oral
im
Oral
im
Oral
im
78.58
75.47
63.18
50
0/4
0/4
0/4
0/4
2/5
0/4
0/4
0/4
0/4
0/4
0/4
0/4
3/4
0/4
0/4
0/4
O
O
4-F-Phenyl
4-CF3-Phenyl
Phenyl
NH
R
O
10
11
12
13
14
15
100
24.32
98.49
32.07
41.51
58.37
87.17
73.36
100
O
O
4-F-
Phenyl
4-CF3-Phenyl
NH
R
Cl
O
Phenyl
99.01
98.08
57.69
4-F-
Phenyl
O
O
4-CF3-Phenyl
16
96
96
Oral
im
68.3
75.84
0/4
0/4
NH
R
O
O
O
—
—
17
18
96
96
Oral
im
88.76
43.58
0/4
0/4
CHCOOCH2CH3
O
O
O
O
96
96
Oral
im
85.87
41.11
0/4
0/4
CHCOOCH2CH3
Cl
O
O
O
CHCOOCH2CH3
—
19
96
96
Oral
im
95.18
35.32
0/4
0/4
H
O
O
O
b-Arteether
3
48
Oral
100
5/5
H
O
OEt
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6. The corresponding dispiro-bis-1,2,4-trioxepanes are formed as minor products;
data not included.
7.61 (m, 9H); EIMS (m/z) 460.2 (M+H)+; FT-IR (cmÀ1) 1620.9, 3400.8; HRMS
Calcd. for C29H30O3NF: 459.2210. Found: 459.2186.
9-(1-Biphenyl-4-yl-vinyl)-7,8,12-trioxa-spiro[5.6]dodec-3-yl]-(4-trifluoromethyl-
phenyl)-amine (16): Yield: 62%; 1H NMR (200 MHz, CDCl3) d 1.42–2.10 (m, 10H),
3.41 (m, 1H), 3.77–3.89 (m, 1H), 3.98–4.14 (m, 1H), 5.12 (dd, 1H, J = 10.9,
2.7 Hz), 5.39 and 5.52 (2Â s, 2H), 6.54–6.59 (d, 2H, J = 8.4 Hz), 7.25–7.62 (m,
11H); EIMS (m/z) 510.1 (M+H)+; FT-IR (cmÀ1) 1620.9, 3400.8.
9-(1-Biphenyl-4-yl-vinyl)-7,8,12-trioxa-spiro[5.6]dodec-3-yl]-(4-trifluoromethyl-
phenyl)-amine (16a, Less Polar), 1H NMR (200 MHz, CDCl3) d 1.39–2.04 (m, 10H),
3.41 (brm, 1H), 3.78–3.85 (m, 2H, 1CH and 1NH), 4.03–4.15 (m, 1H), 5.12 (dd,
1H, J = 11.2, 3.0 Hz), 5.40 and 5.52 (2Â s, 2H), 6.57 (d, 2H, J = 8.5 Hz), 7.25–7.62
(m, 11H); EIMS (m/z) 510.1 (M+H)+; HRMS Calcd. for C30H30O3NF3: 510.2178
Found: 510.2170.
9-(1-Biphenyl-4-yl-vinyl)-7,8,12-trioxa-spiro[5.6]dodec-3-yl]-(4-trifluoromethyl-
phenyl)-amine (16b, More Polar), 1H NMR (200 MHz, CDCl3) d 1.53–2.19 (m,
10H), 3.41 (brm, 1H), 3.82 (td, 1H, J = 12.4, 3.2 Hz), 3.90 (s, NH), 3.98–4.10 (m,
1H), 5.12 (dd, 1H, J = 11.2, 3.2 Hz), 5.39 and 5.57 (2Â s, 2H), 6.58 (d, 2H,
J = 8.5 Hz), 7.25–7.61 (m, 11H); EIMS (m/z) 510.2 (M+H)+; HRMS Calcd. for
C
30H30O3NF3: 509.2178. Found: 509.2171.
8. Spectral data of ester functionalized trioxepanes: 9-(1-biphenyl-4-yl-vinyl)-7,8,12-
trioxa-spiro[5.6]dodec-3-ylidene]-acetic acid ethyl ester (19): Yield 55%, mp 80–
84 °C, 1H NMR (200 MHz, CDCl3) d 1.27 (t, 3H, J = 7.2 Hz), 1.70–2.35 (m, 8H),
2.86–3.04 (m, 2H), 3.82 (td, 1H, J = 10.9, 3.1 Hz), 4.01–4.19 (m, 3H), 5.13 (dd, 1H,
J = 11.2, 2.8 Hz), 5.39 and 5.51 (2Â s, 2H), 5.66 and 5.68 (s, together integrating
for 1H), 7.24–7.60 (m, 9H); 13C NMR (50 MHz, CDCl3) d 14.66 (CH3) 25.34 (CH2),
25.51 (CH2), 29.14 (CH2), 29.78 (CH2), 29.93 (CH2), 31.71 (CH2), 32.43 (CH2),
33.68 (CH2), 33.91 (CH2), 34.21 (CH2), 34.97 (CH2), 36.32 (CH2), 37.30 (CH2),
37.64 (CH2), 59.97 (CH), 60.04 (CH), 60.94 (CH2), 85.80 (CH), 106.20 (C), 114.96
(CH2), 117.09 (CH2), 127.50 (2Â CH), 128.42 (2Â CH), 128.76 (2Â CH), 128.91
(3Â CH), 134.07 (C), 138.31 (C), 144.00 (C), 145.28 (C), 159.94 (C), 160.39 (CH),
166.90 (C); MS (m/z) 435.2 (M+H)+; FT-IR (cmÀ1) 1717.
7. Spectral data of amino functionalized trioxepanes:
Phenyl-[9-(1-phenyl-vinyl)-7,8,12-trioxaspiro[5.6]dodec-3-yl]-amine (8): Yield:
84%; 1H NMR (200 MHz, CDCl3) d 1.25–2.13 (m, 10H), 3.35 (brm, 1H), 3.78–
3.80 (m, 1H), 3.98–4.04 (m, 1H), 5.06 (dd, 1H, J = 11.2, 3.1 Hz), 5.35 and 5.42 (2Â
s, 2H), 6.54–6.66 (m, 3H), 7.10–7.29 (m, 2H), 7.30–7.38 (m, 5H); EIMS (m/z)
366.2 (M+H)+.
(4-Fluoro-phenyl)-[9-(1-phenyl-vinyl)-7,8,12-trioxa-piro
[5.6]dodec-3-yl]-amine
(9): Yield: 85%; 1H NMR (200 MHz, CDCl3) d 1.46–2.05 (m, 10H), 3.29 (brm,
1H), 3.78 (td, 1H, J = 12.2, 3.2 Hz), 3.95–4.12 (m, 1H), 5.08 (dd, 1H, J = 11.0,
3.2 Hz), 5.36 and 5.44 (2Â s, 2H), 6.48–6.55 (t, 2H, J = 8.6 Hz), 6.82–6.91 (m, 2H),
7.26–7.42 (m, 5H); EIMS (m/z) 384.2 (M+H)+; HRMS Calcd. for C23H26O3NF:
383.18967. Found: 383.18982. FT-IR (cmÀ1) 1615.8, 3020.5.
9-(1-Phenyl-vinyl)-7,8,12-trioxa-spiro[5.6]dodec-3-ylidene]-acetic acid ethyl ester
(17): Yield 58%, 1H NMR (200MHz, CDCl3) d 1.26 (t, 3H, J = 7.1 Hz), 1.74–2.99 (m,
10H), 3.80 (td, 1H, J = 12.3, 3.3 Hz), 4.06–4.19 (m, 3H), 5.12 (dd, 1H, J = 11.2,
2.2 Hz), 5.36 and 5.43 (2Â s, 2H), 5.67 and 5.69 (s, together integrating for 1H),
7.29–7.39 (m, 5H); 13C NMR (50 MHz, CDCl3) d 14.71(CH3) 25.42 (CH2), 25.60
(CH2), 31.80 (CH2), 32.54 (CH2), 33.78 (CH2), 34.02 (CH2), 34.27 (CH2), 35.00
(CH2), 36.39 (CH2), 37.72 (CH2), 60.06 (CH), 60.08 (CH), 61.06 (CH2), 86.03 (CH),
106.20 (C), 115.00 (CH2), 116.48 (CH2), 127.07 (2Â CH), 128.24 (CH), 128.82 (2Â
CH), 139.97 (C), 146.48 (C), 160.62 (C), 166.90 (C); MS (m/z) 359.2 (M+H)+; FT-IR
(cmÀ1) 1720.
{9-[1-(4-Chloro-phenyl)-vinyl]-7,8,12-trioxa-spiro[5.6]dodec-3-ylidene}-acetic acid
ethyl ester (18): Yield 57%, 1H NMR (200 MHz, CDCl3) d 1.27 (t, 3H, J = 6.6 Hz),
1.42–2.41 (m, 8H), 2.98–3.04 (m, 2H), 3.78–4.20 (m, 4H), 5.04 (dd, 1H, J = 11.2,
3.1 Hz), 5.39 and 5.44 (2Â s, 2H), 5.65–5.7 (m, 1H), 7.27–7.37 (m, 4H); MS (m/z)
393.2 (M+H)+; FT-IR (cmÀ1) 1721.
9-(1-Phenyl-vinyl)-7,8,12-trioxa-spiro[5.6]dodec-3-yl]-(4-trifluoromethyl-phenyl)-
amine (10): Yield: 53%; 1H NMR (200 MHz, CDCl3) d 1.41–2.27 (m, 10H), 3.40
(brm, 1H), 3.76–3.82 (m, 1H), 3.97–4.10 (m, 1H), 5.07 (dd, 1H, J = 9.0, 3.0 Hz),
5.36 and 5.44 (2Â s, 2H), 6.57 (d, 2H, J = 9.0 Hz), 7.25–7.42 (m, 7H); EIMS (m/z)
434.0 (M+H)+.
{9-[1-(4-Chloro-phenyl)-vinyl]-7,8,12-trioxa-spiro[5.6]dodec-3-yl}-phenyl-amine
(11): Yield: 82%; 1H NMR (200 MHz, CDCl3) d1.41–2.10 (m, 10H), 3.37 (brm, 1H),
3.79 (td, 1H, J = 12.4, 3.1 Hz), 4.08 (m, 1H), 5.02 (dd, 1H, J = 11.3, 3.2 Hz), 5.38
and 5.44 (2Â s, 2H), 6.56–6.67 (m, 3H), 7.12–7.20 (m, 2H), 7.25–7.37 (m, 5H);
EIMS (m/z) 400.1 (M+H)+, 402 (M+2+H)+.
{9-[1-(4-Chloro-phenyl)-vinyl]-7,8,12-trioxa-spiro[5.6]dodec-3-yl}-(4-fluoro-
phenyl)-amine (12): Yield: 77%; 1H NMR (200 MHz, CDCl3) d 1.45–2.10 (m, 10H),
3.24–3.33 (brm, 1H), 3.78 (td, 1H, J = 12.3, 3.0 Hz), 4.00–4.11 (m, 1H), 5.00 (dd,
1H, J = 11.1, 3.2 Hz), 5.38 and 5.43 (2Â s, 2H), 6.48–6.55 (m, 2H), 6.82–6.91 (t,
2H, J = 8.8 Hz), 7.24–7.37 (m, 4H); EIMS (m/z) 418.1 (M+H)+.
{9-[1-(4-Chloro-phenyl)-vinyl]-7,8,12-trioxa-spiro[5.6]dodec-3-yl}-(4-trifluoromethyl-
phenyl)-amine (13): Yield: 60%; 1H NMR (200 MHz, CDCl3) d 0.91–2.10 (m, 10H),
3.65 (brm, 3H), 3.80–3.83 (m, 1H), 3.91–4.11 (m, 1H), 5.08 (dd, 1H, J = 11.2,
3.1 Hz), 5.39 and 5.57 (2Â s, 2H), 6.51–6.53 (m, 2H), 7.23–7.60 (m, 6H); MS (m/z)
453 (M)+, 476 (M+Na)+.
9-(1-Biphenyl-4-yl-vinyl)-7,8,12-trioxa-spiro[5.6]dodec-3-yl]-phenyl-amine (14):
Yield: 83%; 1H NMR (200 MHz, CDCl3) d 1.50–2.33 (m, 10H), 3.37–3.42 (m,
1H), 3.81 (td, 1H, J = 12.3, 3.1 Hz), 3.97–4.14 (m, 1H), 5.11 (dd, 1H, J = 11.6,
3.1 Hz), 5.39 and 5.51 (2Â s, 2H), 6.57–6.67 (m, 3H), 7.12–7.23 (m, 2H), 7.34–
7.62 (m, 9H); EIMS (m/z) 442.1 (M+H)+.
9-(1-Biphenyl-4-yl-vinyl)-7,8,12-trioxa-spiro[5.6]dodec-3-yl]-(4-fluoro-phenyl)-
amine (15): Yield: 86%; 1H NMR (200 MHz, CDCl3) d 1.48–2.16 (m, 10H), 3.29
(brm, 1H), 3.76–3.84 (m, 1H), 3.97–4.13 (m, 1H), 5.11 (dd, 1H, J = 11.1, 2.4 Hz),
5.39 and 5.51 (2Â s, 2H), 6.48–6.54 (m, 2H), 6.82–6.91 (t, 2H, J = 8.6 Hz), 7.24–
9. (a) The in vivo efficacy of compounds was evaluated against Plasmodium yoelii
(MDR) in Swiss mice model. The colony bred Swiss mice (25 1 g) were
inoculated with 1Â106 parasitized RBC on day zero and treatment was
administered to a group of five mice at each dose, from days 0 to 3, in two
divided doses daily. The drug dilutions were prepared in groundnut oil so as to
contain the required amount of the drug (1.2 mg for a dose of 96 mg/kg,) in
0.1 mL and administered either orally or intramuscularly for each dose.
Parasitaemia level were recorded from thin blood smears between day 4 and
28. Mice treated with b-arteether served as positive controls.;
(b) 100% suppression of parasitaemia means no parasites were detected in 50 oil
immersion microscopic fields (parasites if at all present are below the detection
limit). The parasites present below the detection limit can multiply and
eventually can be detected during observation on subsequent days. In such
cases though the drug is providing near 100% suppression of the parasitaemia on
day 4 but will not provide full protection to the treated mice in the 28 days
survival assay.