6-(4′-Aryloxy-phenyl)vinyl-1,2,4-trioxanes: A new series of orally active peroxides effective against multidrug-resistant Plasmodium yoelii in Swiss mice

Article abstract of DOI:10.1016/j.bmcl.2010.06.045

A new series of 6-(4′-aryloxy-phenyl)vinyl-1,2,4-trioxanes 10a-d, 11a-d, and 12a-d have been synthesized and evaluated for their antimalarial activity against multidrug-resistant Plasmodium yoelii in Swiss mice by oral route. Trioxanes 10b and 10c, the tw

Full text of DOI:10.1016/j.bmcl.2010.06.045

Bioorganic & Medicinal Chemistry Letters 20 (2010) 4459–4463
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
6-(40-Aryloxy-phenyl)vinyl-1,2,4-trioxanes: A new series of orally active
peroxides effective against multidrug-resistant Plasmodium yoelii
in Swiss mice q
a
a
a
Chandan Singh a, , Ved Prakash Verma , Niraj Krishna Naikade , Ajit Shankar Singh ,
*
Mohammad Hassam a, Sunil. K. Puri b
a Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226 001, India
b Division of Parasitology, Central Drug Research Institute, Lucknow 226 001, India
a r t i c l e i n f o
a b s t r a c t
A new series of 6-(40-aryloxy-phenyl)vinyl-1,2,4-trioxanes 10a–d, 11a–d, and 12a–d have been synthe-
sized and evaluated for their antimalarial activity against multidrug-resistant Plasmodium yoelii in Swiss
mice by oral route. Trioxanes 10b and 10c, the two most active compounds of the series, provided 100%
protection to the infected mice at 48 mg/kg ꢀ 4 days. Clinically useful drug b-arteether provided 100%
and 20% protection at 48 mg/kg ꢀ 4 days and 24 mg/kg ꢀ 4 days, respectively, in this model.
Ó 2010 Elsevier Ltd. All rights reserved.
Article history:
Received 28 January 2010
Revised 26 May 2010
Accepted 8 June 2010
Available online 12 June 2010
Keywords:
Malaria
Multidrug-resistant
Arteether
1,2,4-Trioxanes
Artemisinin 1, the active principle of Artemisia annua and its
semi-synthetic derivatives, for example, artemether 2, arteether 3
and artesunic acid 4 are the only class of antimalarials which are
effective against multidrug-resistant malaria2,3 (Fig. 1).
Ever since the establishment of the peroxide group present in
the form of 1,2,4-trioxane in artemisinin as the active pharmaco-
phore, considerable efforts have been diverted towards synthesis
of structurally simple synthetic trioxanes. Several synthetic 1,2,4-
trioxanes originating from different laboratories, have shown
promising antimalarial activity both in vitro and in vivo.4 In spite
of this, the search for structurally simpler, cheaper and more effec-
tive synthetic trioxanes remains an area of hot pursuit.
Earlier we had reported a photooxygenation route for the prep-
aration of 1,2,4-trioxanes (Scheme 1).5 Several of the trioxanes pre-
pared by this method had shown promising antimalarial activity.6
Very recently we have extended this methodology for the syn-
thesis of bis- and tris-trioxanes.7 In continuation with these efforts,
herein we report, the synthesis and antimalarial assessment of a
new series of 6-(40-aryloxy-phenyl)vinyl-1,2,4-trioxanes 10a–d,
11a–d, and 12a–d, two of which (10b and 10c) have shown anti-
malarial activity comparable to that of b-arteether by oral route.
Allylic alcohols 8a–d, prepared from p-fluoroacetophenone in
three steps, were photooxygenated to give b-hydroxyhydroperox-
ides 9a–d. In situ acid-catalyzed condensation of b-hydroxyhydr-
operoxides 9a–d with cyclopentanone furnished 1,2,4-trioxanes
10a–d in 48–59% yields (Scheme 2). Similar acid-catalyzed con-
H
H
H
O
O
O
O
O
O
O
O
O
H
H
H
O
O
O
O
O
O
OR
OH
1
2
3
R = Me
R = Et
4
O
Figure 1. Artemisinin and its derivatives.
R1
R2
1
2
O
OH
O OH
OH
/ H+
O O R1
1O2
3
6
Ar
Ar
Ar
O R2
q
5
4
See Ref. 1.
* Corresponding author. Tel.: +91 522 2624273; fax: +91 522 2623405.
E-mail address: chandancdri@yahoo.com (C. Singh).
Scheme 1.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.06.045

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C. Singh et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4459–4463
Table 1
In vivo antimalarial activity of trioxanes 10a–d, 11a–d and 12a–d against multidrug-resistant P. yoelii in Swiss mice by oral route
Compound
Structure
Log Pb
Dose (mg/kg ꢀ 4 days)
% Suppression of parasitaemia on day 4a
Cured/treated
3/5
O
O
O
10a
5.14
96
100
O
O
96
48
24
100
100
100
5/5
5/5
0/5
O
O
6.13
6.13
10b
10c
O
96
48
24
100
100
100
5/5
5/5
0/5
O
O
O
O
O
96
48
100
100
5/5
0/5
O
O
6.81
10d
O
O
O
O
11a
11b
5.55
6.55
96
96
100
100
3/5
2/5
O
O
O
O
O
O
O
O
11c
6.55
96
92.81
0/5
O
O
O
O
11d
12a
12b
7.23
6.19
7.19
96
96
96
84.39
0/5
4/5
3/5
O
O
O
O
100
O
O
O
O
100
O
O
O
O
12c
12d
7.19
7.86
96
96
93.15
0/5
4/5
O
O
O
O
100
O
H
O
O
O
48
24
100
100
5/5
1/5
3
3.84
H
O
OEt
a
Percent suppression = [(CꢁT)/C] ꢀ 100, where C is parasitaemia in control group and T is parasitaemia in treated group.
Log P values have been calculated from Chemdraw ultra 7.0.
b

C. Singh et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4459–4463
4461
O
O
O
O
O
O
Ar
O
Ar
O
Ar
O
O
O
O
12a-d
11a-d
10a-d
Figure 2. Trioxanes 10a–d, 11a–d, and 12a–d.
O
O
OH
OEt
O
c
b
a
+
5a-d
O
O
O
Ar
Ar
F
Ar
7a-d
8a-d
6a-d
d
OH
OH
OH
OH
OH
OH
O
O
9a-d
Ar
5c
5d
5a
5b
e
O
O
O
(a)
(b)
(c)
(d)
O
Ar =
,
,
,
Ar
10a-d
Scheme 2. Reagents and conditions: (a) K2CO3/DMSO, reflux, 2–4 h; (b) (OEt)2P(O)CH2CO2Et/NaH, THF, rt, 6–18 h; (c) LiAlH4/THF, 0 °C, 1 h; (d) 1O2/CH3CN, ꢁ10 to 0 °C, 4–
12 h; (e) cyclopentanone/CH3CN, concd HCl, rt, 1 h.
densation of the hydroperoxides 9a–d with cyclohexanone and 2-
adamantanone at room temperature furnished 1,2,4-trioxanes
11a–d, and 12a–d (Fig. 2) in 45–64% and 49–70% yields,
respectively.8
Trioxanes 10a–d, 11a–d, and 12a–d were evaluated for their
antimalarial activity at 96 mg/kg ꢀ 4 days against multidrug-resis-
tant Plasmodium yoelii in mice by oral route.9,10 Trioxanes 10b, 10c,
and 10d which showed 100% protection at this dose were further
screened at 48 mg/kg ꢀ 4 days. Trioxanes 10b and 10c which
showed 100% protection at 48 mg/kg ꢀ 4 days, were further tested
at 24 mg/kg ꢀ 4 days. b-Arteether was used as a positive control.
The results are summarized in Table 1.
Acknowledgments
V.P.V., N.N., A.S.S., and M.H. are thankful to the Council of Scien-
tific and Industrial Research (CSIR) and University of Grants Com-
mission (UGC), New Delhi for the award of Senior Research
Fellowship.
References and notes
1. CDRI Communication No. 7544.
2. For reviews on artemisinin and its analogues see: (a) Klayman, D. L. Science
1985, 228, 1049; (b) Luo, X. D.; Shen, C. C. Med. Res. Rev. 1987, 7, 29; (c)
Cumming, J. N.; Ploypradith, P.; Posner, G. H. Adv. Pharmacol. 1997, 37, 253; (d)
Bhattacharya, A. K.; Sharma, R. P. Heterocycles 1999, 51, 1681; (e) Borstnik, K.;
Paik, I.; Shapiro, T. A.; Posner, G. H. Int. J. Parasitol. 2002, 32, 1661; (f)
Ploypradith, P. Acta Trop. 2004, 89, 329; (g) O’Neill, P. M.; Posner, G. H. J. Med.
Chem. 2004, 47, 2945; (h) Tang, Y.; Dong, Y.; Vennerstrom, J. L. Med. Res. Rev.
2004, 24, 425; (i) Jefford, C. W. Curr. Opin. Investig. Drugs 2004, 5, 866; (j)
O’Neill, P. M; Chadwick, J.; Rawe, S. L. In Chemistry of Peroxides; Wiley:
Chichester, 2006; Vol. 2. pp. 1279–1346.
3. (a) Asthana, O. P.; Srivastava, J. S.; Valecha, N. J. Parasitic Dis. 1997, 211, 1; (b)
WHO: Facts on ACTs (Artemisinin-based Combination Therapies), http://
www.rbm.who.int/cmc.; (c) Posner, G. H.; Paik, I.-H.; Chang, W.; Borstnik, K.;
Sinishtaj, S.; Rosenthal, A. S.; Shapiro, T. A. J. Med. Chem. 2007, 50, 2516.
4. (a) Kepler, J. A.; Philip, A.; Lee, Y. W.; Matthew, C.; Morey, M. C.; Ivy, F.; Carroll,
F. I. J. Med. Chem. 1988, 31, 713; (b) Peters, W.; Robinson, B. L.; Tovey, G.;
Rossier, J. C.; Jefford, C. W. Ann. Trop. Med. Parasitol. 1993, 87, 1; (c) Peters, W.;
Robinson, B. L.; Rossier, J. C.; Jefford, C. W. Ann. Trop. Med. Parasitol. 1993, 87, 9;
(d) Peters, W.; Robinson, B. L.; Tovey, G.; Rossier, J. C.; Jefford, C. W. Ann. Trop.
Med. Parasitol. 1993, 87, 111; (e) Posner, G. H.; Maxwell, J. P.; O’Dowd, H.;
Krasavin, M.; Xie, S.; Shapiro, T. A. Bioorg. Med. Chem. 2000, 8, 1361; (f) Posner,
G. H.; Jeon, H. B.; Parker, M. H.; Krasavin, M.; Paik, I.-H.; Shapiro, T. A. J. Med.
Chem. 2001, 44, 3054; (g) Posner, G. H.; Jeon, H. B.; Polypradith, P.; Paik, I.-H.;
Borstnik, K.; Xie, S.; Shapiro, T. A. J. Med. Chem. 2002, 45, 3824; (h) Griesbeck, A.
G.; El-Idreesy, T. T.; Fiege, M.; Brun, R. Org. Lett. 2002, 24, 4193; (i) O’Neill, P. M.;
As can be seen from Table 1, all the cyclopentane-based triox-
anes 10a–d showed promising activity. Trioxanes 10b and 10c,
the two most active compounds of the series, provided 100% pro-
tection at 48 mg/kg ꢀ 4 days by oral route. Even at 24 mg/
kg ꢀ 4 days both these compounds showed 100% suppression of
parasitaemia on day 4, though none of the treated mice survived
till day 28. Thus, the activity profile of both these compounds is
comparable with that of arteether. Cyclohexane-based trioxanes
11a–d showed moderate activity; only 11a and 11b provided sig-
nificant protection at 96 mg/kg ꢀ 4 days. Among the adaman-
tane-based compounds, trioxanes 12a and 12d were the most
active compounds. Both of these provided 80% protection at
96 mg/kg ꢀ 4 days by oral route.
In conclusion we have prepared a new series of 1,2,4-trioxanes.
Cyclopentane-based trioxanes 10b and 10c, the two most active
compounds of the series, showed activity profile comparable to
that of b-arteether.

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C. Singh et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4459–4463
Mukhtar, A.; Ward, S. A.; Bickley, J. F.; Davies, J.; Bachi, M. D.; Stocks, P. A. Org.
114.97 (CH), 116.23 (CH2), 119.27 (CH), 120.46 (CH), 125.30 (CH), 127.04 (CH),
127.60 (CH), 128.20 (CH), 128.33 (CH), 130.41 (CH), 130.76 (C), 134.19 (C),
134.75 (C), 143.16 (C), 155.05 (C), 157.79 (C); FAB-MS (m/z) 403 [M+H]+; HRMS
calcd for C26H26O4 402.1831; found, 402.1828. 3-{1-[4-(Naphthalen-1-yloxy)-
phenyl]-vinyl}-1,2,5-trioxa-spiro[5.5]undecane (11c). This was obtained in 58%
yield as oil; IR (neat, cmꢁ1) 1598; 1H NMR (200 MHz, CDCl3) d 1.39–1.65 (m,
8H), 1.96–2.08 (m, 1H), 2.18–2.35 (m, 1H), 3.79 (dd, 1H, J = 11.9 and 2.9 Hz),
4.01 (dd, 1H, J = 11.9 and 10.3 Hz), 5.21–5.30 (m, 2H), 5.48 (s, 1H), 7.01 (d, 3H,
Ar, J = 8.7 Hz), 7.34–7.55 (m, 5H, Ar), 7.66 (d, 1H, Ar, J = 8.1 Hz), 7.89 (dd, 1H, Ar,
J = 5.4 and 1.6 Hz), 8.17 (dd, 1H, Ar, J = 6.9 and 2.8 Hz); 13C NMR (50 MHz,
CDCl3) d 22.74 (CH2), 22.79 (CH2), 25.99 (CH2), 29.46 (CH2), 35.10 (CH2), 63.11
(CH2), 80.72 (CH), 103.06 (C), 114.50 (CH), 116.09 (CH2), 118.66 (CH), 122.47
(CH), 124.22 (CH), 126.23 (CH), 126.5 (CH), 127.09 (CH), 127.36 (C), 128.26
(CH), 128.32 (CH), 133.9 (C), 135.42 (C), 143.19 (C), 153.0 (C), 158.55 (C); FAB-
MS (m/z) 403 [M+H]+; HRMS calcd for C26H26O4 402.1831; found, 402.1830. 3-
Lett. 2004, 18, 3035; (j) Griesbeck, A. G.; EI-Idreesy, T. T.; Lex, J. Tetrahedron
2006, 62, 10615; (k) Posner, G. H.; Chang, W.; Hess, L.; Woodard, L.; Sinishtaj,
S.; Usera, A. R.; Maio, W.; Rosenthal, A. S.; Kalinda, A. S.; Angelo, J. G. D.;
Petersen, K. S.; Stohler, R.; Chollet, J.; Santo-Tomas, J.; Snyder, C.; Rottmann, M.;
Wittlin, S.; Burn, R.; Shapiro, T. A. J. Med. Chem. 2008, 51, 1035; (l) Griesbeck, A.
G.; Neudorfl, J.; Horauf, A.; Specht, S.; Raabe, A. J. Med. Chem. 2009, 52, 3420.
5. Singh, C. Tetrahedron Lett. 1990, 31, 6901.
6. (a) Singh, C.; Misra, D.; Saxena, G.; Chandra, S. Bioorg. Med. Chem. Lett. 1992, 2,
497; (b) Singh, C.; Misra, D.; Saxena, G.; Chandra, S. Bioorg. Med. Chem. Lett.
1995, 5, 1913; (c) Singh, C.; Gupta, N.; Puri, S. K. Bioorg. Med. Chem. Lett. 2003,
13, 3447; (d) Singh, C.; Malik, H.; Puri, S. K. Bioorg. Med. Chem. 2004, 12, 1177;
(e) Singh, C.; Gupta, N.; Puri, S. K. Bioorg. Med. Chem. 2004, 12, 5553; (f) Singh,
C.; Srivastav, N. C.; Puri, S. K. Bioorg. Med. Chem. 2004, 12, 5745; (g) Singh, C.;
Malik, H.; Puri, S. K. Bioorg. Med. Chem. Lett. 2004, 14, 459; (h) Singh, C.; Malik,
H.; Puri, S. K. Bioorg. Med. Chem. Lett. 2005, 15, 4484; (i) Singh, C.; Malik, H.;
Puri, S. K. J. Med. Chem. 2006, 49, 2794; (j) Singh, C.; Kanchan, R.; Srivastava, D.;
Puri, S. K. Bioorg. Med. Chem. Lett. 2006, 16, 584; (k) Singh, C.; Kanchan, R.;
Sharma, U.; Puri, S. K. J. Med. Chem. 2007, 50, 521.
{1-[4-(Biphenyl-4-yloxy)-phenyl]-vinyl}-1,2,5-trioxa-spiro[5.5]undecane
(11d).
This was obtained in 64% yield as white solid, mp 54–56 °C; IR (KBr, cmꢁ1
)
1594; 1H NMR (300 MHz, CDCl3) d 1.49–1.67 (m, 8H), 2.0–2.09 (m, 1H), 2.21–
2.30 (m, 1H), 3.81 (dd, 1H, J = 11.9 and 2.9 Hz), 4.02 (dd, 1H, J = 11.9 and
10.5 Hz), 5.26 (dd, 1H, J = 10.4 and 2.8 Hz), 5.33 and 5.51 (2ꢀ s, 2H), 7.05 (d, 2H,
Ar, J = 8.7 Hz), 7.11 (d, 2H, Ar, J = 8.7 Hz), 7.33–7.48 (m, 5H, Ar), 7.60 (dd, 4H, Ar,
J = 9 and 2.1 Hz); 13C NMR (75 MHz, CDCl3) d 22.51 (CH2), 22.55 (CH2), 25.76
(CH2), 29.25 (CH2), 34.86 (CH2), 65.85 (CH2), 80.5 (CH), 102.83 (C), 115.96
(CH2), 118.93 (CH), 119.51 (CH), 127.12 (CH), 127.3 (CH), 128.09 (CH), 128.69
(CH), 129 (CH), 133.93 (C), 136.85 (C), 140.68 (C), 142.98 (C), 156.61 (C), 157.53
(C); ESI (m/z) 428 [M+H]+; HRMS calcd for C28H28O4 428.1988; found,
428.1990. Trioxane (12a). This was obtained in 49% yield as white solid, mp
53–56 °C; IR (KBr, cmꢁ1) 1591; 1H NMR (200 MHz, CDCl3) d 1.59–2.10 (m, 13H),
2.96 (s, 1H), 3.78 (dd, 1H, J = 12 and 3.3 Hz), 3.98 (dd, 1H, J = 11.8 and 10.5 Hz),
5.22–5.28 (m, 2H), 5.48 (s, 1H), 6.95–7.16 (m, 5H, Ar), 7.31–7.39 (m, 4H, Ar);
13C NMR (50 MHz, CDCl3) d 27.59 (2ꢀ CH), 29.83 (CH), 33.44 (CH2), 33.68 (CH2),
33.91 (CH2), 34.01 (CH2), 36.67 (CH), 37.63 (CH2), 62.57 (CH2), 80.53 (CH),
105.08 (C), 116.03 (CH2), 119.03 (CH), 119.57 (CH), 123.99 (CH), 128.23 (CH),
130.24 (CH), 13403 (C), 143.20 (C), 157.26 (C), 157.85 (C); FAB-MS (m/z) 405
[M+H]+; HRMS. calcd for C26H28O4: 404.1988, found: 404.1967. Trioxane (12b).
7. Singh, C.; Verma, V. P.; Naikade, N. K.; Singh, A. S.; Hassam, M.; Puri, S. K. J. Med.
Chem. 2008, 51, 7581.
8. (a) General procedure for the preparation of 6-(40-aryloxy-phenyl)vinyl-1,2,4-
trioxanes 10a–d, 11a–d, and 12a–d: (compound 10a is taken as
a
representative example). A solution of 3-(4-phenoxy-phenyl)-but-2-en-1-ol
8a (1 g, 4.16 mmol) and methylene blue (10 mg) in CH3CN (100 mL) was
irradiated with 500 W tungsten-halogen lamp at ꢁ10 to 0 °C while oxygen gas
was bubbled slowly into the reaction mixture for 6 h. Cyclopentanone
(3.15 mL, 37.5 mmol, 9 equiv) and HCl (0.1 mL) were added and the reaction
mixture was stirred at room temperature for 1 h. Usual workup followed by
column chromatography over silica gel furnished trioxane. 8-[1-(4-Phenoxy-
phenyl)-vinyl]-6,7,10-trioxa-spiro[4.5]decane (10a) (672 mg, 48% yield) as
a
white solid, mp 51–52 °C; IR (KBr, cmꢁ1) 1590; 1H NMR (200 MHz, CDCl3) d
1.66–1.98 (m, 7H), 2.47–2.59 (m, 1H), 3.86 (d, 2H, J = 6.2 Hz), 5.26–5.33 (m,
2H), 5.47 (s, 1H), 6.95–7.16 (m, 5H, Ar), 7.32–7.39 (m, 4H, Ar); 13C NMR
(50 MHz, CDCl3) d 23.80 (CH2), 25.21 (CH2), 33.21 (CH2), 37.46 (CH2), 65.47
(CH2), 80.73 (CH), 115.01 (C), 116.21 (CH2), 119.0 (CH), 124.03 (CH), 128.28
(CH), 130.26 (CH), 133.85 (C), 142.99 (C), 157.23 (C), 157.90 (C); FAB-MS (m/z)
339 [M+H]+; HRMS calcd for C21H22O4 338.1518; found, 338.1529. 8-{1-[4-
(Naphthalen-2-yloxy)-phenyl]-vinyl}6,7,10-trioxa-spiro[4.5]decane (10b). This
was obtained in 52% yield as white solid, mp 87–90 °C; IR (KBr, cmꢁ1) 1591;
1H NMR (200 MHz, CDCl3) d 1.67–1.99 (m, 7H), 2.48–2.60 (m, 1H), 3.88 (d, 2H,
J = 6.3 Hz), 5.28–5.34 (m, 2H), 5.50 (s, 1H), 7.04 (dd, 2H, Ar, J = 6.4 and 2.2 Hz),
7.24–7.28 (m, 1H, Ar), 7.35–7.52 (m, 5H, Ar), 7.73 (dd, 1H, Ar, J = 6.9 and
2.2 Hz), 7.84 (dd, 2H, Ar, J = 9.1 and 2.7 Hz); 13C NMR (50 MHz, CDCl3) d 23.83
(CH2), 25.27 (CH2), 33.26 (CH2), 37.48 (CH2), 65.43 (CH2), 80.68 (CH), 114.98
(C), 116.30 (CH2), 119.24 (CH), 120.49 (CH), 125.33 (CH), 127.05 (CH), 127.66
(CH), 128.23 (CH), 128.40 (CH), 130.40 (CH), 130.80 (C), 134.08 (C), 134.79 (C),
143.08 (C), 155.03 (C), 158.17 (C); FAB-MS (m/z) 389 [M+H]+; HRMS calcd for
This was obtained in 53% yield as white solid, mp 103–105 °C; IR (KBr, cmꢁ1
)
1593; 1H NMR (200 MHz, CDCl3) d 1.61–2.11 (m, 13H), 2.9 (s, 1H), 3.80 (dd, 1H,
J = 12 and 3 Hz), 4.0 (dd, 1H, J = 11.9 and 10.4 Hz), 5.24–5.30 (m, 2H), 5.50 (s,
1H), 7.03 (d, 2H, Ar, J = 8.6 Hz), 7.26 (dd, 1H, Ar, J = 8.9 and 2.6 Hz), 7.35–7.52
(m, 5H, Ar), 7.74 (dd, 1H, Ar, J = 9.6 and 1.9 Hz), 7.86 (dd, 2H, Ar, J = 9.1 and
2.6 Hz); 13C NMR (50 MHz, CDCl3) d 27.59 (2ꢀ CH), 29.83 (CH), 33.44 (CH2),
33.68 (CH2), 33.91 (CH2), 34.01 (CH2), 36.67 (CH), 37.63 (CH2), 62.57 (CH2),
80.54 (CH), 105.11 (C), 114.96 (CH), 116.17 (CH2), 119.27 (CH), 120.45 (CH),
125.29 (CH), 127.03 (CH), 127.60 (CH), 128.20 (CH), 128.30 (CH), 130.40 (CH),
130.74 (C), 134.25 (C), 134.74 (C), 143.17 (C), 155.05 (C), 157.76 (C); FAB-MS
(m/z) 455 [M+H]+; HRMS calcd for C30H30O4 454.2144; found, 454.2156.
Trioxane (12c). This was obtained in 49% yield as oil; IR (neat, cmꢁ1) 1593; 1H
NMR (200 MHz, CDCl3) d 1.58–2.11 (m, 13H), 2.97 (s, 1H), 3.81 (dd, 1H, J = 11.8
and 3 Hz), 4.0 (dd, 1H, J = 11.7 and 10.3 Hz), 5.24–5.29 (m, 2H), 5.49 (s, 1H),
7.01 (d, 3H, Ar, J = 8.6 Hz), 7.35–7.55 (m, 5H, Ar), 7.66 (d, 1H, Ar, J = 8.3 Hz), 7.90
(dd, 1H, Ar, J = 6 and 2.4 Hz), 8.15–8.20 (m, 1H, Ar); 13C NMR (50 MHz, CDCl3) d
27.35 (2ꢀ CH), 29.59 (CH), 33.19 (CH2), 33.44 (CH2), 33.67 (CH2), 33.77 (CH2),
36.43 (CH), 37.39 (CH2), 62.35 (CH2), 80.28 (CH), 104.84 (C), 114.23 (CH),
115.75 (CH2), 118.42 (CH), 122.23 (CH), 123.95 (CH), 125.98 (CH), 126.25 (CH),
126.84 (CH), 127.10 (CH), 128.03 (CH), 133.71 (C), 135.16 (C), 142.95 (C),
152.76 (C), 158.27 (C); FAB-MS (m/z) 455 [M+H]+; HRMS calcd for C30H30O4
454.2144; found, 454.2143. Trioxane (12d). This was obtained in 70% yield as
white solid, mp 122–125 °C; IR (KBr, cmꢁ1) 1592; 1H NMR (300 MHz, CDCl3) d
1.61–2.13 (m, 13H), 2.98 (s, 1H), 3.82 (dd, 1H, J = 11.9 and 3 Hz), 4.01 (dd, 1H,
J = 11.8 and 10.4 Hz), 5.28 (dd, 1H, J = 10.5 and 2.9 Hz), 5.32 and 5.51 (2ꢀ s, 2H),
7.05 (d, 2H, Ar, J = 8.8 Hz), 7.11 (d, 2H, Ar, J = 8.7 Hz), 7.33–7.49 (m, 5H, Ar), 7.60
(dd, 4H, Ar, J = 9 and 2.3 Hz); 13C NMR (75 MHz, CDCl3) d 27.39 (2ꢀ CH), 29.65
(CH), 33.23 (CH2), 33.47 (CH2), 33.7 (CH2), 33.80 (CH2), 36.46 (CH), 37.43 (CH2),
62.36 (CH2), 80.34 (CH), 104.89 (C), 115.91 (CH2), 118.96 (CH), 119.51 (CH),
127.14 (CH), 127.31 (CH), 128.08 (CH), 128.7 (CH), 129.01 (CH), 134.02 (C),
136.86 (C), 140.70 (C), 143.01 (C), 156.64 (C), 157.52 (C); FAB-MS (m/z) 481
[M+H]+; HRMS calcd for C32H32O4 480.2301; found, 480.2250. (b) The
compounds reported in this communication are stable at room temperature;
the stability studies at higher temperature have not been done.
C25H24O4 388.1675; found, 388.1674. 8-{1-[4-(Naphthalen-1-yloxy)-phenyl]-
vinyl}-6,7,10-trioxa-spiro[4.5]decane (10c). This was obtained in 57% yield as
oil; IR (neat, cmꢁ1) 1599; 1H NMR (200 MHz, CDCl3) d 1.71–1.99 (m, 7H), 2.48–
2.60 (m, 1H), 3.88 (d, 2H, J = 6.2 Hz), 5.29–5.34 (m, 2H), 5.48 (s, 1H), 6.99–7.03
(m, 3H, Ar), 7.36–7.57 (m, 5H, Ar), 7.66 (d, 1H, Ar, J = 8.3 Hz), 7.90 (dd, 1H, Ar,
J = 6.4 and 2.7 Hz), 8.17 (dd, 1H, Ar, J = 6.9 and 2.7 Hz); 13C NMR (50 MHz,
CDCl3) d 23.81 (CH2), 25.22 (CH2), 33.24 (CH2), 37.48 (CH2), 65.5 (CH2), 80.74
(CH), 114.55 (CH), 115.02 (C), 116.20 (CH2), 118.63 (CH), 122.47 (CH), 124.24
(CH), 126.23 (CH), 126.51 (CH), 127.10 (CH), 128.28 (CH), 128.34 (CH), 133.78
(C), 135.43 (C), 142.99 (C), 152.97 (C), 158.58 (C); FAB-MS (m/z) 389 [M+H]+;
HRMS calcd for
C25H24O4 388.1674; found, 388.1672. 8-{1-[4-(Biphenyl-4-
yloxy)-phenyl]-vinyl}-6,7,10-trioxa-spiro[4.5]decane (10d). This was obtained in
59% yield as oil; IR (KBr, cmꢁ1) 1598; 1H NMR (300 MHz, CDCl3) d 1.75–2.02 (m,
7H), 2.54–2.63 (m, 1H), 3.93 (d, 2H, J = 6.4 Hz), 5.35–5.38 (m, 2H), 5.53 (s, 1H),
7.08 (d, 2H, Ar, J = 8.7 Hz), 7.15 (d, 2H, Ar, J = 8.6 Hz), 7.35–7.51 (m, 5H, Ar), 7.63
(dd, 4H, Ar, J = 8.6 and 2.2 Hz); 13C NMR (75 MHz, CDCl3) d 23.5 (CH2), 24.9
(CH2), 32.94 (CH2), 37.15 (CH2), 65.12 (CH2), 80.4 (CH), 114.68 (C), 115.96
(CH2), 118.82 (CH), 119.47 (CH), 127.02 (CH), 127.23 (CH), 128.62 (CH), 128.6
(CH), 128.93 (CH), 133.71 (C), 136.75 (C), 140.55 (C), 142.58 (C), 156.5 (C),
157.48 (C); ESI (m/z) 415 [M+H]+; HRMS calcd for C27H26O4 414.1831; found,
414.1834. 3-[1-(4-Phenoxy-phenyl)-vinyl]-1,2,5-trioxa-spiro[5.5]undecane (11a).
This was obtained in 46% yield as white solid, mp 54–55 °C; IR (KBr, cmꢁ1
)
9. (a) Peters, W. Techniques for the study of drug response in experimental
malaria. In Chemotherapy and drug resistance in malaria; Academic Press:
London, 1970; pp. 64–136. (b) In vivo test procedure: The colony bred Swiss
mice (25 1 g) were inoculated with 1 ꢀ 106 parasitized RBC on day zero and
treatment was administered to a group of five mice at each dose, from day 0 to
3, in two divided doses daily. The drug dilutions of compounds 10a–d, 11a–d,
and 12a–d 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, 0.6 mg for a dose of 48 mg/
kg and 0.3 mg for a dose of 24 mg/kg) in 0.1 ml and administered orally for
each dose. Parasitaemia levels were recorded from thin blood smears between
days 4 and 28. The animals which did not develop patent infection till day 28
were recorded as cured.11 Mice treated with b-arteether served as positive
control. Multidrug-resistant Plasmodium yoelii nigeriensis used in this study is
resistant to chloroquine, mefloquine and halofantrine.
1590; 1H NMR (200 MHz, CDCl3) d 1.38–1.63 (m, 8H), 1.95–2.08 (m, 1H), 2.17–
2.29 (m, 1H), 3.78 (dd, 1H, J = 11.8 and 3.3 Hz), 3.99 (dd, 1H, J = 11.9 and
10.2 Hz), 5.23 (dd, 1H, J = 10.6 and 3.5 Hz), 5.29 and 5.48 (2 ꢀ s, 2H), 6.95–7.16
(m, 5H, Ar), 7.32–7.39 (m, 4H, Ar); 13C NMR (50 MHz, CDCl3) d 22.73 (CH2),
22.76 (CH2), 25.97 (CH2), 29.44 (CH2), 35.08 (CH2), 63.09 (CH2), 80.70 (CH),
103.04 (C), 116.12 (CH2), 119.02 (CH), 119.58 (CH), 123.99 (CH), 128.25 (CH),
130.24 (CH), 133.96 (CH), 143.16 (C), 157.24 (C), 157.86 (C); FAB-MS (m/z) 353
[M+H]+; HRMS calcd for C22H24O4 352.1675; found, 352.1677. 3-{1-[4-
(Naphthalen-2-yloxy)-phenyl]-vinyl}-1,2,5-trioxa-spiro[5.5]undecane (11b). This
was obtained in 45% yield as white solid, mp 108–110 °C; IR (KBr, cmꢁ1) 1596;
1H NMR (200 MHz, CDCl3) d 1.45–1.65 (m, 8H), 1.97–2.10 (m, 1H), 2.18-2.32
(m, 1H), 3.80 (dd, 1H, J = 11.9 and 3 Hz), 4.02 (dd, 1H, J = 11.9 and 10.3 Hz),
5.23–5.31 (m, 2H), 5.51 (s, 1H), 7.0–7.08 (m, 2H, Ar), 7.27 (dd, 1H, Ar, J = 8.8 and
2.4 Hz), 7.35–7.52 (m, 5H, Ar), 7.73 (dd, 1H, Ar, J = 6.6 and 2.0 Hz), 7.85 (dd, 2H,
Ar, J = 9.3 and 2.3 Hz); 13C NMR (50 MHz, CDCl3) d 22.74 (CH2), 22.79 (CH2),
25.99 (CH2), 29.46 (CH2), 35.09 (CH2), 63.09 (CH2), 80.70 (CH), 103.07 (C),
10. (a) One hundred percent protection means none of the treated mice developed
patent infection during the 28 days observation period and hence recorded as
cured. Similarly, 20% protection means only one out of five mice was cured. (b)

C. Singh et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4459–4463
4463
One hundred percent 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 day survival assay.
11. Puri, S. K.; Singh, N. Expl. Parasitol. 2000, 94, 8.