Synthesis of novel 1,2,4-trioxanes and antimalarial evaluation against multidrug-resistant Plasmodium yoelii nigeriensis

Article abstract of DOI:10.1016/j.bmcl.2021.128305

Malaria epidemics represent one of the life-threatening diseases to low-income lying countries which subsequently affect the economic and social condition of mankind. In continuation in the development of a novel series of 1,2,4-trioxanes 13a1-c1, 13a2-c2, and 13a3-c3 have been prepared and further converted into their hemisuccinate derivatives 14a1-c1, 14a2-c2, and 14a3-c3 respectively. All these new compounds were evaluated for their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in mice by both oral and intramuscular (im) routes. Hydroxy-functionalized trioxane 13a1 showed 80% protection and its hemisuccinate derivative 14a1 showed 100% protection at a dose of 48 mg/kg × 4 days by both routes, which is twice active than artemisinin by oral route.

Full text of DOI:10.1016/j.bmcl.2021.128305

Bioorg. Med. Chem. Lett. 49 (2021) 128305
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of novel 1,2,4-trioxanes and antimalarial evaluation against
multidrug-resistant Plasmodium yoelii nigeriensis
,
Monika Shuklab, Mohammad Hassama *, Dinesh Kumar Yadavc, Siddharth Sharmac,
,b,*
Chandan Singha, Sunil K. Purid, Rahul Shrivastavae, Ved Prakash Vermaa
a Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India
b Department of Chemistry, Banasthali University, Banasthali Newai 304022, Rajasthan, India
c Department of Chemistry, Mohanlal Sukhadia University, Udaipur 313001, India
d Parasitology Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India
e Department of Chemistry, Manipal University Jaipur, VPO-DehmiKalan, off Jaipur-Ajmer Express Way, Jaipur, Rajasthan, India
A R T I C L E I N F O
A B S T R A C T
Keywords:
Malaria epidemics represent one of the life-threatening diseases to low-income lying countries which subse-
quently affect the economic and social condition of mankind. In continuation in the development of a novel
series of 1,2,4-trioxanes 13a1-c1, 13a2-c2, and 13a3-c3 have been prepared and further converted into their
hemisuccinate derivatives 14a1-c1, 14a2-c2, and 14a3-c3 respectively. All these new compounds were evalu-
ated for their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in mice by both oral
and intramuscular (im) routes. Hydroxy-functionalized trioxane 13a1 showed 80% protection and its hemi-
succinate derivative 14a1 showed 100% protection at a dose of 48 mg/kg × 4 days by both routes, which is twice
active than artemisinin by oral route.
Photooxygenation
β-Hydroxyhydroperoxide
1,2,4-Trioxane
Antimalarial activity
Multidrug-resistant
Malaria is one of the major diseases that cause higher mortality
among the low-income tropical and sub-tropical areas of the world.
Despite comprehensive global efforts for the eradication of malaria,
about 40% of the world population still is at risk of the disease. Of these
2.5 billion people at risk, more than 500 million become ill and more
than a million, mostly children, die of malaria every year.1 The rapid
emergence of multidrug-resistant P. falciparum has been further
complicated the problem against commonly used antimalarial drugs.2–4
Artemisinin 1, and its semi-synthetic analogs are currently the drugs of
choice for the treatment of malaria caused by multidrug-resistant
P. falciparum.5–9 The lesser abundance from natural resources has
made the artemisinin circumscribed used for the synthesis of semi-
synthetic analogs.10 The discovery of peroxide group present in the
form of 1,2,4-trioxane in artemisinin as an active pharmacophore for its
antimalarial activity, has encouraged the scientist to develop simple,
economical, and effective substitute having 1,2,4-trioxane units.11 Since
then, numerous simple molecules containing 1,2,4-trioxanes have been
synthesized and evaluated antimalarial activity by the different group
including us.12–19
antimalarial activity of hydroxy-functionalized trioxanes and their
hemisuccinates derivatives, hemisuccinate 14a1 has shown a better
antimalarial profile than artemisinin by both oral and im routes. A
graphical representation of the evolution of our work on trioxanes
resulting in the current series of molecules is shown in Fig 1.20–22
Hydroxy-functionalized trioxanes 13a1–c1, 13a2–c2, and 13a3–c3,
and their corresponding hemisuccinate derivatives 14a1–c1, 14a2–c2,
and 14a3–c3 were prepared by the procedure shown in Scheme 1. Thus,
the reaction of p-fluoroacetophenone 6 with 2,7-dihydroxynaphthalene
7a in refluxing in DMSO furnished ketone 8a in 41% yield. A similar
reaction of p-fluoroacetophenone 6 with 1,5-dihydroxynaphthalene 7b
and quinol 7c, furnished ketones 8b and 8c in 32% and 31% yields,
respectively. Compounds 8a–c on reaction with ethyl chloroacetate
furnished ketoesters 9a–c in 86–93% yields. Wittig reaction of com-
pounds 9a–c with triethyl phosphonoacetate/NaH furnished
α
,β-unsaturated esters 10a–c in 75–92% yields. Reduction of
,β-unsaturated esters 10a–c with LiAlH4 furnished allylic alcohols
α
11a–c in 75–86% yields. Dye-sensitized photooxygenation23 of allylic
alcohols 11a–c furnished β-hydroxyhydroperoxides 12a–c, which were
reacted in situ with cyclopentanone, cyclohexanone and, 2-
In continuation with these efforts herein, we report the synthesis and
* Corresponding authors at: Department of Chemistry, Banasthali University, Banasthali Newai 304022, Rajasthan, India (V.P. Verma).
E-mail addresses: hassam2@gmail.com (M. Hassam), vedprakash@banasthali.in (V. Prakash Verma).
https://doi.org/10.1016/j.bmcl.2021.128305
Received 16 June 2021; Received in revised form 28 July 2021; Accepted 30 July 2021
Available online 6 August 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.

M. Shukla et al.
Bioorganic & Medicinal Chemistry Letters 49 (2021) 128305
Fig. 1. Graphical depiction of the evolution of our work on trioxanes leading to the current series of hydroxy-functionalized 1,2,4-trioxanes and hemisuccinate.
Scheme 1. The synthesis of compounds 13a1-c1, 13a2-c2, 13a3-c3 and 14a1–c1, 14a2–c2, 14a3–c3; Reaction conditions: (i) Anhyd. K2CO3/DMSO, reflux, 4 h; (ii)
Anhyd. K2CO3/ClCH2COEt, Acetone, reflux, 8 h; (iii) (OEt)2P(O)CH2CO2Et/NaH, THF, rt., 16–21 h; (iv) LAH/THF, 0 ◦C, 1 h; (v) 1O2/CH3CN, THF, ꢀ 10 to 0 ◦C, 6–8 h;
(vi) Cyclopentanone, cyclohexanone and 2-adamantanone/CH3CN, conc. HCl, rt, 1 h. (vii) Succinic anhydride, Et3N, DMAP, CH2Cl2, rt., 3 h.
adamantanone to furnish trioxanes 13a1–c1, 13a2–c2 and 13a3–c3 in
48–69% yields (Scheme 1). These hydroxy-functionalized trioxanes
were converted into hemisuccinate derivatives 14a1–c1, 14a2–c2 and
14a3–c3 by treating with triethylamine and succinic anhydride at room
temperature.24
initially at a dose of 48 mg/kg × 4 days by both oral and intramuscular
(im) antimalarial activity.25–27 Trioxanes 13c1, 13c2, 13c3, hemi-
succinates 14c1, 14c2 and 14c3 were screened at 96 mg/kg. Trioxane
13a1, the most active compound of the series, showed 100% clearance
of parasitaemia by both oral and im routes at 48 mg/kg × 4 days and
80% of the treated mice survived beyond day 28. Trioxane 13b3, the
next best compound of the series, showed 100% clearance of para-
sitaemia by oral route at 48 mg/kg × 4 days and 40% of the treated mice
Trioxanes 13a1, 13b1, 13a2, 13b2, 13a3, 3b3 and hemisuccinates
14a1, 14b1, 14a2, 14b2, 14a3, 14b3 (Table 1), were screened for
antimalarial activity against multidrug-resistant P. yoelii in Swiss mice
2

M. Shukla et al.
Bioorganic & Medicinal Chemistry Letters 49 (2021) 128305
Table 1
Blood schizontocidal activity of hydroxy-functionalized trioxanes 13a1-c1, 13a2-c2, 13a3-c3 and hemisuccinates 14a1-c1, 14a2-c2, and 14a3-c3, against multidrug-
resistant P. yoelii in Swiss mice via oral and im routes.
Compd.
Structure
Log P
Dose Mg/kg × 4 days
Route
% supp. on day-4a,b
Cured/Treated mice
13a1
5.49
48
48
oral
im
100
100
4/5
4/5
13b1
5.49
48
48
oral
im
44.12
46.18
0/5
0/5
13c1
13a2
13b2
4.49
5.91
5.91
96
96
oral
im
38.40
85.23
0/5
0/5
48
48
oral
im
83.49
71.60
0/5
0/5
48
48
oral
im
38.24
46.18
0/5
0/5
13c2
13a3
13b3
4.91
6.54
6.54
96
96
oral
im
45.36
72.42
0/5
0/5
48
48
oral
im
83.17
51.39
0/5
0/5
48
48
oral
im
100
2/5
0/5
46.18
13c3
14a1
5.55
5.39
96
48
96
oral
oral
im
100
5/5
0/5
0/5
85.47
100
48
24
48
24
oral
oral
im
100
100
100
100
5/5
0/5
5/5
4/5
im
14b1
5.39
48
48
oral
im
39.41
28.32
0/5
0/5
14c1
14a2
4.39
5.81
96
96
oral
im
44.34
77.76
0/5
0/5
48
48
oral
im
100
100
1/5
3/5
14b2
5.81
48
48
oral
im
49.77
26.57
0/5
0/5
(continued on next page)
3

M. Shukla et al.
Bioorganic & Medicinal Chemistry Letters 49 (2021) 128305
Table 1 (continued)
Compd.
Structure
Log P
Dose Mg/kg × 4 days
Route
% supp. on day-4a,b
Cured/Treated mice
14c2
14a3
4.81
6.44
96
96
oral
im
10.03
28.41
0/5
0/5
48
48
oral
im
77.38
58.82
0/5
0/5
14b3
6.44
48
48
oral
im
27.49
42.23
0/5
0/5
14c3
1
5.44
3.17
96
96
oral
im
35.65
100
0/5
2/5
96
48
24
oral
im
100
100
100
0/5
5/5
4/5
im
a
Percent suppression = [(Cꢀ T)/C] × 100, where C = parasitaemia in control group and T = parasitaemia in treated group.
log P values have been calculated from ChemDraw Professional 15.1.
b
survived beyond day 28; there was no survival when the compound was
succinate derivatives 14a1–c1, 14a2–c2, and 14a3–c3, respectively.
Hydroxy-functionalized trioxane 13a1 provided 80% protection and its
hemisuccinate derivative 14a1 showed 100% protection at a dose of 48
mg/kg × 4 days by both routes, which is twice active than artemisinin by
oral route. Hopefully, the outcome of our finding the antimalarial ac-
tivity of current trioxanes series by both routes helps the scientist in
finding the better drug candidate in fighting against malaria.
given intramuscularly. Trioxane 13c3, showed 100% clearance of par-
asitaemia by oral route at 96 mg/kg × 4 days and 100% of the treated
mice survived beyond day 28. Even at dose 48 mg/kg × 4 days it gave
86% suppression of parasitaemia by oral route, none of the treated mice
survived beyond day 28; when it administered through im route at 96
mg/kg × 4 days it gave 100% suppression of parasitaemia but none of
the treated mice survived beyond day 28. Trioxanes 13a2, 13a3, 13b1,
13b2, 13c1 and 13c2 showed only moderate suppression of para-
sitaemia and none of the treated mice survived.
Declaration of Competing Interest
Hemisuccinate 14a1, the most active compound of the series,
showed 100% clearance of parasitaemia by both oral and im routes at
48 mg/kg × 4 days and all the treated mice survived beyond day 28.
Even at 24 mg/kg × 4 days it showed 100% clearance of parasitaemia
and 80% of the treated mice survived beyond day 28; when the com-
pound was given intramuscularly; there was no survival, when the
compound was given orally. Hemisuccinate 14a2, the next best com-
pound of the series, showed 100% clearance of parasitaemia by both oral
and im routes at 48 mg/kg × 4 days and 60% of the treated mice sur-
vived beyond day 28; when the compound was given by im route, but
only 10% of the treated mice survived when compound was given orally.
Hemisuccinate 14c3, showed 100% clearance of parasitaemia by im
route at 96 mg/kg × 4 days and 40% of the treated mice survived
beyond day 28. Hemisuccinates 14a3 showed 58–77% suppression of
parasitaemia by both oral and im routes at 48 mg/kg × 4 days and none
of the treated mice survived till day 28. Other hemisuccinates 14b1,
14b2, 14b3, 14c1 and 14c2 showed poor antimalarial activity.
The present work reports a series of hydroxy-functionalized triox-
anes 13a1–c1, 13a2–c2, 13a3–c3, and their corresponding hemi
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgements
V.P.V thanks to the Department of Science and Technology, New
Delhi, India for their research grant. This research work was partially
financed by DST-SERB communication no. DST-YSS/2015/001838 and
DST-SERB File Number: EEQ/2019/000078.
Conflicts of interest
The authors confirm that this article content has no conflict of
interest.
Appendix A. Supplementary data
Supplementary data (1H and 13C NMR Spectra of 8a–c, 9a–c, 10a–c,
4

M. Shukla et al.
Bioorganic & Medicinal Chemistry Letters 49 (2021) 128305
solid, mp 175–177 ◦C; IR (KBr, cm-1) 1655, 3209; 1H NMR (400 MHz, CDCl3) δ 2.59
(s, 3H), 5.89 (s, phenolic OH), 6.89 (d, 1H, Ar, J = 7.3 Hz), 7.01 (d, 2H, Ar, J = 8.8
Hz), 7.17 (d, 1H, Ar, J = 6.8 Hz), 7.31 (t, 1H, Ar, J = 7.5 Hz), 7.47 (t, 1H, Ar, J = 7.5
Hz), 7.58 (d, 1H, Ar, J = 8.5 Hz), 7.95 (d, 2H, Ar, J = 8.8 Hz), 8.11 (d, 1H, Ar, J = 8.5
Hz); 13C NMR (100 MHz, CDCl3) δ 26.52 (CH3), 109.48 (CH), 114.41 (CH), 116.74
(CH), 116.80 (CH), 119.03 (CH), 125.11 (CH), 126.17 (C), 126.52 (CH), 128.48 (C),
130.76 (CH), 131.66 (C), 150.88 (C), 151.82 (C), 162.83 (C), 197.12 (C); ESI (m/z)
279 [M+H]+. 1-[4-(4-Hydroxy-phenoxy)-phenyl]-ethanone (8c). Yield 31%, white
solid, mp 150–153 ◦C; IR (KBr, cm-1) 1656, 3316; 1H NMR (400 MHz, CDCl3) δ 2.58
(s, 3H), 5.21 (s, phenolic OH), 6.87 (d, 2H, Ar J = 9.0 Hz), 6.94 (d, 2H, Ar, J = 8.9
Hz), 6.97 (d, 2H, Ar, J = 9.0 Hz), 7.92 (d, 2H, Ar, J = 8.9 Hz); 13C NMR (100 MHz,
CDCl3) δ 26.68 (CH3), 116.53 (CH), 116.79 (CH), 122.12 (CH), 130.84 (CH), 131.51
148.66 (C), 152.96 (C), 163.18 (C), 197.30 (C); ESI (m/z) 229 [M+H]+. General
procedure for the preparation of esters 9a–c: preparation of ester 9a. A mixture of 8a (8
g, 28.77 mmol), ethyl chloroacetate (5.26 mL, 43.16 mmol, 1.5 equiv) and anhyd.
K2CO3 (11.91 g, 86.33 mmol, 3.0 equiv) in acetone (50 mL) was refluxed for 8 h.
After completion of the reaction (monitored by TLC), the reaction mixture was
cooled to room temperature, filter and combined organic layer was dried over
anhydrous Na2SO4 and concentrated and the crude product was purified by column
chromatography over silica gel (60–120 mesh) using EtOAc/Hexane (2:98) as eluent
furnished compound 9a (9.0 g, 86% yield) as a white solid, mp 115-120 ◦C.
Compounds 9b and 9c were prepared by the above procedure. [7-(4-Acetyl-phenoxy)-
naphthalen-2-yloxy]-acetic acid ethyl ester (9a). Yield 86%, white solid, mp 115–120
◦C; IR (KBr, cm-1) 1680, 1752; 1H NMR (400 MHz, CDCl3) δ 1.30 (t, 3H, J = 7.2 Hz),
2.58 (s, CH3), 4.28 (q, 2H, J = 7.2 Hz), 4.71 (s, 2H), 6.97 (d, 1H, Ar, J = 2.4 Hz),
7.05 (d, 2H, Ar, J = 8.9 Hz), 7.11 (dd, 1H, Ar, J = 8.8 and 2.4 Hz), 7.20 (dd, 1H, Ar, J
= 8.9 and 2.5 Hz), 7.31 (d, 1H, Ar, J = 2.3 Hz), 7.77 (d, 1H, Ar, J = 9 Hz), 7.80 (d,
1H, Ar, J = 8.9 Hz), 7.95 (d, 2H, Ar, J = 8.9 Hz); 13C NMR (100 MHz, CDCl3) δ 14.36
(CH3), 26.70 (CH3), 61.71 (CH2), 65.51 (CH2), 106.72 (CH), 115.48 (CH), 117.81
(CH), 118.23 (CH), 118.48 (CH), 126.81 (C), 129.86 (CH), 130.17 (CH), 130.82
(CH), 132.22 (CH), 135.52 (C), 154.18 (C), 156.71 (C), 162.02 (C), 168.88 (C),
197.04 (C); FAB-MS (m/z) 365 [M+H]+. [5-(4-Acetyl-phenoxy)-naphthalen-1-yloxy]-
acetic acid ethyl ester (9b). Yield 93%, white solid, mp 95–98 ◦C; IR (KBr, cm-1) 1672,
1744; 1H NMR (400 MHz, CDCl3) δ 1.30 (t, 3H, J = 7.2 Hz), 2.53 (s, CH3), 4.29 (q,
2H, J = 7.2 Hz), 4.81 (s, 2H), 6.73 (d, 1H, Ar, J = 7.4 Hz), 6.96 (d, 2H, Ar, J = 8.9
Hz), 7.14 (dd, 1H, Ar, J = 7.5 and 1 Hz), 7.32 (t, 1H, Ar, J = 7.7 Hz), 7.45 (dd, 1H,
Ar, J = 8.5 and 7.5 Hz), 7.59 (d, 1H, Ar, J = 8.4 Hz), 7.90 (d, 2H, Ar, J = 8.9 Hz),
8.23 (d, 1H, Ar, J = 8.5 Hz); 13C NMR (100 MHz, CDCl3) δ 14.40 (CH3), 26.64 (CH3),
61.68 (CH2), 66.01 (CH2), 106.1 (CH), 115.42 (CH), 116.94 (CH), 117.19 (CH),
119.64 (CH), 125.65 (CH), 126.37 (CH), 127.56 (C), 128.54 (C), 130.88 (CH), 132.0
(C), 150.99 (C), 154.1 (C), 162.94 (C), 168.87 (C), 196.93 (C); FAB-MS (m/z) 365 [M
+H]+.ESI (m/z) 365 [M+H]+. [4-(4-Acetyl-phenoxy)-phenoxy]-acetic acid ethyl ester
(9c). Yield 86%, oil; IR (Neat, cm-1) 1677, 1757; 1H NMR (400 MHz, CDCl3) δ 1.31 (t,
3H, J = 7.2 Hz), 2.56 (s, 3H), 4.29 (q, 2H, J = 7.2 Hz), 4.63 (s, 2H), 6.93–6.95 (m,
4H, Ar), 7.02 (d, 2H, Ar, J = 9.1 Hz), 7.92 (d, 2H, Ar, J = 8.9 Hz); 13C NMR (100
MHz, CDCl3) δ 14.37 (CH3), 26.65 (CH3), 61.66 (CH2), 66.04 (CH2), 116.24 (CH),
116.70 (CH), 121.86 (CH), 130.78 (CH), 131.70 (C), 149.50 (C), 155.04 (C), 162.81
(C), 169.02 (C), 196.99 (C); ESI (m/z) 471 [M+Na]+; HRMS calcd for C27H28O6
448.1885; found, 488.1884.ESI (m/z) 315 [M+H]+. General procedure for the
11a-c, 13a1–a3, 13b1–b3, 13c1–c3, 14a1–a3, 14b1–b3, and 14c1–c3)
to this article can be found online at https://doi.org/10.1016/j.bmcl.20
21.128305.
References
1 WHO World malaria report 2019. https://www.who.int/ publications/i/item/world-
malaria-report-2019 (accessed March 1, 2020).
2 Battle KE, Lucas TCD, Nguyen M, et al. Mapping the global endemicity and clinical
burden of Plasmodium vivax, 2000–17: a spatial and temporal modelling study.
Lancet. 2019;394:332–343.
3 Hussain H, Specht S, Sarite SR, et al. A new class of phenazines with activity against a
chloroquine resistant Plasmodium falciparum strain and antimicrobial activity.
J Med Chem. 2011;54:4913–4917.
4 Miller LH, Ackerman HC, Su XZ, Wellems TE. Malaria biology and disease
pathogenesis: insights for new treatments. Nat Med. 2013;19:156–167.
5 Rodrigues T, Moreira R, Lopes F. New hope in the fight against malaria? Future Med
Chem. 2011;3:1–3.
6 Klayman DL. Qinghaosu (artemisinin): an antimalarial drug from China. Science.
1985;228:1049–1055.
7 O’Neill PM, Posner GH. A medicinal chemistry perspective on artemisinin and
related endoperoxides. J Med Chem. 2004;47:2945–2964.
8 Tang Y, Dong Y, Vennerstrom JL. Synthetic peroxides as antimalarials. Med Res Rev.
2004;24:425–448.
9 Kumari A, Karnatak M, Singh D, et al. Eur J Med Chem. 2019;163:804–829.
10 Bhattacharya AK, Sharma RP. Recent developments on the chemistry and biological
activity of artemisinin and related antimalarials. Heterocycles. 1999;51:1681–1745.
11 Jefford CW. New development in synthetic peroxidic drugs as artemisinin mimics.
Drug Discov Today. 2007;12:487–494.
12 Muraleedharan KM, Avery MA. Progress in the development of peroxide-based
antiparasitic agents. Drug Discov Today. 2009;14:793–803.
13 Griesbeck AG, Blunk D, El-Idreesy T, Raabe A. Bicyclic peroxides and perorthoester
with 1,2,4-trioxane structures. Angew Chem Int Ed. 2007;46:8883–8886.
14 O’Neill PM, Mukhtar A, Ward SA, et al. Application of thiol-olefin co-oxygenation
methodology to a new synthesis of the 1,2,4-trioxane pharmacophore. Org Lett. 2004;
6:3035–3038.
15 Bloodworth AJ, Shah A. Synthesis of 1,2,4-trioxanes via intramolecular
oxymercuration. J Chem Soc Chem Commun. 1991;947:948.
16 Posner GH, Milhous WK. Olefin oxidative cleavage and dioxetane formation using
triethylsilyl hydrotrioxide: applications to preparation of potential antimalarial
1,2,4-trioxanes. Tetrahedron Lett. 1991;32:4235–4238.
17 Singh C, Misra D, Saxena G, Chandra S. In vivo potent antimalarial 1,2,4-trioxanes:
synthesis and activity of 8-(R-arylvinyl)-6,7,10-trioxaspiro[4,5]decanes and 3-(R-
arylvinyl)-1,2,5-trioxaspiro[5,5]undecanes against Plasmodium berghei in mice.
Bioorg Med Chem Lett. 1995;5:1913–1916.
18 Singh C, Verma VP, Naikade NK, Singh AS, Hassam M, Puri SK. Novel bis- and tris-
1,2,4-trioxanes: synthesis and antimalarial activity against multidrug-resistant
Plasmodium yoelii in Swiss mice. J Med Chem. 2008;51:7581–7592.
19 Singh C, Hassam M, Naikade NK, Verma VP, Singh AS, Puri SK. Synthesis and
antimalarial assessment of a new series of orally active amino-functionalized spiro
1,2,4-trioxanes. J Med Chem. 2010;53:7587–7598.
preparation of α,β-unsaturated esters 10a-c: preparation of compound 10a. To a stirred
slurry of NaH (60% dispersion in mineral oil, 6.15 g, 250 mmol, 4.0 equiv), in dried
THF (20 mL) kept at 0 ◦C under N2 atmosphere, a solution of triethyl
phosphonoacetate (38.46 g, 153 mmol, 4.0 equiv) in dried THF (50 mL) was added,
and the reaction mixture was allowed to stir at rt for 1 h. The ketone 9a (14 g, 38.46
mmol) dissolved in dried THF (100 mL) was added dropwise and the reaction
mixture was further stirred at room temperature for 20 h. The reaction mixture was
quenched with water (100 mL), extracted with ether (3 × 200 mL). The organic layer
was dried over anhyd. Na2SO4, concentrated and purified by column
20 Singh C, Misra D, Saxena G, Chandra S. in vivo potent antimalarial 1,2,4-trioxanes:
Synthesis and activity of 8-(α-arylvinyl)-6,7,10-trioxaspiro[4,5]decanes and 3-
(α-arylvinyl)-1,2,5-trioxaspiro[5,5]undecanes against Plasmodium berghei in mice.
Bioorg Med Chem Lett. 1995;17:1991–11916.
21 Singh C, Kanchan R, Srivastava D, Puri SK. 8-(1-Naphthalen-2-yl-vinyl)-6,7,10-
trioxaspiro (4.5) decane, a new 1,2,4-trioxane effective against rodent and simian
malaria. Bioorg Med Chem Lett. 2006;16:584–586.
chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (1:99) as eluent
furnished diester 10a (14.69 g, 84% yield) as an oil. Compounds 10b and 10c were
prepared by the above procedure 3-[4-(7-Ethoxycarbonylmethoxy-naphthalen-2-
yloxy)-phenyl]-but-2-enoic acid ethyl ester (10a). Yield 84%, oil; IR (Neat, cm-1) 1709,
1759; 1H NMR (400 MHz, CDCl3) δ 1.27 (t, 3H, J = 7.2 Hz), 1.29 (t, 3H, J = 7.2 Hz),
2.56 (d, 3H, J = 1.2 Hz), 4.19 (q, 2H, J = 7.2 Hz), 4.26 (q, 2H, J = 7.2 Hz), 4.68 (s,
2H), 6.12 (d, 1H, J = 1.2 Hz), 6.92 (d, 1H, Ar, J = 2.5 Hz), 7.01 (d, 2H, Ar, J = 8.8
Hz), 7.10 (dd, 1H, Ar, J = 8.8 and 2.4 Hz), 7.15 (dd, 1H, Ar, J = 9 and 2.5 Hz), 7.21
22 Singh C, Verma VP, Naikade NK, Singh AS, Hassam M, Puri SK. 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. Bioorg Med Chem Lett. 2010;20:
4459–4463.
23 Singh C. Preparation of β-hydroxyhydroperoxides by photooxygenation of allylic
alcohols and their elaboration into 1,2,4-trioxanes. Tetrahedron Lett. 1990;31:
6901–6902.
(d, 1H, Ar, J = 2.3 Hz), 7.46 (d, 2H, Ar, J = 8.9 Hz), 7.73 (t, 2H, Ar, J = 8.5 Hz); 13
NMR (100 MHz, CDCl3) δ 14.36 (CH3), 14.54 (CH3), 17.98 (CH3), 60.03 (CH2),
61.67 (CH2), 65.53 (CH2), 106.65 (CH), 114.14 (CH), 116.56 (CH), 117.82 (CH),
118.20 (CH), 118.82 (CH), 126.42 (C), 128.09 (CH), 129.80 (CH), 129.96 (C),
C
24 General procedure for the preparation of ketones 8a-c: preparation of ketone 8a. A
mixture of p-fluoroacetophenone 6 (17.0 g, 123 mmol), 2,7-dihydroxynaphthalene
7a (39.42 g, 246 mmol, 2.0 equiv) and anhyd. K2CO3 (67.89 g, 492 mmol, 4.0 equiv)
in DMSO (50 mL) was refluxed for 4 h, with continuous stirring. After completion of
the reaction (monitored by TLC), the reaction mixture was cooled to room
temperature, diluted with water (100 mL) and extracted with ether (3 × 200 mL).
The organic layer was dried over anhyd. Na2SO4 and concentrated to furnish a crude
product, which was purified by column chromatography over silica gel (60–120
mesh) using EtOAc/Hexane (2:98) as eluent furnished ketone 8a (14.04 g, 41%
yield) as a white solid, mp 140–142 ◦C. Compounds 8b–c were prepared by the
above procedure by condensing p-fluoroacetophenone with 1,5-dihydroxynaphtha-
lene 7b and quinol 7c, respectively. 1-[4-(7-Hydroxy-naphthalen-2-yloxy)-phenyl]-
135.55 (CH), 137.19 (C), 154.77 (C), 155.35 (C), 156.65 (C), 158.30 (C), 167.12 (C),
168.92 (C); ESI (m/z) 435 [M+H]+, 457 [M+Na]+. 3-[4-(5-Ethoxycarbonylmethoxy-
naphthalen-1-yloxy)-phenyl]-but-2-enoic acid ethyl ester (10b). Yield 92%, oil; IR (Neat,
cm-1) 1709, 1760; 1H NMR (400 MHz, CDCl3) δ 1.27–1.32 (m, 6H), 2.54 (d, 3H, J =
1.2 Hz), 4.18 (q, 2H, J = 7.2 Hz), 4.29 (q, 2H, J = 7.2 Hz), 4.81 (s, 2H), 6.09 (d, 1H, J
= 1 Hz), 6.74 (d, 1H, Ar, J = 7.5 Hz), 6.96 (d, 2H, Ar, J = 8.8 Hz), 7.06 (dd, 1H, Ar, J
= 7.4 and 1 Hz), 7.33 (t, 1H, Ar, J = 7.8 Hz), 7.39-7.44 (m, 3H, Ar), 7.71 (d, 1H, Ar, J
= 8.5 Hz), 8.17 (d, 1H, Ar, J = 8.5 Hz); 13C NMR (100 MHz, CDCl3) δ 14.40 (CH3),
14.55 (CH3), 17.97 (CH3), 60.01 (CH2), 61.66 (CH2), 65.96 (CH2), 105.99 (CH),
115.56 (CH), 115.89 (CH), 116.35 (CH), 117.83 (CH), 118.70 (CH), 125.64 (CH),
126.08 (CH), 127.40 (C), 128.08 (CH), 128.43 (C), 136.69 (C), 152.0 (C), 153.96 (C),
154.83 (C), 159.34 (C), 167.16 (C), 168.93 (C); ESI (m/z) 435 [M+H]+. 3-[4-(4-
Ethoxycarbonylmethoxy-phenoxy)-phenyl]-but-2-enoic acid ethyl ester (10c). Yield 75%,
oil; IR (Neat, cm-1) 1755; 1H NMR (400 MHz, CDCl3) δ 1.33 (t, 2 × 2H, J = 7.1 Hz),
2.58 (d, 3H, J = 1.2 Hz), 4.22 (q, 2H, J = 7.1 Hz), 4.30 (q, 2H, J = 7.1 Hz), 4.64 (s,
2H), 6.12-6.13 (m, 1H), 6.92-6.95 (m, 4H, Ar), 7.01 (d, 2H, Ar, J = 9.1 Hz), 7.45 (d,
ethanone (8a). Yield 41%, white solid, mp 140–142 ◦C; IR (KBr, cm-1) 1655, 3429; 1
H
NMR (400 MHz, CDCl3) δ 2.59 (s, 3H), 5.52 (s, phenolic OH), 7.10–7.03 (m, 5H, Ar),
7.28–7.26 (m, 1H, Ar), 7.76 (d, 1H, Ar, J = 8.5 Hz), 7.79 (d, 2H, Ar, J = 8.8 Hz); 13
NMR (100 MHz, CDCl3) δ 26.73 (CH3), 109.22 (CH), 114.98 (CH), 117.46 (CH),
118.06 (CH), 126.38 (C), 130.01 (CH), 130.31 (CH), 130.89 (CH), 132.11 (C),
C
135.87 (C), 154.09 (C), 154.56 (C), 162.18 (C), 197.37 (C); FAB-MS (m/z) 279 [M+
H]+. 1-[4-(5-Hydroxy-naphthalen-1-yloxy)-phenyl]-ethanone (8b). Yield 32%, white
5

M. Shukla et al.
Bioorganic & Medicinal Chemistry Letters 49 (2021) 128305
2H, Ar, J = 9.1 Hz); 13C NMR (100 MHz, CDCl3) δ 14.39 (CH3), 14.56 (CH3), 17.96
found, 398.17. 2-(7-{4-[1-(1,2,5-Trioxa-spiro[5.5]undec-3-yl)-vinyl]-phenoxy}-
naphthalen-2-yloxy)-ethanol (13a2). Yield 60%, white solid, mp 107–109 ◦C; IR (KBr,
cm-1) 1598, 3516; 1H NMR (400 MHz, CDCl3) δ 1.40–1.64 (m, 8H), 1.96–2.03 (m,
2H), 2.17–2.2 (m, 1H), 3.77 (dd, 1H, J = 11.9 and 2.9 Hz), 3.95–4.01 (m, 3H), 4.18
(t, 2H, J = 4.3 Hz), 5.20–5.27 (m, 3H), 5.28 and 5.47 (2 × s, 2H), 7.00–7.02 (m, 3H,
Ar), 7.06–7.10 (m, 2H, Ar), 7.19 (d, 1H, Ar, J = 2.3 Hz), 7.37 (d, 2H, Ar, J = 8.8 Hz),
7.70 (d, 1H, Ar, J = 9 Hz), 7.73 (d, 1H, Ar, J = 8.9 Hz); 13C NMR (100 MHz, CDCl3) δ
22.50 (CH2), 22.54 (CH2) 25.74 (CH2), 29.21 (CH2), 34.85 (CH2), 61.67 (CH2),
62.86 (CH2), 69.39 (CH2), 80.46 (CH), 102.87 (C), 106.47 (CH), 113.67 (CH),
116.02 (CH2), 117.84 (CH), 119.23 (CH), 126.05 (C), 128.10 (CH), 129.61 (CH),
129.90 (CH), 134.02 (C), 135.79 (C), 142.90 (C), 155.68 (C), 157.42 (C), 157.46 (C);
ESI (m/z) 485 [M+Na]+; HRMS calcd for C28H30O6 462.2042; found, 462.2040. 2-
(5-{4-[1-(1,2,5-Trioxa-spiro[5.5]undec-3-yl)-vinyl]-phenoxy}-naphthalen-1-yloxy)-
ethanol (13b2). Yield 48%, oil; IR (Neat, cm-1) 1598, 3421; 1H NMR (300 MHz,
CDCl3) δ 1.45–1.65 (m, 9H), 1.98-2.07 (m, 1H), 2.18–2.28 (m, 1H), 3.79 (dd, 1H, J =
11.9 and 3 Hz), 4.0 (dd, 1H, J = 11.9 and 10.4 Hz), 4.13 (t, 2H, J = 4.8 Hz), 4.31 (t,
2H, J = 4.2 Hz), 5.23 (dd, 1H, J = 10.7 and 2.6 Hz), 5.29 and 5.48 (2 × s, 2H), 6.9 (d,
1H, Ar, J = 7.5 Hz), 6.98 (dd, 2H, Ar, J = 6.7 and 2 Hz), 7.05 (dd, 1H, Ar, J = 7.5 and
0.7 Hz), 7.35-7.44 (m, 4H, Ar), 7.76 (d, 1H, Ar, J = 8.5 Hz), 8.10 (d, 1H, Ar, J = 8.5
Hz); 13C NMR (75 MHz, CDCl3) δ 22.48 (CH2), 22.52 (CH2), 25.75 (CH2), 29.24
(CH2), 34.86 (CH2), 61.77 (CH2), 62.85 (CH2), 69.91 (CH2), 80.5 (CH), 102.83 (C),
106.09 (CH), 114.98 (CH), 115.31 (CH), 115.83 (CH2), 118.01 (CH), 118.22 (CH),
125.43 (CH), 126.34 (CH), 127.49 (C), 128.12 (CH), 128.36 (C), 133.63 (C), 142.99
(C), 152.53 (C), 154.6 (C), 158.43 (C); FAB-MS (m/z) 463 [M+H]+; HRMS calcd for
(CH3), 60.02 (CH2), 61.65 (CH2), 66.13 (CH2), 116.15 (CH), 116.25 (CH), 117.49
(CH), 121.27 (CH), 127.98 (CH), 136.41 (C), 150.58 (C), 154.57 (C), 154.85 (C),
159.37 (C), 167.17 (C), 169.12 (C); EI+ (m/z) 384. General procedure for the
preparation of allylic alcohols 11a-c: preparation of allylic alcohol (11a). To a
magnetically stirred, ice-cooled mixture of LiAlH4 (3.49 g, 92 mmol, 4.0 equiv) in
dried THF (100 mL) diester 10a (10 g, 23.04 mmol) was added under nitrogen
atmosphere and the reaction mixture was allowed to stir for 1 h at 0 ◦C. The reaction
mixture was quenched with 5% aqueous NaOH (5 mL) and water (10 mL) and. The
organic layer was decanted, dried over anhyd. Na2SO4, concentrated to furnish a
crude product which was crystallized in ethyl acetate furnished allylic alcohol 11a
(6.04 g, 75% yield) as a white solid, mp 120–122 ◦C. Allylic alcohols 11b and 11c
were prepared by the above procedure. 3-{4-[7-(2-Hydroxy-ethoxy)-naphthalen-2-yloxy]-
phenyl}-but-2-en-1-ol (11a) Yield 75%, white solid, mp 120–122 ◦C; IR (KBr, cm-1
)
1680, 3283; 1H NMR (400 MHz, DMSO-d6) δ 1.99 (d, 3H, J = 1 Hz), 3.76 (q, 2H, J =
5.3 Hz), 4.06 (t, 2H, J = 4.8 Hz), 4.16 (t, 2H, J = 4.8 Hz), 4.73 (t, 1H, J = 5.4 Hz),
4.91 (t, 1H, J = 5.5 Hz), 5.88-5.91 (m, 1H), 7.05 (d, 2H, Ar, J = 8.8 Hz), 7.07–7.12
(m, 2H, Ar), 7.27 (dd, 2H, Ar, J = 7.5 and 2.4 Hz), 7.48 (d, 2H, Ar, J = 8.8 Hz), 7.81
(d, 1H, Ar, J = 8.9 Hz), 7.87 (d, 1H, Ar, J = 8.9 Hz); 13C NMR (100 MHz, DMSO-d6) δ
16.07 (CH3), 58.70 (CH2), 59.97 (CH2), 70.02 (CH2), 106.65 (CH), 113.14 (CH),
117.41 (CH), 118.06 (CH), 119.28 (CH), 125.56 (CH), 127.46 (CH), 128.65 (CH),
129.62 (CH), 130.26 (CH), 133.98 (C), 135.98 (C), 138.39 (C), 155.68 (C), 156.05
(C), 157.74 (C); ESI (m/z) 323 [M+Na]+ESI (m/z) 351 [M+H]+. 3-{4-[5-(2-Hydroxy-
ethoxy)-naphthalen-1-yloxy]-phenyl}-but-2-en-1-ol (11b). Yield 86%, white solid, mp
114–117 ◦C; IR (KBr, cm-1) 1594, 3233; 1H NMR (400 MHz, DMSO-d6) δ 1.97 (s, 3H),
3.87 (q, 2H, J = 5.3 Hz), 4.14 (t, 2H J = 5.7 Hz), 4.18 (t, 2H, J = 4.7 Hz), 4.72 (t, 1H,
J = 5.4 Hz), 5.02 (t, 1H, J = 5.7 Hz), 5.85-5.88 (m, 1H), 6.96 (d, 2H, Ar, J = 8.7 Hz),
7.04 (d, 1H, Ar, J = 7.6 Hz), 7.07 (d, 1H, Ar, J = 7.5 Hz), 7.42-7.49 (m, 4H, Ar), 7.58
(d, 1H, Ar, J = 8.4 Hz), 8.09 (d, 1H, Ar, J = 8.5 Hz); 13C NMR (100 MHz, CDCl3) δ
16.25 (CH3), 60.17 (CH2), 61.83 (CH2), 69.84 (CH2), 105.97 (CH), 114.93 (CH),
115.04 (CH), 117.67 (CH), 118.17 (CH), 125.45 (CH), 125.90 (CH), 126.22 (CH),
127.33 (CH), 128.29 (CH), 137.41 (C), 137.83 (C), 152.83 (C), 154.51 (C), 157.61
(C);ESI (m/z) 351[M+H]+. 3-{4-[4-(2-Hydroxy-ethoxy)-phenoxy]-phenyl}-but-2-en-1-
ol (11c). Yield 84%, white solid, mp 92–93 ◦C; IR (KBr, cm-1) 1597, 3342; 1H NMR
(400 MHz, Acetone-d6) δ 2.01 (d, 3H, J = 1.1 Hz), 2.92 (brs, 1OH), 3.76 (t, 1OH, J =
5.4 Hz), 3.87 (q, 2H, J = 5.4 Hz), 4.27 (t, 2H, J = 4.6 Hz), 5.94–5.90 (m, 1H), 6.88
(d, 2H, Ar, J = 8.9 Hz), 6.97 (s, 4H, Ar), 7.41 (d, 2H, Ar, J = 8.8 Hz); 13C NMR (100
MHz, Acetone-d6) δ 16.01 (CH3), 59.83 (CH2), 61.42 (CH2), 71.04 (CH2), 116.53
(CH), 118.01 (CH), 121.64 (CH), 127.80 (CH), 128.46 (CH), 135.47 (C), 138.42 (C),
150.96 (C), 156.56 (C), 158.70 (C);ESI (m/z) 323 [M+Na]+. General procedure for
the preparation 1,2,4-trioxanes: preparation of trioxane 13a1. A solution of allylic
alcohol 11a (1 g, 2.85 mmol) and methylene blue (5 mg) was taken in 250 mL double
jacket flask, in a mixture of acetonitrile (100 mL) and THF (100 mL) was irradiated
with 500 W tungsten–halogen lamp at -0 ◦C to -10 ◦C, while a slow stream of O2 was
bubbled into the reaction mixture for 6 h. The reaction mixture was concentrated on
a rotatory evaporator at room temperature and then dissolved in acetonitrile (20
mL), cyclopentanone (1.44 mL, 17.14 mmol, 6.0 equiv) and conc. HCl (0.05 mL)
were added and the reaction mixture was stirred for 1 h at rt. The reaction mixture
was concentrated under vacuum at the room temperature, and the crude product was
purified by column chromatography over silica gel (60-120 mesh) using EtOAc/
Hexane (5:95) as eluent furnished trioxane 13a1 (691 mg, 54% yield) as a white
crystalline solid, mp 76–80 ◦C. Trioxanes 13b1, 13c1, were prepared from allylic
alcohols 11b–c using the above procedure and trioxanes 13a2–c2 and 13a3–13c3
were prepared from allylic alcohols 11a–c by replacing cyclopentanone with
cyclohexanone and 2-admantanone, respectively. 2-(7-{4-[1-(6,7,10-Trioxa-spiro
[4.5]dec-8-yl)-vinyl]-phenoxy}-naphthalen-2-yloxy)-ethanol (13a1). Yield 54%, white
solid, mp 76–80 ◦C; IR (KBr, cm-1) 1593, 3510; 1H NMR (300 MHz, CDCl3) δ
1.66–1.95 (m, 7H), 2.04 (brs, OH), 2.46–2.52 (m, 1H), 3.87 (d, 2H, J = 6.4 Hz), 4.01
(brs, 2H), 4.17 (t, 2H, J = 4.2 Hz), 5.30-5.26 (m, 2H), 5.48 (s, 1H), 7.04–7.01 (m, 3H,
Ar), 7.08 (t, 1H, Ar, J =2.5 Hz), 7.11 (t, 1H, Ar, J =2.3 Hz), 7.21 (d, 1H, Ar, J = 2.3
Hz), 7.38 (d, 2H, Ar, J = 8.7 Hz), 7.73 (t, 2H, Ar, J = 8.9 Hz); 13C NMR (100 MHz,
CDCl3) δ 23.57 (CH2), 24.98 (CH2), 33.01 (CH2), 37.23 (CH2), 61.66 (CH2), 65.24
(CH2), 69.40 (CH2), 80.48 (CH), 106.5 (CH), 113.74 (CH), 114.82 (C), 116.10
(CH2), 117.85 (CH), 119.18 (CH), 126.07 (C), 128.11 (CH), 129.60 (CH), 129.9
(CH), 133.89 (C), 135.80 (C), 142.71 (C), 155.64 (C), 157.47 (C); ESI (m/z) 471 [M+
Na]+; HRMS calcd for C27H28O6 448.1885; found, 488.1884. 2-(5-{4-[1-(6,7,10-
Trioxa-spiro[4.5]dec-8-yl)-vinyl]-phenoxy}-naphthalen-1-yloxy)-ethanol (13b1). Yield
59%, oil; IR (Neat, cm-1) 1504, 3409; 1H NMR (300 MHz, CDCl3) δ 1.72–1.94 (m,
7H), 2.49–2.58 (m, 1H), 2.78 (brs, OH), 3.88 (d, 2H, J = 6.1 Hz), 4.10 (t, 2H, J = 4.3
Hz), 4.25 (t, 2H, J = 4.3 Hz), 5.28–5.33 (m, 2H), 5.47 (s, 1H), 6.85 (d, 1H, Ar, J = 7.7
Hz), 6.98 (d, 2H, Ar, J = 8.8 Hz), 7.05 (d, 1H, Ar, J = 7.5 Hz), 7.34-7.42 (m, 4H, Ar),
7.76 (d, 1H, Ar, J = 8.5 Hz), 8.13 (d, 1H, Ar, J = 8.5 Hz); 13C NMR (50 MHz, CDCl3) δ
23.79 (CH2), 25.2 (CH2), 33.23 (CH2), 37.45 (CH2), 61.89 (CH2), 65.45 (CH2),
70.16 (CH2), 80.7 (CH), 106.28 (CH), 115.03 (C), 115.11 (CH), 115.58 (CH), 116.17
(CH2), 118.42 (CH), 118.94 (CH), 125.61 (CH), 126.59 (CH), 127.63 (C), 128.29
(CH), 128.56 (C), 133.63 (C), 142.91 (C), 152.65 (C), 154.86 (C), 158.66 (C); FAB-
MS (m/z) 449 [M+H]+; HRMS. calcd for C27H28O6 448.1886; found, 448.1867. 2-(4-
{4-[1-(6,7,10-Trioxa-spiro[4.5]dec-8-yl)-vinyl]-phenoxy}-phenoxy)-ethanol (13c1).
Yield 63%, oil; IR (Neat, cm-1) 1598, 3446; 1H NMR (300 MHz, CDCl3) δ 1.68–1.93
(m, 7H), 2.32 (brs, OH), 2.48–2.56 (m, 1H), 3.86 (d, CH2, J = 6.2 Hz), 3.98 (d, 2H, J
= 4.2 Hz), 4.09 (t, 2H, J = 4 Hz), 5.26–5.30 (m, 2H), 5.49 (s,1H), 6.91 (dd, 4H, Ar, J
= 9.3 and 2.9 Hz), 7.0 (d, 2H, Ar, J = 9.2 Hz), 7.34 (d, 2H, Ar, J = 7.9 Hz); 13C NMR
(75 MHz, CDCl3) d 23.53 (CH2), 24.94 (CH2), 32.96 (CH2), 37.19 (CH2), 61.63
(CH2), 65.22 (CH2), 69.92 (CH2), 80.48 (CH), 114.75 (C), 115.77 (CH2), 115.88
(CH), 117.61 (CH), 121.18 (CH), 127.92 (CH), 132.96 (C), 142.7 (C), 150.28 (C),
155.3 (C), 158.69 (C); ESI (m/z) 399 [M+H]+; HRMS calcd for C23H26O6 398.1729;
C
28H30O6 462.2042; found, 462.2040. 2-(4-{4-[1-(1,2,5-Trioxa-spiro[5.5]undec-3-yl)-
vinyl]-phenoxy}-phenoxy)-ethanol (13c2). Yield 69%, oil; IR (Neat, cm-1) 1599, 3447;
1H NMR (400 MHz, CDCl3) δ 1.41–1.60 (m, 8H), 1.95–1.99 (m, 2H), 2.16–2.21 (m,
1H), 3.73 (dd, 1H, J = 11.9 and 3 Hz), 3.92–.97 (m, 3H), 4.06 (t, 2H, J = 4.2 Hz),
5.19 (dd, 1H, J = 10.4 and 2.8 Hz), 5.24 and 5.42 (2 × s, 2H), 6.87 (d, 2H, Ar, J = 6.3
Hz), 6.89 (d, 2H, Ar, J = 6.3 Hz), 6.96 (d, 2H, Ar, J = 9.1 Hz), 7.30 (d, 2H, Ar, J = 8.7
Hz); 13C NMR (100 MHz, CDCl3) δ 22.50 (CH2), 22.54 (CH2), 25.75 (CH2), 29.21
(CH2), 34.87 (CH2), 61.74 (CH2), 62.89 (CH2), 69.89 (CH2), 80.50 (CH), 102.83
(C), 115.71 (CH2), 115.89 (CH), 117.67 (CH), 121.22 (CH), 127.95 (CH), 133.11 (C),
142.93 (C), 150.35 (C), 155.30 (C), 158.70 (C); ESI (m/z) 413 [M+H]+; HRMS calcd
for C24H28O6 412.1886; found, 412.1886. Trioxane (13a3). Yield 62%, white solid,
mp 60–63 ◦C; IR (KBr, cm-1) 1599, 3435; 1H NMR (300 MHz, CDCl3) δ 2.12–1.60 (m,
13H), 2.24 (brs, OH), 2.98 (brs, 1H), 3.82 (dd, 1H, J = 11.9 and 3 Hz), 3.98–4.05 (m,
3H), 4.17 (t, 2H, J = 4.1 Hz), 5.26-5.31 (m, 2H), 5.51 (s, 1H), 7.04 (d, 3H, Ar, J = 8.7
Hz), 7.09-7.14 (m, 2H, Ar), 7.23 (d, 1H, Ar, J = 2.3 Hz), 7.41 (d, 2H, Ar, J = 8.6 Hz),
7.74 (dd, 2H, Ar, J = 10.5 and 9.0 Hz); 13C NMR (75 MHz, CDCl3) δ 27.3 (CH), 29.55
(CH), 33.15 (CH2), 33.39 (CH2) 33.62 (CH2), 33.73 (CH2), 36.38 (CH), 37.33
(CH2), 61.55 (CH2), 62.28 (CH2), 69.38 (CH2), 80.22 (CH), 104.87 (C), 106.43
(CH), 113.62 (CH), 115.9 (CH2), 117.76 (CH), 117.79 (CH), 119.18 (CH), 125.99
(C), 128.01 (CH), 129.54 (CH), 129.84 (CH), 134.02 (C), 135.75 (C), 142.86 (C),
155.62 (C), 157.35 (C), 157.43 (C); ESI (m/z) 537 [M+Na]+; Anal. calcd for
C
32H34O6 C, 74.69, H, 6.66; found, C, 74.49, H, 6.78. HRMS (EI+) calcd for C32H34O6
514.2357; found, 514.2357. Trioxane (13b3). Yield 66%, oil; IR (Neat, cm-1) 1598,
3421; 1H NMR (300 MHz, CDCl3) δ 1.65–2.09 (m, 13H), 2.42 (brs, OH), 2.97 (brs,
1H), 3.8 (dd, 1H, J = 11.9 and 2.9 Hz), 3.99 (dd, 1H, J = 11.8 and 10.7 Hz), 4.12 (t,
2H, J = 4.7 Hz), 4.28 (t, 2H, J = 4.3 Hz), 5.24-5.29 (m, 2H), 5.48 (s, 1H), 6.87 (d, 1H,
Ar, J = 7.7 Hz), 6.98 (d, 2H, Ar, J = 8.7 Hz), 7.05 (d, 1H, Ar, J = 7.4 Hz), 7.36-7.4
(m, 4H, Ar), 7.76 (d, 1H, Ar, J = 8.5 Hz), 8.11 (d, 1H, Ar, J = 8.4 Hz); 13C NMR (75
MHz, CDCl3) δ 27.31 (2 × CH), 29.57 (CH), 33.15 (CH2), 33.4 (CH2), 33.63 (CH2),
33.73 (CH2), 36.38 (CH), 37.35 (CH2), 61.69 (CH2), 62.31 (CH2), 69.88 (CH2),
80.25 (CH), 104.84 (C), 106.02 (CH), 114.91 (CH), 115.26 (CH), 115.7 (CH2),
117.99 (CH), 118.19 (CH), 125.36 (CH), 126.28 (CH), 127.36 (C), 128.3 (CH),
133.57 (C), 142.9 (C), 152.45 (C), 154.56 (C), 158.36 (C); ESI (m/z) 537 [M+Na]+;
Anal. calcd for C32H34O6 C, 74.69, H, 6.66; found, C, 74.49, H, 6.78; HRMS (EI+)
calcd for C32H34O6 514.2357; found, 514.2357. Trioxane (13c3). Yield 53%, whit
solid, mp 95–98 ◦C; IR (KBr, cm-1) 1601, 3463; 1H NMR (300 MHz, CDCl3) δ
1.60–2.07 (m, 13H), 2.32 (brs, OH), 2.96 (brs, 1H), 3.78 (dd, 1H, J = 11.9 and 2.7
Hz), 3.94-4.01 (m, 3H), 4.08 (t, 2H, J = 4 Hz), 5.22–5.27 (m, 2H), 5.46 (s, 1H), 6.91
(dd, 4H, Ar, J = 9.3 and 2.8 Hz), 6.99 (d, 2H, Ar, J = 7.8 Hz), 7.35 (d, 2H, Ar, J =
10.2 Hz); 13C NMR (75 MHz, CDCl3) δ 27.33 (2 × CH), 29.58 (CH), 33.17 (CH2),
33.41 (CH2), 33.65 (CH2), 33.74 (CH2), 36.40 (CH), 37.37 (CH2), 61.63 (CH2),
62.32 (CH2), 69.94 (CH2), 80.29 (CH), 104.83 (C), 115.58 (CH2), 115.89 (CH),
117.65 (CH), 121.13 (CH), 127.88 (CH), 133.16 (C), 142.95 (C), 150.34 (C), 155.29
(C), 158.64 (C); ESI (m/z) 465 [M+H]+; HRMS calcd for C28H32O6 464.2199; found,
464.2169. General procedure for the preparation of hemisuccinates 14a1–14c3:
Preparation of hemisuccinates 14a1. A solution of trioxane 13a1 (150 mg, 0.33 mmol),
Et3N (0.1 mL, 0.99 mmol, 3.0 equiv), succinic anhydride (100 mg, 1.0 mmol 3.0
equiv) and DMAP (2 mg) in DCM (20 mL) was stirred for 3 h at room temperature.
Reaction mixture was quenched by adding 10% HCl solution and extracted with
DCM (3 × 25 mL). Solvent was evaporated and crude product was purified by the
column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (1:4) as
eluent furnished hemisuccinate 14a1 (161 mg, 88% yield) as a white solid, mp 85–90
◦C. Hemisuccinates 14a2–a3, 14b1–b3 and 14c1–c3 were prepared by the above
procedure. Succinic acid mono-[2-(7-{4-[1-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-vinyl]-
phenoxy}-naphthalen-2-yloxy)-ethyl] ester (14a1). Yield 88%, white solid, mp 85–90
◦C; IR (KBr, cm-1) 1508, 1690, 1731; 1H NMR (400 MHz, CDCl3) δ 1.69–1.91 (m, 7H),
2.46–2.52 (m, 1H), 2.64 (s, 4H), 3.84–3.87 (m, 2H), 4.22 (t, 2H, J = 4.7 Hz), 4.48 (t,
2H, J = 4.3 Hz), 5.26–5.29 (m, 2H), 5.46 (s, 1H), 7.97 (d, 1H, Ar, J = 2.3 Hz), 7.0 (d,
2H, Ar, J = 8.8 Hz), 7.07 (td, 2H, Ar, J = 8.8 and 2.3 Hz), 7.18 (d, 1H, Ar, J = 2.3
Hz), 7.38 (d, 2H, Ar, J = 8.8 Hz), 7.69 (d, 1H, Ar, J = 8.8 Hz), 7.73 (d, 1H, Ar, J = 8.8
Hz); 13C NMR (100 MHz, CDCl3) δ 23.57 (CH2), 24.98 (CH2), 28.87 (CH2), 28.97
(CH2), 33.0 (CH2), 37.22 (CH2), 63.25 (CH2), 65.24 (CH2), 65.97 (CH2), 80.45
6

M. Shukla et al.
(CH), 106.43 (CH), 113.71 (CH), 114.83 (C), 116.10 (CH2), 117.88 (CH), 119.18
Bioorganic & Medicinal Chemistry Letters 49 (2021) 128305
(14a3). Yield 76%, oil; IR (Neat, cm-1) 1506, 1629, 3421; 1H NMR (300 MHz, CDCl3)
δ 1.60–2.11 (m, 13H), 2.67 (s, 4H), 2.96 (brs, 1H), 3.81 (dd, 1H, J = 11.9 and 3 Hz),
4.0 (dd, 1H, J = 11.8 and 10.6 Hz), 4.26 (t, 2H, J = 4.9 Hz), 4.51 (t, 2H, J = 4.4 Hz),
5.27 (dd, 1H, J = 10.7 and 2.7 Hz), 5.31 and 5.50 (2 × s, 2H), 7.01-7.13 (m, 5H, Ar),
7.22 (d, 1H, Ar, J = 2.2 Hz), 7.40 (d, 2H, Ar, J = 8.7 Hz), 7.74 (t, 2H, Ar, J = 8.9 Hz);
13C NMR (75 MHz, CDCl3) δ 27.39 (2 × CH), 29.04 (2 × CH2), 29.67 (CH), 33.24
(CH2), 33.48 (CH2), 33.71 (CH2), 33.81 (CH2), 36.45 (CH), 37.43 (CH2), 62.36
(CH2), 63.27 (CH2), 66.08 (CH2), 80.34 (CH), 104.94 (C), 106.63 (CH), 113.73
(CH), 115.93 (CH2), 117.91 (CH), 119.22 (CH), 126.13 (C), 128.10 (CH), 129.62
(CH), 129.88 (CH), 134.15 (C), 135.8 (C), 143.03 (C), 155.71 (C), 157.35 (C), 157.45
(C), 172.28 (C), 177.23 (C); ESI (m/z) 637 [M+Na]+; Anal. calcd for C36H38O9 C,
70.34, H.6.23; found, C, 70.14, H.6.74. Hemisuccinate (14b3). Yield 98%, oil; IR
(Neat, cm-1) 1598, 1734; 1H NMR (300 MHz, CDCl3) δ 1.59–2.11 (m, 13H), 2.70 (s,
4H), 2.96 (brs, 1H), 3.80 (dd, 1H, J = 11.9 and 3 Hz), 3.98 (dd, 1H, J = 11.8 and
10.6 Hz), 4.36 (t, 2H, J = 4.9 Hz), 4.63 (t, 2H, J = 4.4 Hz), 5.23-5.28 (m, 2H), 5.47
(s, 1H), 6.85 (d, 1H, Ar, J = 7.6 Hz), 6.97 (d, 2H, Ar, J = 8.8 Hz), 7.05 (dd, 1H, Ar, J
= 7.5 and 0.7 Hz), 7.35-7.44 (m, 4H, Ar), 7.75 (d, 1H, Ar, J = 8.5 Hz), 8.08 (d, 1H,
Ar, J = 8.5 Hz); 13C NMR (75 MHz, CDCl3) δ 27.35 (2 × CH), 29.01 (CH2), 29.03
(CH2), 29.60 (CH), 33.19 (CH2), 33.43 (CH2), 33.67 (CH2), 33.77 (CH2), 36.42
(CH), 37.39 (CH2), 62.35 (CH2), 63.25 (CH2), 66.51 (CH2), 80.29 (CH), 104.88 (C),
105.91 (CH), 115.05 (CH), 115.41 (CH), 115.72 (CH2), 118.18 (CH), 118.28 (CH),
125.47 (CH), 126.22 (CH), 127.45 (C), 128.01 (CH), 133.58 (C), 142.95 (C), 152.36
(C), 154.50 (C), 158.44 (C), 172.35 (C), 177.62 (C); ESI (m/z) 637 [M+Na]+; Anal.
calcd for C36H38O9 C, 70.34, H.6.23; found, C, 70.16, H.6.67. Hemisuccinate (14c3).
Yield 95%, oil; IR (Neat, cm-1) 1601, 3463; 1H NMR (300 MHz, CDCl3) δ 1.58–2.09
(m, 13H), 2.69 (s, 4H), 2.95 (brs, 1H), 3.78 (dd, 1H, J = 11.9 and 3 Hz), 3.97 (dd,
1H, J = 11.9 and 10.5 Hz), 4.17 (t, 2H, J = 4.8 Hz), 4.46 (t, 2H, J = 4.5 Hz), 5.22-
5.26 (m, 2H), 5.45 (s, 1H), 6.9 (dd, 4H, Ar, J = 6.8 and 2.2 Hz), 6.99 (d, 2H, Ar, J =
9.1 Hz), 7.34 (d, 2H, Ar, J = 8.7 Hz); 13C NMR (75 MHz, CDCl3) δ 27.3 (2 × CH),
28.93 (CH2), 28.98 (CH2), 29.55 (CH), 33.13 (CH2), 33.38 (CH2), 33.62 (CH2),
33.71 (CH2), 36.36 (CH), 37.34 (CH2), 62.29 (CH2), 63.32 (CH2), 66.54 (CH2),
80.24 (CH), 104.83 (C), 115.56 (CH2), 116 (CH), 117.64 (CH), 121.10 (CH), 127.86
(CH), 133.14 (C), 142.91 (C), 150.40 (C), 155.06 (C), 158.6 (C), 172.27 (C), 177.83
(C); ESI (m/z) 565 [M+H]+; Anal. calcd for C32H36O9 C, 68.07, H, 6.43; found, C,
68.01, H, 6.67.
(CH), 126.10 (C), 128.10 (CH), 129.60 (CH), 129.88 (CH), 133.87 (C), 135.72 (C),
142.65 (C), 155.63 (C), 157.28 (C), 157.43 (C), 172.31 (C), 177.16 (C); FAB-MS (m/
z) 549 [M+H]+; HRMS calcd for C31H32O9 548.2046; found, 548.1845. Succinic acid
mono-[2-(5-{4-[1-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-vinyl]-phenoxy}-naphthalen-1-
yloxy)-ethyl] ester (14b1). Yield 86%, oil; IR (Neat, cm-1) 1504, 3409; 1H NMR (300
MHz, CDCl3) δ 1.68–1.96 (m, 7H), 2.48–2.57 (m, 1H), 2.71 (s, 4H), 3.87 (d, 2H, J = 6
Hz), 4.37 (t, 2H, J = 4.7 Hz), 4.64 (t, 2H, J = 4.3 Hz), 5.28–5.31 (m, 2H), 5.47 (s,
1H), 6.86 (d, 1H, Ar, J = 7.6 Hz), 6.97 (d, 2H, Ar, J = 8.7 Hz), 7.06 (d, 1H, Ar, J =
7.5 Hz), 7.35–7.45 (m, 4H, Ar), 7.74 (d, 1H, Ar, J = 8.5 Hz), 8.08 (d, 1H, Ar, J = 8.5
Hz); 13C NMR (50 MHz, CDCl3) δ 23.55 (CH2), 24.96 (CH2), 29.04 (CH2), 33.0
(CH2), 37.22 (CH2), 63.27 (CH2), 65.25 (CH2), 66.52 (CH2), 80.5 (CH), 105.92
(CH), 115.05 (C), 115.48 (CH), 115.93 (CH2), 118.15 (CH), 118.32 (CH), 125.48
(CH), 126.24 (CH), 127.46 (C), 128.07 (CH), 128.36 (C), 133.4 (C), 142.74 (C),
152.34 (C), 154.52 (C), 158.5 (C), 172.37 (C), 177.51 (C); FAB-MS (m/z) 549 [M+H]
+; HRMS. calcd for C31H32O9 548.2046; found, 548.2046. Succinic acid mono-[2-(4-
{4-[1-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-vinyl]-phenoxy}-phenoxy)-ethyl] ester (14c1).
Yield 90%, white solid, mp 72–75 ◦C; IR (KBr, cm-1) 1596, 3434; 1H NMR (300 MHz,
CDCl3) δ 1.70–1.86 (m, 7H), 2.49–2.53 (m, 1H), 2.71 (s, 4H), 3.86 (d, 2H, J = 6.2
Hz), 4.18 (t, 2H, J = 5 Hz), 4.47 (t, 2H, J = 4.6 Hz), 5.26-5.3 (m, 2H), 5.45 (s,1H),
6.89-7.01 (m, 6H, Ar), 7.34 (dd, 2H, Ar, J = 6.7 and 2 Hz); 13C NMR (75 MHz, CDCl3)
δ 23.54 (CH2), 24.95 (CH2), 28.9 (CH2), 28.98 (CH2), 32.98 (CH2), 37.21 (CH2),
61.37 (CH2), 65.24 (CH2), 66.6 (CH2), 80.51 (CH), 114.78 (C), 115.78 (CH2),
116.05 (CH), 117.66 (CH), 121.18 (CH), 127.95 (CH), 133.02 (C), 142.75 (C),
150.44 (C), 155.13 (C), 158.69 (C) 172.26 (C), 177.19 (C); ESI (m/z) 516 [M+NH4]
+; HRMS calcd for C27H30O9 498.1890; found, 498.1884. Succinic acid mono-[2-(7-
{4-[1-(1,2,5-trioxa-spiro[5.5]undec-3-yl)-vinyl]-phenoxy}-naphthalen-2-yloxy)-ethyl]
ester (14a2).Yield 79%, white solid, mp 115–120 ◦C; IR (KBr, cm-1) 1508, 1717,
3420; 1H NMR (400 MHz, CDCl3) δ 1.41–1.61 (m, 8H), 1.96–2.01 (m, 1H), 2.17–2.20
(m, 1H), 2.64 (s, 4H), 3.77 (dd, 1H, J = 11.9 and 2.9 Hz), 3.98 (dd, 1H, J = 11.9 and
10.5 Hz), 4.25 (t, 2H, J = 4.8 Hz), 4.48 (t, 2H, J = 4.5 Hz), 5.22 (dd, 1H, J = 10.5 and
2.8 Hz), 5.27 and 5.47 (2 × s, 2H), 6.97 (d, 1H, Ar, J = 2.4 Hz), 7.0 (d, 2H, Ar, J =
8.8 Hz), 7.07 (dt, 2H, Ar, J = 8.8 and 2.4 Hz), 7.18 (d, 1H, Ar, J = 2.3 Hz), 7.37 (d,
2H, Ar, J = 8.8 Hz), 7.70 (d, 1H, Ar, J = 8.9 Hz), 7.72 (d, 1H, Ar, J = 8.8 Hz); 13
C
NMR (75 MHz, CDCl3) δ 22.46 (CH2), 22.50 (CH2), 25.7 (CH2), 28.95 (CH2) 29.22
(CH2), 34.79 (CH2), 62.79 (CH2), 63.21 (CH2), 66.01 (CH2), 80.43 (CH), 102.85
(C), 106.55 (CH), 113.70 (CH), 115.95 (CH2), 117.86 (CH), 119.16 (CH), 126.08 (C),
128.07 (CH), 129.56 (CH), 129.83 (CH), 134.0 (C), 135.74 (C), 142.92 (C), 155.63
(C), 157.29 (C), 157.41 (C), 172.23 (C), 177.8 (C); ESI (m/z) 585 [M+Na]+; HRMS
calcd for C32H34O9 562.2203; found, 562.2203. Succinic acid mono-[2-(5-{4-[1-
(1,2,5-trioxa-spiro[5.5]undec-3-yl)-vinyl]-phenoxy}-naphthalen-1-yloxy)-ethyl] ester
(14b2). Yield 86%, oil; IR (Neat, cm-1) 1503, 1725; 1H NMR (300 MHz, CDCl3) δ
1.45–1.65 (m, 8H), 2.00–2 09 (m, 1H), 2.19–2.28 (m, 1H), 2.71 (s, 4H), 3.79 (dd, 1H,
J = 11.9 and 3 Hz), 4.0 (dd, 1H, J = 11.8 and 10.5 Hz), 4.37 (t, 2H, J = 4.9 Hz), 4.63
(t, 2H, J = 4.3 Hz), 5.23 (dd, 1H, J = 10.5 and 2.7 Hz), 5.29 and 5.47 (2 × s, 2H),
6.86 (d, 1H, Ar, J = 7.6 Hz), 6.98 (d, 2H, Ar, J = 8.8 Hz), 7.05 (d, 1H, Ar, J = 7.3 Hz),
25 The animals used for the present experiments were duly notedand approved by the
Institutional Animal Ethics Committee of Central drug research institute (CDRI),
Lucknow, UP, India and the Committee for the Purpose of Control and Supervision of
Experiments on Animals (CPCSEA), Government of India (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 X 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 13a1-c1, 13a2-c2, 13a3-c3, 14a1-c1, 14a2-c2, and 14a3-c3 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.27 Mice treated with
β-arteether served as positive control. Multidrug-resistant Plasmodium yoelii
nigeriensis used in this study is resistant to chloroquine, mefloquine and halofantrine.
26 (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) 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 days survival assay.
7.35-7.44 (m, 4H, Ar), 7.75 (d, 1H, Ar, J = 8.5 Hz), 8.08 (d, 1H, Ar, J = 8.5 Hz); 13
C
NMR (75 MHz, CDCl3) δ 22.47 (CH2), 22.51 (CH2), 25.71 (CH2), 29.01 (CH2), 29.2
(CH2), 34.82 (CH2), 62.84 (CH2), 63.24 (CH2), 66.50 (CH2), 80.47 (CH), 102.83
(C), 105.89 (CH), 115.06 (CH), 115.46 (CH), 115.83 (CH2), 118.17 (CH), 118.31
(CH), 125.46 (CH), 126.22 (CH), 127.45 (C), 128.03 (CH), 128.34 (C), 133.51 (C),
142.9 (C), 152.35 (C), 154.49 (C), 158.47 (C), 172.38 (C), 177.79 (C); ESI (m/z) 585
[M+Na]+; HRMS calcd for C32H34O9 562.2203; found, 562.2203. Succinic acid mono-
[2-(4-{4-[1-(1,2,5-trioxa-spiro[5.5]undec-3-yl)-vinyl]-phenoxy}-phenoxy)-ethyl] ester
(14c2). Yield 85%, white solid, mp 52–55 ◦C; IR (KBr, cm-1) 1596, 3434; 1H NMR
(300 MHz, CDCl3) δ 1.43–1.65 (m, 8H), 1.97–2.06 (m, 1H), 2.19–2.27 (m, 1H), 2.71
(s, 4H), 3.77 (dd, 1H, J = 11.9 and 2.9 Hz), 4.18 (t, 2H, J = 4.9 Hz), 4.47 (t, 2H, J =
4.5 Hz), 5.22 (dd, 1H, J = 10.3 and 2.7 Hz), 5.28 and 5.46 (2 × s, 2H), 6.91 (d, 4H,
Ar, J = 8.7 Hz), 6.99 (d, 2H, Ar, J = 9.2 Hz), 7.34 (d, 2H, Ar, J = 8.7 Hz); 13C NMR
(75 MHz, CDCl3) δ 22.52 (CH2), 22.56 (CH2), 28.94 (CH2), 29.03 (CH2), 29.27
(CH2), 34.88 (CH2), 62.9 (CH2), 63.41 (CH2), 66.67 (CH2), 80.55 (CH), 102.86 (C),
115.71 (CH2), 116.12 (CH), 117.75 (CH), 121.18 (CH), 127.99 (CH), 133.21 (C),
143.03 (C), 150.55 (C), 155.17 (C), 158.7 (C), 172.27 (C), 177.2 (C); ESI (m/z) 530
[M+NH4]+; HRMS calcd for C28H32O9 512.2046; found, 512.2086. Hemisuccinate
27 Puri SK, Singh N. Azithromycin: antimalarial profile against blood- and sporozoite-
induced infections in mice and monkeys. Expl Parasitol. 2000;94:8–14.
7