New orally active diphenylmethyl-based ester analogues of dihydroartemisinin: Synthesis and antimalarial assessment against multidrug-resistant Plasmodium yoelii nigeriensis in mice

Article abstract of DOI:10.1016/j.bmcl.2016.02.019

A new series of ester analogues of artemisinin 8a–f, incorporating diphenylmethyl as pharmacologically privileged substructure, and 8g–j have been prepared and evaluated for their antimalarial activity against multidrug-resistant (MDR) Plasmodium yoelii nigeriensis in Swiss mice via oral route. These diphenylmethyl-based ester analogues 8a–f were found to be 2–4 folds more active than the antimalarial drugs β-arteether 4 and artesunic acid 5. Ester 8a, the most active compound of the series, provided complete protection to the infected mice at 24?mg/kg?×?4?days as well as 12?mg/kg?×?4?days, respectively. In this model β-arteether provided 100% and 20% protection at 48?mg/kg?×?4?days and 24?mg/kg?×?4?days, respectively.

Full text of DOI:10.1016/j.bmcl.2016.02.019

Accepted Manuscript
New Orally Active Diphenylmethyl-based Ester Analogues of Dihydroartemi-
sinin: Synthesis and Antimalarial Assessment against multidrug-resistant Plas-
modium Yoelii Nigeriensis in mice
Sandeep Chaudhary, Niraj K. Naikade, Mohit K. Tiwari, Lalit Yadav, Bharti
Rajesh K. Shyamlal, Sunil.K. Puri
PII:
S0960-894X(16)30122-6
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.02.019
BMCL 23570
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 January 2016
3 February 2016
8 February 2016
Please cite this article as: Chaudhary, S., Naikade, N.K., Tiwari, M.K., Yadav, L., Shyamlal, B.R.K., Puri, Sunil.K.,
New Orally Active Diphenylmethyl-based Ester Analogues of Dihydroartemisinin: Synthesis and Antimalarial
Assessment against multidrug-resistant Plasmodium Yoelii Nigeriensis in mice, Bioorganic & Medicinal Chemistry
Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.02.019
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New Orally Active Diphenylmethyl-based Ester Analogues of
Dihydroartemisinin: Synthesis and Antimalarial Assessment
against multidrug-resistant Plasmodium Yoelii Nigeriensis in
mice
Sandeep Chaudhary, a, b, c, * Niraj K. Naikade,c Mohit K. Tiwari, a Lalit Yadav, a Bharti
Rajesh K. Shyamlala and Sunil. K. Puri,d,*
aDepartment of Chemistry & bMaterials Research Centre, Malaviya National Institute of Technology, Jawaharlal Nehru
Marg, Jaipur-302017, India
cDivision of Medicinal and Process Chemistry and dDivision of Parasitology, CSIR-Central Drug Research Institute, Sector
10, Jankipuram Extension, Sitapur Road, Lucknow-226031, India
This is where the receipt/accepted dates will go; Received Month XX, 2000; Accepted Month XX, 2000 [BMCL RECEIPT]
Abstract— A new series of ester analogues of artemisinin 8a-f, incorporating diphenylmethyl as pharmacologically privileged
substructure, and 8g-j have been prepared and evaluated for their antimalarial activity against multidrug-resistant (MDR) Plasmodium
yoelii nigeriensis in Swiss mice via oral route. These diphenylmethyl-based ester analogues 8a-f were found to be 2-4 folds more active
than the antimalarial drugs β-arteether 4 and artesunic acid 5. Ester 8a, the most active compound of the series, provided complete
protection to the infected mice at 24 mg/kg × 4 days as well as 12 mg/kg × 4 days, respectively. In this model β-arteether provided 100%
and 20% protection at 48 mg/kg × 4 days and 24 mg/kg × 4 days, respectively. ©2000 Elsevier Science Ltd. All rights reserved.
several efforts have been made to improve the antimalarial
activity of artemisinin derivatives by oral route.6 However,
these new derivatives are only marginally more active than
artemether and artesunic acid. Therefore, the search for the
next generation artemisinin analogues continues to define
an active area of scientific research.
The discovery of artemisinin 1, as the active principle of
the Chinese traditional drug against malaria, Artemisia
annua, is a major breakthrough in malaria chemotherapy.1
The derivatives of artemisinin, e.g. dihydroartemisinin 2,
artemether 3, arteether 4, and artesunic acid 5 (figure.1),
are more active than the parent compound, and are
currently the drugs of choice for the treatment of malaria
caused by multidrug-resistant P. falciparum.2, 3
We recently reported the synthesis of lipophilic ether and
ester derivatives of dihydroartemisinin, incorporating
pharmacologically privileged substructures such as
biphenyl, adamantane and flourene, most of which showed
high order of antimalarial activity against multidrug-
resistant (MDR) P. yoelii nigeriensis in Swiss mice by oral
route.4 In these studies, we noticed quite unique
observation that α-isomers (in the case of ether derivatives)
and the ester derivatives (which are formed exclusively as
α-isomers5) were found to show promising antimalarial
activity in comparison to their β-isomers. Similar
observations were also obtained on synthetic antimalarial
1, 2, 4-trioxanes, wherein molecules built around
adamantane, biphenyl and flourene scaffolds show high
15
H
H
H
5
2
1
O
H
4
6
7
8
O
O
O
3
O
5a
8a
14
O
O
O
13
12a
O
O
O
O
12
H
H
H
H
O
O
O
11
10
O
9
O
16
OR
O
O
OH
OH
O
5
3, R = Me
4, R = Et
1
2
Figure 1. Artemisinin and its clinically useful derivatives.
While these compounds show high efficacy when
administered by systemic routes, they are comparatively
less active when given by oral route. In recent years,
Keywords: Dihydroartemisinin; Arteether; Antimalarial; Multi-drug resistant; 1, 2, 4-trioxanes
*Corresponding author. Tel.: +91-0141-2713319; fax: +91-141-2529029; e-mail: schaudhary.chy@mnit.ac.in, sk_puri@cdri.res.in

order of antimalarial activity by oral routes.6 Furthermore,
several reports are available in the literature wherein
compounds having these pharmacologically privileged
substructures as part of molecular architecture show
promising biological activities.7
H
O
O
O
O
H
R
Compd.
No.
O
m.p. (in 0C)
% yield
O
R =
Chemical literature reveals that, compounds build around
diphenylmethyl scaffold also show promising biological
activities.8 Inspired by its promising role in improving
biological activity, we prepared ester derivatives 8a-f,
incorporating diphenylmethyl group as pharmacologically
privileged substructures and evaluated them for their
antimalarial activity against multidrug-resistant P. yoelii
nigeriensis in Swiss mice. Herein, we report the synthesis
and antimalarial activity of a new series of ester
derivatives of dihydroartemisinin 8a-f, some of which
were found to be orally 2 to 4-folds more active than β-
arteether. We also report, for the first time, in vivo
antimalarial activity of some previously reported esters 8g-
j which were assessed against multidrug-resistant P. yoelii
nigeriensis in Swiss mice via oral route. These known
esters were earliar assessed against chloroquine-sensitive
P. berghei strain.
70-71
72-73
59
61
8a
8b
H2
C
F
H2C
68-70
81-83
83-85
51
48
54
8c
8d
8e
F
Cl
H2
C
H
O
Cl
Br
O
O
H
2
SOCl2
O
RCOCl
RCOOH
(a)
O
R
H2C
7
6
O
8a-j
Scheme 1 Reagents and conditions: (a)Triethylamine , Dry CH2CI2 , 0oC, 2h.
Br
OMe
Cl
OMe
H2C
65-67
55
8f
8a
R =
H2C
8d R =
8f
H2C
R =
OMe
Cl
Br
OMe
CH3
99- 101
Oily
94
59
60
8g
8h
8i
CH2CH2CH2CH2CH3
H2C
8b
R =
8g
R = CH3
Oily
CH2CH2CH2CH2CH2CH3
H2C
8e R =
8h R =
CH2CH2CH2CH2CH3
F
Oily
62
8j
H2C H2C
8i
8j
CH2CH2CH2CH2CH2CH3
R =
R =
Br
8c R =
H2C
For the synthesis of ester derivatives 8b-f, the synthesis of
carboxylic acid 6b-f was carried out using the literature
procedure (Scheme 2).11
H2C H2C
F
R
R
R
R
R
R
ii
iii
i
6b-f
Dihydroartemisinin 2 was prepared from artemisinin 1
using the literature procedure.9 The acid chlorides RCOCl
7a-j were prepared from the corresponding carboxylic
OEt
OEt
O
O
O
9b R = H
9c R = F
9d R = Cl
9e R = Br
9f R = OMe
10b R = H
10c R = F
10d R = Cl
10e R = Br
10f R = OMe
11b R = H
11c R = F
11d R = Cl
11e R = Br
11f R = OMe
o
acids 6a-j by heating with thionyl chloride at 50 C-60 oC
for 2-3 h and then reacted in situ with dihydroartemisinin 2
in the presence of Et3N in dry CH2Cl2 at 0 C for 2h to
furnish ester derivatives 8a-j in 48-94% yields (scheme 1,
Table 1).10 The known ester derivatives 8a10a, 8g10b,c, and
8h-j10d, were also prepared in a similar way (scheme 1,
Table 1).
Scheme 2. Reagents and conditions: (i) Triethylphosphonoacetate, NaH,
dry THF, 0 ºC-rt, 10 h. (ii) H2, 10% Pd/C, MeOH, rt, 2 h. (iii) LiOH,
CH3CN:H2O (1:1), rt, 3 h. (iv) SOCl2, reflux, 2 h. (v) Et3N, dry DCM, 0
ºC-rt, 3 h.
o
Antimalarial drugs β-arteether and artesunic acid, when
given orally at 48 mg/kg × 4 days provide 100% protection
to the mice infected with multidrug-resistant P. yoelii
nigeriensis. At 24 mg/kg × 4 days, while artesunic acid
does not provide any protection, β-arteether provides only
Table 1: Ester derivatives 8a-j.

20% protection. Since the aim of the present study was to
select compounds having activity profile better than that of
β-arteether and artesunic acid, all the prepared ester
derivatives 8a-j were initially screened against multidrug-
resistant P. yoelii nigeriensis in Swiss mice at 48 mg/kg ×
4 days by oral route.12 All these esters provided 100%
protection at this dose except ester 8g and therefore all
these active compounds were further screened at 24 mg/kg
× 4 days. Compounds 8a-f which showed 100% protection
at 24 mg/kg × 4 days were further tested at 12 mg/kg × 4
days. Compounds 8a, 8c and 8f which showed 100% or
partial protection at 12 mg/kg × 4 days were further tested
at 6 mg/kg × 4 days. The results are summarized in Table
3.
than 8g; both were found to be equally potent as β-
arteether and artesunic acid.
Table 2. Blood schizontocidal activity of esters 12-14 against multidrug-
resistant (MDR) strain P. yoelii nigeriensis in Swiss mice via oral route12
(Data taken from ref. 4a-e)
Dose
% suppression
(mg / kg
× 4
Cured /
Treated
Compd.
Log P
Of Parasitaemia
on day 4b,c
days)a
48
24
12
6
48
24
12
6
100
100
100
86.33
100
100
100
64.44
100
100
100
100
100
100
100
100
100
100
100
100
100
100
92.95
100
100
100
100
100
100
100
100
100
100
100
100
5/5
10/10
10/10
0/5
6.91
6.85
12a
12b
5/5
10/10
10/10
0/5
5/5
7/10
3/5
5/5
5/5
1/5
5/5
6/10
2/5
0/5
0/5
5/5
5/5
2/5
0/5
5/5
3/5
5/5
5/5
1/5
5/5
5/5
0/5
5/5
1/5
0/5
0/5
5/5
0/5
H
H
H
O
48
24
12
48
24
12
48
24
12
48
24
48
24
12
6
48
24
48
24
12
48
24
12
48
24
48
24
O
O
O
O
O
O
6.02
6.75
12c + 13c
12d
O
O
H
R
H
H
O
O
O
O
OR
OR
O
12a-d
13a-d
14a and 14c-d
6.91
6.85
13a
13b
H2C
c
R =
R =
a
H2C
R =
R =
H2C H2C
O
6.75
d
H2C
13d
b
6.89
5.99
14a
14c
Figure 2. Structure of active ether derivatives of dihydroartemisinin 12a-
d and 13a-d and ester derivatives of dihydroartemisinin 14a and 14c-d.
In search for new artemisinin derivatives having high
efficacy and greater bioavailability by oral route, we had
recently reported a series of ether and ester derivatives of
dihydroartemisinin, incorporating adamantane, biphenyl
and fluorene moieties. Several of these lipophilic
derivatives 12-14 were found to be 2-4 times more active
than β-arteether by oral route (Figure 2, Table 2).4, 5, 6 In
that study, we had observed earliar that the α-isomers i.e.
12a-d of these ether derivatives were significantly more
active than the corresponding β-isomers 13a-d. Similarly,
among ester derivatives, fluorene-based ester 14d was
found significantly more active than 14a and 14c (Figure
2). This observation was found fully in compliment with
the Janssen et al. model; that increased lipophilicity is
accompanied by increase in oral bioavailability and hence
increased in antimalarial activity.4b
6.79
14d
3.84
3.84
3.04
-arteether
-Arteether
48
24
100
100
Artesunic
acid
aThe drug dilutions of compounds were prepared in ground oil and
administered to a group of mice at each dose, from day 0-3, once daily.
bPercent suppression= [(C- T) / C]  100; where C= parasitaemia in
c
control group, and T= parasitaemia in treated group. 100% suppression
of parasitaemia means no parasites were detected in 50 oil immersion
fields during microscopic observation.13
Subsequently, to understand the effect of aromatic ring on
antimalarial activity of artemisinin, we prepared ester 8j.
This compound was also found to be as equally potent as
β-arteether and artesunic acid. These results suggest us that
non-bulky substituent at C-10 position of artemisinin
derivatives do not significantly improve antimalarial
activity. Then, we prepared bulky ester derivatives 8a-f
(Log P 6.90-8.27) incorporating diphenylmethyl group
which were more lipophilic than that of the active ether
derivatives 12a-d (Log P 5.51-6.91) and the ester
derivatives 14a and 14c-d and screened them against
multi-drug resistant P.yoelii via oral route.4
This unique observation has, however, suggested us that a
bulkier group on the α-face of the molecule has beneficial
effect on antimalarial activity.4c Thus, to give insight into
this observation; we initially prepared simple non-bulky
esters 8g-j and assessed them for their antimalarial activity
(Table 3). The ester 8g, the acetate of dihydroartemisinin
having Log P value of 3.37, was found to be less potent
than β-arteether and artesunic acid. We then prepared
straight chain containing ester derivatives 8h (Log P
=5.28) and 8i (Log P =5.70) having greater lipophilicity
Table 3. Blood schizontocidal activity of esters 8a-j against multidrug-

resistant (MDR) strain P. yoelii nigeriensis in Swiss mice via oral route.12
8f, showed 100% suppression of parasitaemia at 24 mg/kg
× 4 days and 12 mg/kg × 4 days and provided 100% and
80% protection, respectively to the treated mice. Even at 6
Dose
% suppression
(mg / kg
× 4
Cured /
Treated
Compd.
Log P
Of Parasitaemia
mg/kg
× 4 days, it shows 100% suppression of
on day 4b,c
days)a
parasitaemia on day 4 but none of the treated mice
survived beyond day 28. Ester 8b, 8d and 8e, the next most
active ester showed complete clearance of parasitaemia at
24 mg/kg × 4 days and 12 mg/kg × 4 days and provided
100% and 80% protection, respectively to the treated mice.
At 12 mg/kg × 4 days, 8b, 8d and 8e showed 100%, 96%
and 100 %, respectively suppression of parasitaemia on
day 4 but none of the treated mice survived beyond day 28.
48
24
12
6
48
24
12
48
24
12
6
48
24
12
48
24
12
48
24
12
6
48
24
48
24
48
24
48
24
48
24
48
24
100
100
100
100
100
100
100
100
100
100
100
100
100
96
100
100
100
100
100
100
100
100
99
100
100
100
100
100
100
100
100
100
100
5/5
5/5
10/10
0/5
5/5
5/5
0/5
5/5
5/5
8/10
0/5
5/5
5/5
0/5
5/5
5/5
0/5
5/5
5/5
8/10
0/5
2/5
0/5
5/5
0/5
5/5
1/5
5/5
1/5
5/5
1/5
0/5
0/5
6.97
7.15
8a
8b
7.47
8.27
8.81
8c
8d
8e
In conclusion, we have prepared a new series of highly
active lipophilic ester derivatives of dihydroartemisinin 8a-
f
incorporating
diphenylmethyl
group
as
pharmacologically privileged substructures and evaluated
them for their antimalarial activity against multidrug-
resistant P. yoelii nigeriensis in Swiss mice via oral route,
all of which show better activity profile than that of β-
arteether and artesunic acid. For the first time, we also
report the in vivo antimalarial activity of some previously
reported esters 8g-j which were assessed against
multidrug-resistant P. yoelii nigeriensis in Swiss mice via
oral route. Compound 8a, the most active compound of the
series, was found to be four times more active than β-
arteether and artesunic acid. This study justifies that
introduction of more bulky lipophilic group on the α-face
of the dihydroartemisinin significantly enhance
antimalarial activity. Hence, the easy preparation of these
artemisinin compounds with high order of antimalarial
activity qualifies these compounds for further
developmental studies.
6.90
8f
3.37
5.28
5.70
5.63
3.84
3.84
3.04
8g
8h
8i
8j
-arteether
-Arteether
48
24
100
100
5/5
0/5
Artesunic
acid
Acknowledgement
aThe drug dilutions of compounds were prepared in ground oil and
administered to a group of mice at each dose, from day 0-3, once daily.
bPercent suppression= [(C- T) / C]  100; where C= parasitaemia in
c
control group, and T= parasitaemia in treated group. 100% suppression
S.C. thanks MNIT Jaipur for providing Seed Grant. S.C.
and N.K.N are thankful to the Council of Scientific and
Industrial Research (CSIR), New Delhi for the award of
Senior Research Fellowship. B.R.K.S. is thankful to the
University Grant Commission (UGC), New Delhi for the
award of Junior Research Fellowship. L.Y. is thankful to
the Department of Science and Technology (DST), New
Delhi for the award of Junior Research Fellowship (Project
No. CS-067/2013). S.C. is thankful to Dr. Chandan Singh,
CSIR-Central Drug Research Institute, Lucknow for
providing necessary chemicals and lab facilities. M.K.T. is
thankful to MNIT Jaipur for providing institute fellowship.
S.C. thanks SAIF, CSIR-CDRI, Lucknow and Materials
Research Centre, MNIT Jaipur for providing analytical
facilities.
of parasitaemia means no parasites were detected in 50 oil immersion
fields during microscopic observation.13
As can be seen from Table 3, all these compounds
provided 100% protection at 48 mg/kg × 4 days and
therefore all these derivatives are at least as effective as β-
arteether which provided 100% and 20% protection at 48
mg/kg × 4 days and 24 mg/kg × 4 days, respectively. Since
the present work on ester derivatives is an extension of our
previous studies,4 it is worthwhile to compare the
biological activities of these two series. The most active
fluorene derivative 14d, provided 100% protection at 24
mg/kg. At 12 mg/kg × 4 days, it showed 100% clearance
of parasitaemia on day 4 but none of the treated mice
survived beyond day 28. Whereas the diphenylmethyl-
based ester 8a, the most active compound of the series,
provides 100% protection at both 24 mg/kg × 4 days as
well as 12 mg/kg × 4 days and was found to be four times
more active than β-arteether and artesunic acid. Even at 6
References and Notes
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Lin, J. M.; Ni, M.-Y.; Tou, Y.-Y.; Wa, Z.-H.; Wu Y.-L.; Chou, W.
S. Acta Chim. Sinica, 1979, 37, 129.
mg/kg
× 4 days, it shows 100% suppression of
parasitaemia on day 4 but none of the treated mice
survived beyond day 28. The next most active ester 8c and
2.
For reviews on artemisinin and its analogues see: (a) Klayman, D.
L. Science 1985, 228, 1049-1055. (b) Luo, X. D.; Shen, C. C. Med.

Res. Rev. 1987, 7, 29-52. (c) Cumming, J. N.; Ploypradith, P.;
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9.
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European Patent 98305595.5, Dated 14-07-1998. (a) General
Procedure for Esterification of Dihydroartemisinin (Compound
8b as representative): To a solution of dihydroartemisinin (0.50 g,
1.75 mmol) and Biphenyl-4-carbonyl chloride (1.14 g, 3 eq., 5.25
mmol) dissolved in dry dichloromethane (30 mL) was added
triethylamine (0.73 ml, 3 eq., 5.29 mmol) dropwise at 00C. The
mixture was stirred at the same temperature for 2h. The reaction
mixture was then quenched with saturated sodium bicarbonate
solution (25 mL) and extracted with dichloromethane (3 x 25 mL).
The organic layer was washed with 10% aqueous HCl solution (2 x
20 mL), then with water, dried over anhyd. Na2SO4 and concentrated
under reduced pressure. The crude product on column
chromatography over silica gel using ethylacetate/hexane (1:25) as
eluant gave pure 8b (465 mg, 57%) as a white solid. (b) Selected
Spectral Data: 8a: White solid; FT-IR (KBr, cm-1): 2929.5, 2875.4,
1749.5, 1453.5, 1142.1, 1116.2, 752.2; 1H NMR (200 MHz, CDCl3)
 0.58 (d, 3H, J= 7.0 Hz, CH3), 0.94 (d, 3H, J= 4.8 Hz, CH3), 1.25-
2.06 (m, 10H), 1.43 (s, 3H, CH3), 2.29-2.56 (m, 2H), 5.12 (s, 1H,
benzylic H), 5.43 (s, 1H, C12-H), 5.82 (d, 1H, J= 9.8 Hz, C10-H),
7.31 (m, 10H, Aromatic H); 13C NMR (50 MHz, CDCl3)  12.22
(CH3), 20.64( CH3), 22.37 (CH2), 24.99 (CH2), 26.36 (CH3), 30.13
(CH2), 32.32 (CH), 34.47 (CH2), 36.59 (CH2), 37.65 (CH), 45.65
(CH), 51.92 (CH), 57.19 (CH), 80.53 (C), 91.91 (CH), 92.97 (CH),
104.85 (C), 127.60 (CH), 127.76 (CH), 128.78 (CH), 129.07 (CH),
129.33 (CH), 138.59 (C), 138.86 (C), 171.76 (C); ESMS (m/z): 501
[M + Na]+; Anal. Calcd for (C29H34O6): C 72.78 H 7.16; Found C
73.03 H 6.96. 8b: White solid; FT-IR (KBr, cm-1) 2929.9, 2877.2,
1747.2, 1653.9, 1529.6, 1450.4, 1350.9, 1275.6, 1216.2, 1145.2,
1097.4, 1014.1, 755.9; 1H NMR (200 MHz, CDCl3)  0.84 (d, 3H, J
= 7.1 Hz, CH3), 0.98 (d, 3H, J = 5.3 Hz, CH3), 1.25-2.08 (m, 10H),
1.45 (s, 3H, CH3), 2.31-2.38 (m, 1H), 2.53-2.63 (m, 1H), 3.14-3.23
(m, 2H, COCH2), 4.62 (t, 1H, J = 8.1 Hz, benzylic H, ), 5.50 (s, 1H,
C12-H), 5.92 (d, 1H, J = 9.8 Hz, C10-H), 7.28-7.41 (m, 4H), 7.51-
7.58 (m, 2H), 7.75 (d, 2H, J = 7.4 Hz), ; 13C NMR (50 MHz, CDCl3)
 12.61 (CH3), 20.65 (CH3), 22.46 (CH2), 25.03 (CH2), 26.38 (CH3),
32.11 (CH), 34.53 (CH2), 36.63 (CH2), 37.72 (CH), 39.10 (CH2),
43.77 (CH), 45.68 (CH), 51.98 (CH), 80.55 (C), 91.90 (CH), 92.77
(CH), 104.90 (C), 120.30 (CH), 120.42 (CH), 124.77 (CH), 124.94
(CH), 127.68 (CH), 127.88 (CH), 128.01 (CH), 141.20 (C), 146.41
(C), 146.66 (C), 171.88 (C); ESMS (m/z): 508 [M + NH4]+, 513 [M
+ Na]+; Anal. Calcd for (C30H34O6): C 73.45 H 6.99; Found C 73.30
H 6.95. 8c: White solid; mp 68-70 ºC; FT-IR (KBr, cm-1) 1748.9,
3.
4.
5.
6.
Haynes, R. K.; Chan, H. –W.; Cheung, M.-K.; Lam, W. –L.; Soo,
M, -K.; Tsang, H.-W.; Voerste, A.; Williams, I. D. Eur. J. Org.
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(a) Singh, C.; Kanchan, R.; Puri, S. K. Indian Patent Appl. No. 1554
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6,737,438 B2, 2004. (c) Singh, C.; Kanchan, R.; Sharma, U.; Puri,
S. K. J. Med. Chem., 2007, 50 (3), 521-527.
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(a) Craig, P. N. Drug Compendium. In Comprehensive Medicinal
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Vennerstrom, J. L.; Arbe-Barnes, S.; Brun, R.; Charman, S. A.;
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Matile, H.; McIntosh, K.; Padmanilayam, M.; Santo Tomas, J.;
Scheurer, C.; Scorneaux, B.; Tang, Y.; Urwyler, H.; Wittlin S.;
Charman, W. N. Nature 2004, 430, 900-904. (c) Augeri, D. J.; Robl,
J. A.; Betebenner, D. A.; Magnin, D. R.; Khanna, A.; Robertson, J.
G.; Wang, A.; Simpkins, L. M.; Taunk, P.; Huang, Q.; Han, S. -P.;
Abboa-Offei, B.; Cap, M.; Xin, L.; Tao, L.; Tozzo, E.; Welzel, G.
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Kirby, M. S.; Parker, R. A.; Hamann, L. G. J. Med. Chem. 2005, 48,
5025 – 5037. (d) Lund, B. W.; Piu, F.; Gauthier, N. K.; Eeg, A.;
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1
1602.9, 1508.1, 1227.4, 1016.3, 756.4; H NMR (200 MHz, CDCl3)
δ 0.51 (d, 3H, J = 7.1 Hz), 0.86-2.57 (m, 12H), 0.95 (d, 3H, J = 5.4
Hz), 1.43 (s, 3H), 3.09 (d, 2H, J = 8 Hz), 4.56 (t, 1H, J = 8 Hz),
5.39 (s, 1H), 5.68 (d, 1H, J = 9.9 Hz), 6.91-7.26 (m, 8H, Ar); 13C
NMR (75 MHz, CDCl3) δ 10.14 (CH3), 18.71 (CH3), 20.46 (CH2),
23.06 (CH2), 24.41 (CH3), 30.10 (CH), 32.51 (CH2), 34.73 (CH2),
35.76 (CH), 39.12 (CH2), 43.74 (CH), 44.06 (CH), 50.04 (CH),
78.59 (C), 89.99 (CH), 90.71 (CH), 102.98 (C), 127.28 (4 × CH),
127.50 (4 × CH ), 131.08 (C), 139.58 (C), 139.95 (C), 168.51 (C);
ESI-MS (m/z) 529.0 [M+H]+; Anal. Calcd for C30H34F2O6: C, 68.17,
H, 6.48; found: C, 68.21, H, 6.49. 8d: White solid; mp 81-83 ºC;
FT-IR (KBr, cm-1) 1750.8, 1604.6, 1509.4, 1227.9, 1014.0, 830.9;
1H (300 MHz, CDCl3) δ 0.56 (d, 3H, J = 7.1 Hz), 0.93-2.06 (m,
10H), 0.97 (d, 3H, J = 5.6 Hz), 1.45 (s, 3H), 2.34-2.53 (m, 2H), 3.11
(d, 2H, J = 8 Hz), 4.56 (t, 1H, J = 8 Hz), 5.40 (s, 1H), 5.69 (d, 1H, J
= 9.9 Hz), 7.14-7.29 (m, 8H, Ar); 13C NMR (75 MHz, CDCl3) δ
10.34 (CH3), 18.91 (CH3), 20.67 (CH2), 23.29 (CH2), 24.67 (CH3),
30.38 (CH), 32.76 (CH2), 34.91 (CH2), 35.99 (CH), 39.37 (CH2),
43.94 (CH), 44.26 (CH), 50.24 (CH), 78.80 (C), 90.20 (CH), 90.93
(CH), 103.19 (C), 127.58 (4 × CH), 127.80 (4 × CH ), 131.38 (C),
139.88 (C), 140.15 (C), 168.82 (C); ESI-MS (m/z) 583.1 [M + Na]+;
8.
(a) (i) Greaves, M.W.; Tan, K. T. Clin Rev Allergy Immunol 2007,
33 (1-2), 134-143. (ii) Katagiri, K.; Arakawa, S.; Hatano, Y.;
Fujiwara, S. The Journal of Dermatology 2006, 33 (2), 75. (b)
Chakraborty, P.; Roy, S. S.; Hossain, S. K.U.; Bhattacharya, S. Free

Anal. Calcd for C30H34Cl2O6: C, 64.17, H, 6.10; found: C, 63.89, H,
6.34. 8e: White solid; mp 83-85 ºC; FT-IR (KBr, cm-1) 1751.4,
1605.3, 1512.8, 1228.5, 1014.9, 831.7; 1H (300 MHz, CDCl3) δ 0.57
(d, 3H, J = 7.1 Hz), 0.90-2.06 (m, 10H), 0.99 (d, 3H, J = 5.6 Hz),
1.47 (s, 3H), 2.33-2.54 (m, 2H), 3.13 (d, 2H, J = 8 Hz), 4.59 (t, 1H,
J = 8 Hz), 5.41 (s, 1H), 5.71 (d, 1H, J = 9.9 Hz), 7.16-7.31 (m, 8H,
Ar); 13C NMR (75 MHz, CDCl3) δ 10.35 (CH3), 18.93 (CH3), 20.68
(CH2), 23.30 (CH2), 24.69 (CH3), 30.40 (CH), 32.78 (CH2), 34.93
(CH2), 36.01 (CH), 39.39 (CH2), 43.96 (CH), 44.29 (CH), 50.26
(CH), 78.81 (C), 90.22 (CH), 90.95 (CH), 103.21 (C), 127.60 (4 ×
CH), 127.82 (4 × CH ), 131.40 (C), 139.89 (C), 140.17 (C), 168.84
(C); ESI-MS (m/z) 671.0 [M + Na]+; Anal. Calcd for C30H34Br2O6: C,
55.40, H, 5.27; found: C, 55.44, H, 5.29. 8f: White solid; mp 65-67
ºC; FT-IR (KBr, cm-1) 1748.2, 1609.8, 1507.7, 1232.5, 1019.0,
834.7; 1H NMR (300 MHz, CDCl3) δ 0.50 (d, 3H, J = 7.1 Hz), 0.92-
2.04 (m, 10H), 0.94 (d, 3H, J = 5.6 Hz), 1.43 (s, 3H), 2.37 (dt, 1H, J
= 14.2 and 3.8 Hz), 2.45-2.49 (m, 1H), 3.07-3.10 (m, 2H), 3.74 (s,
3H), 3.76 (s, 3H), 4.49 (t, 1H, J = 8 Hz), 5.38 (s, 1H), 5.68 (d, 1H, J
= 9.9 Hz), 6.78-7.26 (m, 8H, Ar); 13C NMR (75 MHz, CDCl3) δ
11.79 (CH3), 20.39 (CH3), 22.16 (CH2), 24.78 (CH2), 26.16 (CH3),
31.93 (CH), 34.28 (CH2), 36.42 (CH2), 37.46 (CH), 41.53 (CH2),
45.44 (CH), 45.48 (CH), 51.76 (CH), 55.42 (2 × CH3), 80.32 (C),
91.67 (CH), 92.17 (CH), 104.63 (C), 114.08 (2 × CH), 114.15 (2 ×
CH ), 128.66 (2 × CH), 128.72 (CH), 128.83 (CH), 135.95 (C),
136.20 (C), 158.32 (C), 158.37 (C), 170.87 (C); ESI-MS (m/z)
553.4 [M+H]+; Anal. Calcd for C32H40O8: C, 69.54, H, 7.30; found:
C, 69.59, H, 7.34.
12. (a) Peters, W. In Chemotherapy and drug resistance in malaria;
Academic Press: London, 1970; pp 64-136. (b) In vivo
antimalarial efficacy test: The blood schizontocidal activity of the
test compounds was evaluated in rodent model using multidrug-
resistant strain of Plasmodium yoelii nigeriensis. Multidrug-resistant
Plasmodium yoelii nigeriensis used in this study is resistant to
chloroquine, mefloquine and halofantrine. The colony bred Swiss
mice of either sex (20 ± 2 g) were inoculated intraperitoneally with
1 × 105 P. yoelii (MDR) parasites on day zero, and treatment was
administered to group of five mice at each dose, from day 0 to 3,
once daily. The drug dilutions of all compounds were prepared in
groundnut oil so as to contain the required amount of the drug (0.6
mg/kg for a dose of 48 mg/kg, 0.3 mg for a dose of 24 mg/kg, 0.15
mg for a dose of 12 mg/kg and 0.075 mg for a dose of 6 mg/kg) in
0.1 mL and administered orally for each dose. Parasitaemia level
were recorded from thin blood smears on day 4 and subsequently
twice a week till day 28. The animals which did not develop patent
infection till day 28 were recorded as cured.14 Mice treated with β-
arteether served as positive control.
13. (a) 100% suppression of parasitemia means no parasites were
detected in 50 oil immersion microscopic fields (parasites if at all
present, were 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. (b) 100% protection
means none of the treated mice developed patent infection during
the 28 days observation period and hence were recorded as cured.
Similarly 60% protection means only 3 out of 5 mice were cured.
14. Puri, S. K.; Singh, N. Expl. Parasitol. 2000, 94, 8-14.
11. (a) Tao, Y. T.; Saunders, W. H. Jr. J. Am. Chem. Soc. 1983, 105,
3183-3188. (b) Klemm, L. H.; Bower, G. M. J. Org. Chem. 1958,
23, 344-8. (c) Jagadale, A. R.; Sudalai, A. Tetrahedron Lett. 2007,
48, 4895-4898.

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New Orally Active Diphenylmethyl-based Ester
Analogues of Dihydroartemisinin: Synthesis
and Antimalarial Assessment against
multidrug-resistant Plasmodium Yoelii
Nigeriensis in mice
Sandeep Chaudhary, a, b,c,* Niraj K. Naikade,c Mohit K. Tiwari, a Lalit Yadav, a Bharti Rajesh K. Shyamlala and
Sunil. K. Puri,d,*
aDepartment of Chemistry and bMaterials Research Centre, Malaviya National Institute of Technology, Jawaharlal Nehru
Marg, Jaipur-302017, India
cDivision of Medicinal and Process Chemistry and dDivision of Parasitology, CSIR-Central Drug Research Institute, Sector
10, Jankipuram Extension, Sitapur Road, Lucknow-226031, India
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