Amino- and hydroxy-functionalized 11-azaartemisinins and their derivatives

Article abstract of DOI:10.1021/ol802238d

(Chemical Equation Presented) An efficient conversion of artemisinin 1 into three new amino- and hydroxy-functionalized 11-aza prototypes 9, 11, and 12 has been achieved on a multigram scale by reaction with hydrazine, hydroxylamine, and 2-amino ethanol, respectively. Of these, 9 has been further diversified into a wide range of derivatives including imines, amines, amides, and linker based dimers. Prototypes 11 and 12 have been converted into the corresponding ethers in high yields. Some of these compounds have shown a high order of activity against multidrug-resistant malaria in mice by oral route.

Full text of DOI:10.1021/ol802238d

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5461-5464
Amino- and Hydroxy-Functionalized
11-Azaartemisinins and Their Derivatives
Ajit Shankar Singh,† Ved Prakash Verma,† Mohammad Hassam,†
Naikade Niraj Krishna,† Sunil K. Puri,‡ and Chandan Singh*,†
DiVision of Medicinal and Process Chemistry and DiVision of Parasitology,
Central Drug Research Institute, Lucknow-226001, India
chandancdri@yahoo.com
Received September 26, 2008
ABSTRACT
An efficient conversion of artemisinin 1 into three new amino- and hydroxy-functionalized 11-aza prototypes 9, 11, and 12 has been achieved
on a multigram scale by reaction with hydrazine, hydroxylamine, and 2-amino ethanol, respectively. Of these, 9 has been further diversified
into a wide range of derivatives including imines, amines, amides, and linker based dimers. Prototypes 11 and 12 have been converted into
the corresponding ethers in high yields. Some of these compounds have shown a high order of activity against multidrug-resistant malaria
in mice by oral route.
The discovery of artemisinin 1 as the active principle of the
Chinese traditional drug Artemisia annua is a major mile-
stone in malaria chemotherapy.1 Artemisinin and its more
potent semisynthetic derivatives, e.g., artemether 2, arteether
3, and artesunic acid 4, are effective against both chloroquine-
sensitive and chloroquine-resistant malaria (Figure 1).
These compounds are fast acting and are currently the
drugs of choice for the treatment of cerebral/complicated
† Division of Medicinal and Process Chemistry.
Figure 1. Artemisinin and its derivatives.
‡ Division of Parasitology.
(1) (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.; Posner, G. H. AdV. Pharmacol. 1997, 37, 253–297. (d) Bhattacharya,
A. K.; Sharma, R. P. Heterocycles 1999, 51, 1651–1681. (e) Borstnik, K.;
Paik, I.; Shapiro, T. A.; Posner, G. H. Int. J. Parasitol 2002, 32, 1661–
1667. (f) Ploypradith, P. Acta Trop. 2004, 89, 329–342. (g) O’Neill, P. M.;
Posner, G. H. J. Med. Chem. 2004, 47, 2945–2964. (h) Tang, Y.; Dong,
Y.; Vennerstrom, J. L. Med. Res. ReV. 2004, 24, 425–448. (i) Jefford, C. W.
Drug DiscoVery Today 2007, 12, 487–494.
malaria caused by multidrug-resistant Plasmodium falci-
parum.2 While these drugs show excellent activity by
(2) Meshnick, S. R.; Taylor, T. E.; Kamchonwongpaisan, S. Microbiol.
ReV. 1996, 60, 301–315.
10.1021/ol802238d CCC: $40.75
Published on Web 11/08/2008
2008 American Chemical Society

parenteral route, they show poor absorption by oral route.
The extra acetal-lactone or acetal-acetal linkages are linked
with their poor hydrolytic stability and therefore poor
absorption by oral route. Therefore, conversion of artemisinin
to its orally active derivatives has been an objective of several
recent studies.3
Relevant to the present studies is the conversion of
artemisinin to its aza derivatives, e.g., 5-8 (Figure 2), by
Ziffer et al. and Haynes et al.4-6
stirring with silica gel and 20% H2SO4 in the presence of
2,4-di-tert-butylphenol in CHCl3 to furnish a mixture of
N-amino-11-azaartemisinin 9 and its deoxy analogue N-amino-
10-azadeoxyartemisinin 10, in a combined yield of 59% and
in the ratio of 3:7. The yield of N-amino-11-azaartemisinin
9 improved to 70% when the first step of the reaction
sequence was conducted in MeOH-CHCl3 (7:3) for 1 h at
0 °C; no deoxy analogue was formed under these conditions.
Similarly, the reaction of artemisinin 1 with hydroxylamine
and 2-aminoethanol7 in MeOH-CHCl3 for 1 h at 0 °C
followed by treatment with SiO2/20% H2SO4 in the presence
of 2,4-di-tert-butylphenol in CHCl3 furnished aza derivatives,
N-hydroxy-11-azaartemisinin 11, and N-ethanol-11-azaarte-
misinin 12 in 45% and 52% yields, respectively (Scheme
2). Again, no deoxy analogue was formed in either case.
Scheme 2
.
Synthesis of N-Hydroxy-11-azaartemisin 11 and
N-Ethanol-11-azaartemisin 12
Figure 2. Aza derivatives of artemisinin.
These aza derivatives have shown a better activity profile
than that of aretmisinin. In these derivatives, however,
nitrogen is in the form of an amide group and only limited
number of derivatives can be made. Herein, we report, an
efficient two step conversion of artemisinin 1 into three new
11-azaartemisinin prototypes 9, 11, and 12 with either a free
amino or a free hydroxyl functionality and their subsequent
derivatization.
Having compound 9 with a free amino group and
compounds 11 and 12 with a free hydroxyl group, a stage
was set to use these functionalities as handles and convert
them into a range of derivatives. Amide derivatives 13a-d
were obtained by reacting 9 with benzoyl chloride, p-
bromobenzoyl chloride, p-trifluoromethylbenzoyl chloride,
and 4-phenylbenzoyl chloride in dry benzene in the presence
of Et3N at 0 °C in 60-93% yields (Scheme 3, Table 1).
Our strategy to prepare N-amino-11-azaartemisinin 9 is
shown in Scheme 1. Accordingly, artemisinin 1 was reacted
Scheme 1. Synthesis of N-Amino-11-azaartemisinin 9
Scheme 3. Synthesis of Amides 13a-d
with hydrazine hydrate in MeOH at rt for 1 h, followed by
(3) (a) Hindley, S.; Ward, S. A.; Stoor, R. C.; Searle, N. L.; Bray, P. G.;
Park, B. K.; Davies, J.; O′Neill, P. M. J. Med. Chem. 2002, 45, 1052–
1063. (b) Woo, S. H.; Parker, M. H.; Ploypradith, P.; Northrop, J.; Posner,
G. H. Tetrahedron Lett. 1998, 39, 1533–1536. (c) Singh, C.; Chaudhary,
S.; Puri, S. K. J. Med. Chem. 2006, 49, 7227–7233. (d) Avery, M. A.;
Bonk, J. D.; Chong, W. K. M.; Mehrotra, S.; Miller, R.; Mihous, W.; Coins,
D. K.; Venkatesan, S.; Wyandt, C.; Khan, I.; Avery, B. A. J. Med. Chem.
1995, 38, 5038–5044.
Table 1. Amides 13a-d
(4) (a) Torok, D. S.; Ziffer, H. Tetrahedron Lett. 1995, 36, 829–832.
(b) Torok, D. S.; Ziffer, H.; Meshnick, S. R.; Pan, X.-Q.; Ager, A. J. Med.
Chem. 1995, 38, 5045–5050. (c) Katz, E.; Ma, J.; Kyle, D.; Ziffer, H. Bioorg.
Med. Chem. Lett. 1999, 9, 2969–2972
.
(5) Haynes, R. K.; Wong, H.-N.; Lee, K.-W.; Lung, C.-M.; Shek, L. Y.;
Williams, I. D.; Croft, S. L.; Vivas, L.; Rattray, L.; Stewart, L.; Wong,
V. K. W.; Ko, B. C. B. Chem. Med. Chem. 2007, 2, 1464–1479
.
(6) For synthetic 11-aza -9-desmethylartemisinin see Avery, M. A.;
Bonk, J. D.; Chong, W. K. M.; Mehrotra, S.; Miller, R.; Mihous, W.; Coins,
D. K.; Venkatesan, S.; Wyandt, C.; Khan, I.; Avery, B. A. J. Med. Chem.
Under similar conditions, reaction of 2 equiv of 9 with
1995, 38, 5038–5044
.
terepthoyl chloride and oxalyl chloride resulted in the
5462
Org. Lett., Vol. 10, No. 23, 2008

formation of dimeric compounds 13e and 13f in 20% and
34% yields, respectively (Scheme 4).8
Scheme 6. Synthesis of Ethers 16a-d and 17a-d
Scheme 4. Synthesis of Dimers 13e and 13f
Table 3. Ethers 16a-d and 17a-d
Reaction of 9 with benzaldehyde, p-bromobenzaldehyde,
p-trifluoromethylbenzaldehyde, and 4-phenylbenzaldehyde in
the presence of Amberlyst-15 as a catalyst in dry benzene
at rt furnished the corresponding imines 14a-d in 82-96%
yields. Sodium borohydride reduction of imines 14a-d in
dry benzene at 0 °C provided amines 15a-d, respectively,
in 62-72% yields (Scheme 5, Table 2).
Scheme 5. Synthesis of Imines 14a-d and Amines 15a-d
While compounds 9, 11, and 12 displayed poor antima-
larial activity, some of their derivatives have shown a high
order of activity against multidrug-resistant Plasmodium
yoelii in mice by oral route (Table 4).9 Full activity data
will be reported elsewhere.
Table 2. Imines 14a-d and Amines 15a-d
Table 4. Antimalarial Activity of 9, 11, and 12 and Their
Derivatives 13d, 15d, and 16a by Oral Route
% suppression of
dose
mg/kg × 4 days
parasitaemia
on day 4
entry
mice survived
9
24
48
48
12
6
12
6
24
12
48
24
100
78.11
100
100
94.37
100
100
100
100
100
100
2/5
0/5
0/5
5/5
0/5
5/5
1/5
5/5
2/5
5/5
1/5
11
12
13d
15d
16a
3
Compound 11 was converted to its ether derivatives
16a-d by reaction with benzyl bromide, (3-bromopropyl)-
benzene, 4-phenylbenzyl bromide, and o-fluorobenzyl bro-
mide in dry THF in 60-74% yields. Analogous reaction of
12 with benzyl bromide, (3-bromopropyl)benzene, 4-phe-
nylbenzyl bromide, and o-fluorobenzyl bromide furnished
ethers 17a-d in 62-71% yields (Scheme 6, Table 3).
In conclusion, we have converted artemisinin into three
new 11-aza prototypes 9, 11, and 12, with reactive func-
tionalities available to be converted into a wide spectrum of
Org. Lett., Vol. 10, No. 23, 2008
5463

compounds, some of which have shown a high order of
activity against multidrug-resistant malaria in mice.10
Acknowledgment. A.S.S., V.P.V., M.H., and N.N.K. are
thankful to the CSIR and UGC, New Delhi, for the award
of Senior Research Fellowship.
(7) The reaction of artemisinin with 2-amino ethanol in MeOH has been
reported to give only the deoxy analogue of 12. Reference: Al-Oqail, M. M.;
Galal, A. M.; Ahmad, M. S.; Al-Feshawi, A. M.; El-Feraly, F. S. Molecules
2003, 8, 901–909.
Supporting Information Available: Experimental details
and characterization data and purity/characterization Table,
1H NMR and 13C NMR spectra of compounds 9-12,
13a,b,c,d, e,f, 14a-d, 15a-d, 16a, 16b, 16c, 16d, 17a, 17b,
17c and 17d. This material is available free of charge via
the Internet at http://pubs.acs.org.
(8) For other dimers of artemisinin see (a) Paik, I.-H.; Xie, S.; Shapiro,
T. A.; Labonte, T.; Narducci Sarjeant, A. A.; Baege, A. C.; Posner, G. H.
J. Med. Chem. 2006, 49, 2731–2734. (b) Posner, G. H.; Paik, I.-H.; Chang,
W.; Borstnik, K.; Sinishtaj, S.; Rosenthal, A. S.; Shapiro, T. A. J. Med.
Chem. 2007, 50, 2516–2519. (c) Posner, G. H.; Chang, W.; Hess, L.;
Woodard, L.; Sinishtaj, S.; Usera, A. R.; Maio, W.; Rosenthal, A. S.;
Kalinda, A. S.; D′Angelo, J. G.; Petersen, K. S.; Stohler, R.; Chollet, J.;
Santo-Thomas, J.; Snyder, C.; Rottmann, M.; Wittlin, S.; Brun, R.; Shapiro,
T. A. J. Med. Chem. 2008, 51, 1035–1042.
OL802238D
(9) For in vivo antimalarial efficacy test procedure see reference 3c.
(10) CDRI Communication No.: 7553.
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