Synthesis of novel analogues of zanamivir as neuraminidase inhibitors

Article abstract of DOI:10.1016/j.cclet.2010.06.021

A versatile synthesis of novel zanamivir analogues modified at C-4 and C-8 positions was described. The formation of amides from the acid with corresponding amines, followed by click chemistry generated the triazole substituted compounds as novel analogue

Full text of DOI:10.1016/j.cclet.2010.06.021

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 1338–1341
www.elsevier.com/locate/cclet
Synthesis of novel analogues of zanamivir
as neuraminidase inhibitors
Rui Sheng Xiong a, Qing Jie Zhao a, Hang Hang Zhu b, Zheng Liu c,
Ya Bing Wei b, Jing Shan Shen a,c,
*
a Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
b College of Materials Science and Engineering, Nanjing University of Technology, Nanjing 210009, China
c Topharman Shanghai Co., Ltd., Shanghai 201209, China
Received 23 March 2010
Abstract
A versatile synthesis of novel zanamivir analogues modified at C-4 and C-8 positions was described. The formation of amides
from the acid with corresponding amines, followed by click chemistry generated the triazole substituted compounds as novel
analogues of neuraminidase inhibitors in good yields.
# 2010 Jing Shan Shen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Zanamivir; Triazole; Click chemistry
Neuraminidase (NA) located on the surface of the influenza virus particle plays an important role in the spread of
virus from cell to cell and within the respiratory tract [1]. The genetic stability of the NA enzymatic active center
among all influenza viruses [2] makes it a promising target for therapy of influenza A and B [3]. Reports of structures
of NA complexed with a variety of inhibitors [4–8] provided a detailed understanding involved molecular interactions,
so a lot of compounds were designed and optimized based on structure-based drug design (SBDD) [9]. Consequently,
zanamivir (1) (Fig. 1) was approved by FDA as first NA inhibitor for treatment of influenza A and B in 1999 [10].
However, due to poor oral bioavailability [11] of zanamivir, there is still a need to identify more effective NA
inhibitors against influenza virus. Research on the structure–activity relationships (SAR) of zanamivir analogues [12–
16] have revealed that the glycerol group of 2-deoxy-2,3-didehydro-N-acetyl-D-neuraminic acid (2) lied in the region
of mixed polarity, therefore, the glycerol side chain would be considered to possible structural modifications. In
addition, previous research showed some of C-4 modified compounds, such as etherated compound 3 [17] and triazole
substituted compound 4 [13], whose inhibitory activities to NA were comparable with zanamivir. Therefore, those
results have indicated the structural modification of zanamivir is viable.
As our continuing studies on zanamivir analogues [18], in this communication we would describe the synthesis of
zanamivir analogues modified on C-4 and C-8 positions as shown in Scheme 1.
* Corresponding author at: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
E-mail address: jsshen@mail.shcnc.ac.cn (J.S. Shen).
1001-8417/$ – see front matter # 2010 Jing Shan Shen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.06.021

[(Fig._1)TD$FIG]
R.S. Xiong et al. / Chinese Chemical Letters 21 (2010) 1338–1341
1339
Fig. 1. Zanamivir and its derivatives.
[(Scheme_1)TD$FIG]
Scheme 1. Reagents and conditions: (a) NaIO4, H2O, CH3OH, then NaClO2, cyclohexene, KH2PO4, t-BuOH, H2O; (b) EDCI, HOBt, THF/CH2Cl2
(v/v, 1:2), methylamine (9a), dimethylamine (9b) or pyrrolidine (9c); (c) alkynes, CuSO4Á5H2O, sodium ascorbate, ethanol, H2O, r.t.; (d) NaOH,
CH3OH, then H+-resin, rt.
Modification was firstly implemented on C-8 position. Oxidation of glycerol side chain of mono-protected O-acetyl
compound 7 [18] by NaIO4, followed by NaClO2 [19] in aqueous solution of cyclohexene, t-BuOH and sodium
dihydrogen phosphate afforded carboxylic acid 8 almost quantitatively. Then reaction of compound 8 with
methylamine, dimethylamine or pyrrolidine in the presence of 1-ethyl-3-(3-dimethyllaminopropyl)-carbodiimide
hydrochloride (EDCI) and 1-hydroxybenzo triazole (HOBt) [20] afforded 9a–c in different yields respectively (Table
1).
After completing the structural modification of C-8 position, we next pay our attention to the preparation of the 1,4-
disubstituted-1,2,3-triazole at the C-4 position by the click chemistry, pioneered by Sharpless group, that has been
explored as new approach for the synthesis of drug-like molecules and accelerate the drug discovery process [21]. The
cycloaddition between terminal alkyne and azide now is an attractive tool in construction of libraries of the structure
diversified compounds for studying SAR [22–24]. Using Huisgen cycloaddition catalyzed by Cu(I), triazole 10a–e,
11a–e and 12a–e were obtained by reaction of 9a–c with different alkynes in 60–80% yield. All alkynes with different
substituent groups including aliphatic, cyclic, ester or phenyl groups could give satisfactory yield. Hydrolysis of 10a–
e, 11a–e and 12a–e with NaOH/methanol, then neutralize with H+-resin afforded zanamivir analogues 13a–e, 14a–e
1
and 15a–e in over 86% yield individually (Table 2). H NMR and HRMS spectra of the representative target
compounds were performed [25].
In summary, based on the C-8 modified intermediates 9a–c, the analogues 13a–e, 14a–e and 15a–e were prepared
by using the well-documented Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition. A series of novel zanamivir
Table 1
Synthetic conditions and yields of 9a–c from 8.
Entry
Product
R1
Time (h)
Yielda (%)
1
2
3
9a
9b
9c
CH3NH–
(CH3)2N–
10
16
24
86
55
18
[DT$INLE]
a
Isolated yield.

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R.S. Xiong et al. / Chinese Chemical Letters 21 (2010) 1338–1341
Table 2
Synthetic yields of various intermediates 10a–e, 11a–e and 12a–e and zanamivir analogues 13a–e, 14a–e and 15a–e.
Entry
R1
R2
Product
10a
Yield (%)
Producta
13a
Yield (%)
1
2
3
CH3NH–
CH3NH–
CH3NH–
70
65
75
92
93
92
[DT$INLE]
10b
13b
[DT$INLE]
10c
13c
[DT$INLE]
4
5
CH3NH–
CH3NH–
10d
10e
72
60
13d
13e
92
88
[DT$INLE]
[DT$INLE]
6
7
(CH3)2NH–
(CH3)2NH–
(CH3)2NH–
(CH3)2NH–
(CH3)2NH–
11a
11b
11c
11d
11e
68
75
65
78
80
14a
14b
14c
14d
14e
94
94
95
90
95
[DT$INLE]
[DT$INLE]
8
[DT$INLE]
9
[DT$INLE]
10
[DT$INLE]
11
12
13
14
15
12a
12b
12c
12d
12e
71
74
70
75
75
15a
15b
15c
15d
15e
93
86
90
86
95
[DT$INLE]
[TD$INLINE]
[DT$INLE]
[TD$INLINE]
[DT$INLE]
[TD$INLINE]
[DT$INLE]
[TD$INLINE]
[TD$INLINE]
[DT$INLE]
a
R2 = –COOH (13d, 14d, 15d).
analogues with modification of both C-4 and C-8 were synthesized successfully. Click reaction was a key step to
construct efficiently the triazole cycles, which would allow the preparation of a number of zanamivir analogues for
further SAR studies. The biological evaluations of these analogues are currently underway and will be reported in due
course.
Acknowledgments
This work was supported by National Great Project of Scientific and Technical Supporting Programs Funded by
Ministry of Science & Technology of China (No. 2006BAI01B02).
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[25] The data for representative compounds: 13c: 1H NMR (400 MHz, DMSO-d6): d 7.79 (s, 1 H, CH), 5.81 (d, 1 H, J = 2.4 Hz, 3-H), 5.51 (dd, 1 H,
J = 2.0 Hz, J = 7.2 Hz, 4-H), 4.55 (d, 1 H, J = 10.8 Hz, 6-H), 4.22 (m, 1 H, 5-H), 4.05 (d, 1 H, J = 4.0 Hz, 7-H), 2.64 (d, 3 H, J = 3.6 Hz, CH3),
1.92 (m, 1 H, CH), 1.76 (s, 3 H, NHAc), 0.88 (m, 2 H, CH2), 0.69 (m, 2 H, CH2); HRMS(ESI): m/z calcd. C16H20N5O62Na [MÀH+2Na]+
424.1209, found 424.1232. 13d: 1H NMR (400 MHz, DMSO-d6): d 8.63 (s, 1 H, CH), 7.82 (m, 1 H, NH), 5.91 (d, 1 H, J = 2.3 Hz, 3-H), 5.60
(dd, 1 H, J = 1.9 Hz, J = 9.8 Hz, 4-H), 4.58 (d, 1 H, J = 11.3 Hz, 6-H), 4.33 (m, 1 H, 5-H), 4.09 (s, 1 H, 7-H), 2.64 (d, 3 H, J = 3.6 Hz, CH3), 1.74
(s, 3 H, NHAc); HRMS(ESI): m/z calcd. C14H17N5O8Na [M+Na]+ 406.0975, found 406.0991. 13e: 1H NMR (400 MHz, DMSO-d6): d 8.28 (s, 1
H, CH), 7.03 (m, 4 H, PhH), 6.51 (d, 1 H, J = 7.6 Hz, NH), 5.51 (d, 2 H, J = 4.5 Hz, 3-H and 4-H), 4.46 (m, 1 H, CH, 6-H), 4.29 (m, 1 H, CH, 5-
H), 4.05 (m, 1 H, CH, 7-H), 2.65 (d, 3 H, J = 3.6 Hz, CH3), 1.74 (s, 3 H, NHAc); HRMS(ESI): m/z calcd. C19H22N6O6Na [M+Na]+ 453.1499,
found 453.1515.