Design， Synthesis and Anti-influenza Activities of Novel Neuraminidase Inhibitors†

doi:10.7503/cjcu20200529

Abstract

Abstract:

Based on the X-ray crystal structure of neuraminidase（NA）， we chosed zanamivir， oseltamivir and peramivir as lead compounds， introduced phosphate ester groups to the corresponding amino group， and obtained ten new phosphamide derivatives， including C4 phosphorylated compounds of zanamivir and peramivir precursor， C5 phosphorylated compounds of oseltamivir. Their structures were confirmed by means of nuclear magnetic resonance spectroscopy（NMR） and high resolution mass spectrometry（HRMS）. Molecular dynamics simulations were used to evaluate the interaction of new compounds with NA. Moreover， their abilities to inhibit neuraminidase and influenza viruses were tested. The preliminary results revealed that most new compounds possessed antiviral activities both in enzyme and cell levels. In particular， compound I-8 showed comparable inhibitory activities to oseltamivir with the half maximal inhibitory concentration（IC₅₀） value of 0.397 nmol/L on NA-sensitive enzyme（NAs）， while compound I-6 showed comparable inhibitory activities to oseltamivir with the IC₅₀ value of 0.121 μmol/L on influenza A H3N2， which might be the candidate compounds for further development. Our work might provide some insight into the rational design of anti-flu agents and the discovery of new effective drugs.

Key words: Phosphorylation, Neuraminidase inhibitor, Anti-influenza

CLC Number:

R914.5

TrendMD:

YOU Yipeng, NIE Lin, LIU Jinbiao, FENG Yahui, LU Gui. Design， Synthesis and Anti-influenza Activities of Novel Neuraminidase Inhibitors^†[J]. Chem. J. Chinese Universities, 2020, 41(10): 2279.

Figures/Tables 10

Compd.	Appearance	m.p./℃	[α] $D 20$ (c1, MeOH)	Yield(%)	HRMS(calcd.), m/z^*
I?1	White solid	166.3—167.8	+115.4	85	449.1296(449.1296)
I?2	White solid	170.2—171.4	+32.2	66	453.1649(453.1644)
I?3	White solid	163.7—165.2	+96.2	86	421.0998(421.0983)
I?4	White solid	173.5—174.8	+14.3	60	481.1966(481.1957)
I?5	White solid	180.3—182.1	+18.3	75	445.0976(445.1018)
I?6	White solid	176.5—178.3	-3.54	65	369.0366(369.0705)
I?7	White solid	212.9—214.8	-51.2	83	443.1914(443.1918)
I?8	White solid	208.4—209.8	-29.0	45	415.1594(415.1605)
I?9	White solid	218.7—220.3	-123.3	45	463.1589(463.1605)
I?10	White solid	206.7—207.8	-45.9	69	423.2251(423.2255)

Compd.	Appearance	m.p./℃	[α] $D 20$ (c1, MeOH)	Yield(%)	HRMS(calcd.), m/z^*
I?1	White solid	166.3—167.8	+115.4	85	449.1296(449.1296)
I?2	White solid	170.2—171.4	+32.2	66	453.1649(453.1644)
I?3	White solid	163.7—165.2	+96.2	86	421.0998(421.0983)
I?4	White solid	173.5—174.8	+14.3	60	481.1966(481.1957)
I?5	White solid	180.3—182.1	+18.3	75	445.0976(445.1018)
I?6	White solid	176.5—178.3	-3.54	65	369.0366(369.0705)
I?7	White solid	212.9—214.8	-51.2	83	443.1914(443.1918)
I?8	White solid	208.4—209.8	-29.0	45	415.1594(415.1605)
I?9	White solid	218.7—220.3	-123.3	45	463.1589(463.1605)
I?10	White solid	206.7—207.8	-45.9	69	423.2251(423.2255)

Compd.	¹H NMR(400 MHz), δ	¹³C NMR(101 MHz), δ	³¹P NMR(162 MHz), δ
I?1	5.86(d, J=1.9 Hz, 1H), 4.24(d, J=10.0 Hz, 1H), 4.02(m, 4H), 3.84(m, 3H), 3.61(t, J=8.1 Hz, 3H), 2.03(d, J=3.0 Hz, 3H), 1.27(dd, J=12.6, 6.0 Hz, 6H)	174.6, 167.0, 147.1, 111.8, 78.3, 71.3, 70.2, 64.9, 64.0, 51.4, 50.8, 23.0, 16.5	10.04
I?2	6.00(s, 1H), 4.55(m, 2H), 4.29(d, J=10.0 Hz, 1H), 4.08(m, 2H), 3.89(dd, J=16.5, 8.0 Hz, 2H), 3.65(d, J=8.2 Hz, 2H), 2.07(s, 3H), 1.30(d, J=6.3 Hz, 12H)	174.4, 165.8, 144.0, 112.9, 76.6, 73.3, 70.0, 68.2, 63.1, 50.4, 49.0, 23.0, 22.4	7.83
Compd.	¹H NMR(400 MHz), δ	¹³C NMR(101 MHz), δ	³¹P NMR(162 MHz), δ
I?3	6.03(s, 1H), 4.34(d, J=9.4 Hz, 1H), 4.10(d, J=7.8 Hz, 2H), 3.92(m, 2H), 3.74(dd, J=21.6, 10.7 Hz, 8H), 2.10(s, 3H)	174.5, 165.4, 143.8, 113.0, 76.5, 69.9, 68.0, 63.0, 53.9, 50.2, 49.0, 22.2	12.57
I?4	5.76(s, 1H), 4.17(d, J=10.0 Hz, 1H), 3.92(d, J=7.6 Hz, 6H), 3.80(m, 2H), 3.54(d, J=8.2 Hz, 2H), 1.97(s, 3H), 1.57(d, J=6.0 Hz, 4H), 1.30(s, 4H), 0.83(d, J=6.7 Hz, 6H)	174.3, 167.1, 145.6, 110.8, 76.2, 69.8, 68.1, 67.5, 63.1, 50.3, 31.6, 22.2, 18.2, 12.8
I?5	7.40(t, J=7.8 Hz, 2H), 7.21(m, 3H), 5.69(s, 1H), 4.36(m, 2H), 4.20(d, J=7.1 Hz, 1H), 3.96(dd, J=16.5, 7.9 Hz, 1H), 3.91(d, J=11.9 Hz, 1H), 3.68(m, 2H), 2.09(s, 3H)	174.9, 168.5, 152.3, 150.7, 129.6, 123.7, 120.4, 99.9, 75.1, 69.7, 67.8, 63.0, 50.2, 45.9, 22.1	-2.84
I?6	6.04(s, 1H), 4.46(d, J=6.0 Hz, 1H), 4.42(d, J=6.7 Hz, 1H), 4.33(d, J=5.9 Hz, 1H), 3.94(dd, J=21.2, 9.6 Hz, 2H), 3.75(d, J=9.2 Hz, 1H), 3.70(dd, J=11.6, 5.6 Hz, 1H), 2.11(d, J=5.7 Hz, 3H)	175.0, 164.5, 146.3, 104.7, 75.8, 69.8, 67.6, 63.0, 49.8, 45.7, 22.3
I?7	6.79(s, 1H), 4.11(m, 1H), 4.03(d, J=7.3 Hz, 4H), 3.86(dd, J=10.8, 8.5 Hz, 1H), 3.44(m, 1H), 3.27(m, 1H), 2.79(dd, J=17.8, 5.2 Hz, 1H), 2.30(m, 1H), 2.01(s, 3H), 1.50(m, 4H), 1.32(m, 6H), 0.92(dt, J=10.8, 7.4 Hz, 6H)	174.0, 169.3, 138.9, 130.6, 83.7, 77.3, 64.3, 56.7, 52.0, 34.5, 27.3, 26.8, 23.3, 16.8, 16.4, 9.8	9.12
I?8	6.77(s, 1H), 4.10(d, J=8.6 Hz, 1H), 3.85(td, J=10.6, 6.3 Hz, 1H), 3.68(ddd, J=22.5, 10.0, 6.0 Hz, 6H), 3.40(m, 1H), 3.24(dd, J=13.3, 7.5 Hz, 1H), 2.79(dd, J=17.7, 5.3 Hz, 1H), 2.27(ddt, J=27.1, 22.6, 9.9 Hz, 1H), 2.00(s, 3H), 1.52(m, 4H), 0.91(dt, J=12.6, 7.4 Hz, 6H)	174.1, 169.4, 139.0, 130.6, 83.7, 77.4, 56.9, 54.0, 52.1, 34.6, 27.0, 23.2, 9.7	11.74
I?9	7.40(t, J=7.8 Hz, 2H), 7.19(m, 3H), 6.38(s, 1H), 4.18(d, J=8.6 Hz, 1H), 3.77(m, 1H), 3.51(m, 1H), 3.26(qd, J=10.3, 5.3 Hz, 1H), 2.69(dd, J=17.5, 5.0 Hz, 1H), 2.22(m, 1H), 1.89(s, 3H), 1.49(m, 4H), 0.87(dt, J=25.4, 7.3 Hz, 6H)	175.3, 174.8, 152.6, 131.8, 129.7, 123.6, 120.3, 83.9, 77.3, 56.4, 51.2, 35.2, 25.6, 25.3, 22.4, 8.6	3.50
I?10	7.34(d, J=9.6 Hz, 1H), 4.25(m, 1H), 4.02(m, 4H), 3.64(d, J=9.6 Hz, 1H), 3.50(s, 1H), 2.75(d, J=6.4 Hz, 1H), 2.44(dt, J=12.9, 8.4 Hz, 1H), 2.07(d, J=4.1 Hz, 1H), 1.99(d, J=12.1 Hz, 3H), 1.93(s, 1H), 1.58(m, 4H), 1.28(dd, J=11.9, 6.2 Hz, 6H), 0.81(dt, J=14.6, 7.3 Hz, 6H)	177.4, 172.0, 63.1, 52.2, 52.1, 49.7, 48.8, 43.7, 35.6, 22.9, 22.0, 21.3, 16.2, 10.6	8.43

Compd.	¹H NMR(400 MHz), δ	¹³C NMR(101 MHz), δ	³¹P NMR(162 MHz), δ
I?1	5.86(d, J=1.9 Hz, 1H), 4.24(d, J=10.0 Hz, 1H), 4.02(m, 4H), 3.84(m, 3H), 3.61(t, J=8.1 Hz, 3H), 2.03(d, J=3.0 Hz, 3H), 1.27(dd, J=12.6, 6.0 Hz, 6H)	174.6, 167.0, 147.1, 111.8, 78.3, 71.3, 70.2, 64.9, 64.0, 51.4, 50.8, 23.0, 16.5	10.04
I?2	6.00(s, 1H), 4.55(m, 2H), 4.29(d, J=10.0 Hz, 1H), 4.08(m, 2H), 3.89(dd, J=16.5, 8.0 Hz, 2H), 3.65(d, J=8.2 Hz, 2H), 2.07(s, 3H), 1.30(d, J=6.3 Hz, 12H)	174.4, 165.8, 144.0, 112.9, 76.6, 73.3, 70.0, 68.2, 63.1, 50.4, 49.0, 23.0, 22.4	7.83
Compd.	¹H NMR(400 MHz), δ	¹³C NMR(101 MHz), δ	³¹P NMR(162 MHz), δ
I?3	6.03(s, 1H), 4.34(d, J=9.4 Hz, 1H), 4.10(d, J=7.8 Hz, 2H), 3.92(m, 2H), 3.74(dd, J=21.6, 10.7 Hz, 8H), 2.10(s, 3H)	174.5, 165.4, 143.8, 113.0, 76.5, 69.9, 68.0, 63.0, 53.9, 50.2, 49.0, 22.2	12.57
I?4	5.76(s, 1H), 4.17(d, J=10.0 Hz, 1H), 3.92(d, J=7.6 Hz, 6H), 3.80(m, 2H), 3.54(d, J=8.2 Hz, 2H), 1.97(s, 3H), 1.57(d, J=6.0 Hz, 4H), 1.30(s, 4H), 0.83(d, J=6.7 Hz, 6H)	174.3, 167.1, 145.6, 110.8, 76.2, 69.8, 68.1, 67.5, 63.1, 50.3, 31.6, 22.2, 18.2, 12.8
I?5	7.40(t, J=7.8 Hz, 2H), 7.21(m, 3H), 5.69(s, 1H), 4.36(m, 2H), 4.20(d, J=7.1 Hz, 1H), 3.96(dd, J=16.5, 7.9 Hz, 1H), 3.91(d, J=11.9 Hz, 1H), 3.68(m, 2H), 2.09(s, 3H)	174.9, 168.5, 152.3, 150.7, 129.6, 123.7, 120.4, 99.9, 75.1, 69.7, 67.8, 63.0, 50.2, 45.9, 22.1	-2.84
I?6	6.04(s, 1H), 4.46(d, J=6.0 Hz, 1H), 4.42(d, J=6.7 Hz, 1H), 4.33(d, J=5.9 Hz, 1H), 3.94(dd, J=21.2, 9.6 Hz, 2H), 3.75(d, J=9.2 Hz, 1H), 3.70(dd, J=11.6, 5.6 Hz, 1H), 2.11(d, J=5.7 Hz, 3H)	175.0, 164.5, 146.3, 104.7, 75.8, 69.8, 67.6, 63.0, 49.8, 45.7, 22.3
I?7	6.79(s, 1H), 4.11(m, 1H), 4.03(d, J=7.3 Hz, 4H), 3.86(dd, J=10.8, 8.5 Hz, 1H), 3.44(m, 1H), 3.27(m, 1H), 2.79(dd, J=17.8, 5.2 Hz, 1H), 2.30(m, 1H), 2.01(s, 3H), 1.50(m, 4H), 1.32(m, 6H), 0.92(dt, J=10.8, 7.4 Hz, 6H)	174.0, 169.3, 138.9, 130.6, 83.7, 77.3, 64.3, 56.7, 52.0, 34.5, 27.3, 26.8, 23.3, 16.8, 16.4, 9.8	9.12
I?8	6.77(s, 1H), 4.10(d, J=8.6 Hz, 1H), 3.85(td, J=10.6, 6.3 Hz, 1H), 3.68(ddd, J=22.5, 10.0, 6.0 Hz, 6H), 3.40(m, 1H), 3.24(dd, J=13.3, 7.5 Hz, 1H), 2.79(dd, J=17.7, 5.3 Hz, 1H), 2.27(ddt, J=27.1, 22.6, 9.9 Hz, 1H), 2.00(s, 3H), 1.52(m, 4H), 0.91(dt, J=12.6, 7.4 Hz, 6H)	174.1, 169.4, 139.0, 130.6, 83.7, 77.4, 56.9, 54.0, 52.1, 34.6, 27.0, 23.2, 9.7	11.74
I?9	7.40(t, J=7.8 Hz, 2H), 7.19(m, 3H), 6.38(s, 1H), 4.18(d, J=8.6 Hz, 1H), 3.77(m, 1H), 3.51(m, 1H), 3.26(qd, J=10.3, 5.3 Hz, 1H), 2.69(dd, J=17.5, 5.0 Hz, 1H), 2.22(m, 1H), 1.89(s, 3H), 1.49(m, 4H), 0.87(dt, J=25.4, 7.3 Hz, 6H)	175.3, 174.8, 152.6, 131.8, 129.7, 123.6, 120.3, 83.9, 77.3, 56.4, 51.2, 35.2, 25.6, 25.3, 22.4, 8.6	3.50
I?10	7.34(d, J=9.6 Hz, 1H), 4.25(m, 1H), 4.02(m, 4H), 3.64(d, J=9.6 Hz, 1H), 3.50(s, 1H), 2.75(d, J=6.4 Hz, 1H), 2.44(dt, J=12.9, 8.4 Hz, 1H), 2.07(d, J=4.1 Hz, 1H), 1.99(d, J=12.1 Hz, 3H), 1.93(s, 1H), 1.58(m, 4H), 1.28(dd, J=11.9, 6.2 Hz, 6H), 0.81(dt, J=14.6, 7.3 Hz, 6H)	177.4, 172.0, 63.1, 52.2, 52.1, 49.7, 48.8, 43.7, 35.6, 22.9, 22.0, 21.3, 16.2, 10.6	8.43

Entry	Compd.	IC₅₀of NAs/(μmol·L^-1)	IC₅₀of NAr/(μmol·L^-1)
1	I?1	4.14	95.4
2	I?2	10.9	18.7
3	I?3	3.15	2.86
4	I?4	25.1	32.3
5	I?5	0.1178	0.0757
6	I?6	0.3558	0.259
7	I?7	0.092	55.7
8	I?8	0.000397	7.83
9	I?9	0.239	151
10	I?10	0.1947	—
11	Oseltamivir	0.000291	0.0794
12	4?Amino?DANA	0.286	0.164

Entry	Compd.	IC₅₀/(μmol·L^-1)
Entry	Compd.	H3N2	H1N1
1	I?1	125	54.5
2	I?3	3.15	10.92
3	I?5	0.149	0.292
4	I?6	0.121	0.798
5	I?7	3.23	6.06
6	I?8	6.73	25.9
7	I?9	0.315	9.94
8	I?10	0.619	4.629
9	Oseltamivir	0.0851	0.025
10	4?Amino?DANA	1.23	2.3

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