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Compd.	Yield /%	mp /℃	$ {\left[\alpha \right]}_{589\ \mathrm{n}\mathrm{m}}^{25\ ^\circ {\rm{C}}} $= (±) Value (c : g/100 mL, CH₃OH)	¹HNMR (600 MHz)	¹³C NMR (151 MHz)	HR-ESI-MS (m/z)
2a	56	172-173	+127 (0.011)	(CDCl₃) δ 6.03 (d, J = 2.1 Hz, 1H), 4.36 (d, J = 2.1 Hz, 1H), 4.05-3.96 (m, 1H), 3.93-3.86 (m, 1H), 3.86-3.79 (m, 2H), 3.76 (d, J = 13.7 Hz, 1H), 3.68 (s, 2H), 3.44-3.36 (m, 1H), 3.35 (s, 3H), 3.16-3.12 (m, 1H), 2.50-2.37 (m, 2H), 2.31-2.28 (m, 1H), 2.22-2.19 (m, 1H), 2.18-2.14 (m, 1H), 2.02-2.00 (m, 1H), 1.99-1.95 (m, 1H), 1.95-1.87 (m, 2H), 1.85-1.76 (m, 2H), 1.73 (d, J = 13.7 Hz, 1H), 1.48 (s, 9H).	(CDCl₃) δ 156.1, 136.1, 130.0, 80.8, 76.0, 68.9, 61.8, 60.1, 58.7, 43.4, 34.7, 29.6, 28.7, 28.5 (3), 27.6, 23.7, 22.9, 20.7, 17.8.	[M]⁺: C₂₁H₃₅N₂O₂ 347.269 3, 347.269 0.
2b	24	175-176	+35 (0.011)	(DMSO-d₆) δ 7.93-7.88 (m, 2H), 7.88-7.81 (m, 2H), 6.02-5.82 (m, 1H), 4.05-3.89 (m, 1H), 3.87-3.82 (m, 1H), 3.50-3.46 (m, 2H), 3.33 (s, 3H), 3.28-3.24 (m, 1H), 3.20-3.17 (m, 1H), 3.16 (s, 1H), 3.13-3.08 (m, 1H), 2.42-2.30 (m, 1H), 2.27-2.06 (m, 2H), 2.02-1.89 (m, 2H), 1.85-1.82 (m, 1H), 1.75-1.65 (m, 2H), 1.59-1.55 (m, 2H), 1.53-1.47 (m, 1H), 1.43-1.38 (m, 1H), 1.30-1.20 (m, 1H), 0.86-0.83 (m, 1H).	(DMSO-d₆) δ 136.7, 135.5, 132.6 (2), 129.6 (2), 129.4, 127.5, 74.3, 67.5, 60.0, 58.7, 45.7, 44.6, 33.5, 30.8, 28.9, 27.3, 22.9, 21.7, 19.5, 17.1.	[M]⁺: C₂₂H₃₀BrN₂O₂S 465.120 6, 465.119 7.
2c	19	165-166	+30 (0.020)	(DMSO-d₆) δ 7.79-7.77 (m, J = 1.8 Hz, 1H), 7.75 (dd, J = 7.5, 1.6 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 5.89-5.80 (m, 1H), 4.11 (d, J = 13.9 Hz, 1H), 3.74-3.70 (m, 2H), 3.56-3.52 (m, 1H), 3.43 (s, 3H), 3.36-3.33 (m, 1H), 3.13 (s, 1H), 3.05 (d, J = 13.9 Hz, 1H), 2.97-2.95 (m, 1H), 2.90-2.85 (m, 1H), 2.73-2.63 (m, 1H), 2.55 (d, J = 4.8 Hz, 2H), 2.40-2.37 (m, 1H), 2.34-2.20 (m, 2H), 2.01 (t, J = 4.8 Hz, 2H), 1.94-1.90 (m, 1H), 1.85-1.76 (m, 2H), 1.72-1.66 (m, 1H), 1.58-1.55 (m, 2H), 1.42-1.39 (m, 1H).	(DMSO-d₆) δ 140.6, 138.0, 134.3, 132.5, 131.4, 130.1, 127.7, 119.4, 111.9, 68.9, 66.2, 64.6, 58.6, 57.2, 54.9, 52.6, 34.9, 34.5, 33.5, 28.7, 27.8, 24.2, 23.4, 20.3.	[M]⁺: C₂₄H₃₂N₃ 362.259 1, 362.258 4.
3	42	/(oil)	+31 (0.013)	(CDCl₃) δ 4.05-4.03 (m, 1H), 3.10-3.06 (m, 2H), 2.55-2.50 (m, 1H), 2.49-2.46 (m, 1H), 2.39-2.36 (m, Hz, 1H), 2.21-2.18 (m, 3H), 2.13-2.10 (m, 1H), 2.06 (s, 3H), 2.04-2.00 (m, 1H), 1.79-1.75 (m, 1H), 1.74-1.71 (m, 2H), 1.71-1.64 (m, 2H), 1.36 (s, 9H), 1.32-1.28 (m, 1H), 1.22-1.18 (m, 1H), 1.16-1.11 (m, 1H), 1.00-0.95 (m, 1H), 0.82-0.79 (m, 1H), 0.76-0.72 (m, 1H).	(CDCl₃) δ 153.8, 129.6, 129.4, 78.6, 59.5, 59.0, 44.6, 44.1, 35.2, 30.5, 30.0, 29.5, 27.7, 27.5, 27.4 (3), 25.2, 23.5, 20.6, 19.0.	[M+H]⁺: C₂₁H₃₅N₂O₂ 347.269 3, 347.270 6.
4a	36	/(oil)	+126 (0.006)	(CDCl₃) δ 6.69-6.67 (m, 1H), 4.96 (br, 1H), 3.17-3.14 (m, 1H), 3.08-3.04 (m, 1H), 2.99-2.90 (m, 1H), 2.72-2.68 (m, 2H), 2.64-2.51 (m, 2H), 2.37-2.35 (m, 1H), 2.27-2.24 (m, 2H), 2.16-2.12 (m, 1H), 1.91 (d, J = 6.8 Hz, 2H), 1.88-1.85 (m, 1H), 1.86-1.80 (m, 1H), 1.61-1.57 (m, 2H), 1.53 (d, J = 6.8 Hz, 1H), 1.44-1.40 (m, 1H), 1.37 (s, 9H), 1.12-1.08 (m, 2H).	(CDCl₃) δ 155.1, 146.0, 139.4, 77.9, 54.4, 53.5, 52.4, 48.2, 42.9, 38.7, 35.5, 27.6, 27.5 (3), 26.4, 25.8, 24.7, 22.8, 18.0.	[M+H]⁺: C₂₀H₃₃N₂O₃ 349.248 6, 349.248 7.
4b	37	136-137	+50 (0.008)	(CDCl₃) δ 7.41-7.31 (m, 2H), 6.86-6.84 (m, 1H), 6.78-6.74 (m, 1H), 3.43-3.32 (m, 1H), 3.22-3.18 (m, 2H), 2.73-2.65 (m, 2H), 2.62-2.57 (m, 2H), 2.41 (q, J = 3.3 Hz, 1H), 2.34-2.31 (m, 1H), 2.29-2.26 (m, 1H), 2.23-2.20 (m, 1H), 1.94 (d, J = 3.3 Hz, 2H), 1.91-1.89 (m, 1H), 1.87-1.82 (m, 1H), 1.71-1.67 (m, 2H), 1.63-1.60 (m, 1H), 1.42-1.39 (m, 1H), 1.19 (s, 1H), 1.14-1.08 (m, 2H).	(CDCl₃) δ 163.8, 162.8 (d, J = 12.1 Hz), 161.1 (d, J = 12.1 Hz), 147.9, 139.4, 137.4 (t, J = 6.0 Hz), 109.4 (d, J = 6.0 Hz), 109.2 (d, J = 6.0 Hz), 105.5 (t, J = 25.7 Hz), 54.3, 53.7, 48.6, 42.8, 37.1, 35.5, 28.7, 28.1, 26.4, 24.7, 24.2, 22.6, 18.1.	[M+H]⁺: C₂₂H₂₇F₂N₂O₂ 389.203 5, 389.205 0.
4c	42	190-192	+153 (0.015)	(CDCl₃) δ 7.75 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H), 6.10-6.08 (m, 1H), 4.52-4.50 (m, 2H), 3.90-3.86 (m, 1H), 3.71-3.67 (m, 1H), 3.64 (d, J = 14.5 Hz, 1H), 3.56-3.54 (m, 2H), 3.46-3.37 (m, 1H), 3.10 (d, J = 14.5 Hz, 1H), 2.91 (s, 1H), 2.39 (s, 2H), 2.10-2.07 (m, 1H), 1.98-1.94 (m, 2H), 1.87 (s, 1H), 1.80 (s, 2H), 1.75-1.72 (m, 1H), 1.34-1.27 (m, 1H), 1.24-1.22 (m, 2H).	(CDCl₃) δ 138.8, 137.7, 132.5 (2), 130.6, 129.3 (2), 128.2, 68.6, 58.4, 57.3, 55.1, 54.6, 45.5, 42.5, 33.5, 33.2, 30.7, 23.8, 22.1, 18.4.	[M+H]⁺: C₂₁H₂₈BrN₂O₃S 467.099 9, 467.100 1.
5a	29	153-154	+28 (0.011)	(CDCl₃) δ 3.64-3.60 (m, 1H), 3.47 (s, 1H), 3.40-3.47 (m, 1H), 3.20-3.10 (m, 1H), 2.97-2.87 (m, 1H), 2.75-2.62 (m, 2H), 2.54-2.51 (m, 1H), 2.44-2.36 (m, 1H), 2.17-2.08 (m, 2H), 1.93 (s, 2H), 1.85-1.78 (m, 2H), 1.77-1.66 (m, 2H), 1.43 (s, 9H), 1.40-1.36 (m, 2H), 1.08-1.04 (m, 2H).	(CDCl₃) δ 200.7, 155.6, 151.9, 120.9, 80.9, 57.9, 53.5, 46.3, 45.5, 45.1, 32.5, 27.5, 27.2 (3), 25.9, 24.6, 21.3, 19.7, 18.5.	[M+H]⁺: C₂₀H₃₁N₂O₃ 347.232 9, 347.232 5.
5b	23	128-130	+15 (0.014)	(CDCl₃) δ 7.49-7.32 (m, 2H), 6.95-6.85 (m, 1H), 5.18 (s, 1H), 3.80-3.78 (m, 1H), 3.62-3.60 (m, 1H), 3.50-3.47 (m, 1H), 3.37-3.35 (m, 2H), 3.31-3.28 (m, 1H), 3.19-3.17 (m, 1H), 3.10-3.07 (m, 1H), 2.47-2.44 (m, 1H), 2.35-2.32 (m, 1H), 2.30-2.24 (m, 1H), 2.19-2.16 (m, 1H), 2.13-2.08 (m, 1H), 1.99-1.94 (m, 1H), 1.95-1.86 (m, 1H), 1.77-1.74 (m, 1H), 1.71-1.66 (m, 1H), 1.65-1.60 (m, 1H), 1.57-1.54 (m, 2H).	(CDCl₃) δ 196.6, 168.4 (dt, J = 144.96, 3.02 Hz), 161.8 (dq, J = 249.15, 144.96 Hz, 2C), 152.9, 137.5 (dt, J = 12.08, 4.53 Hz), 125.2, 111.41 (dq, J = 58.89, 4.53 Hz, 2C), 106.4 (dt, J = 99.66, 25.67 Hz), 57.3, 55.8, 51.9, 47.8, 45.7, 29.6, 23.7, 22.4, 21.3, 19.8, 17.9, 17.4.	[M+H]⁺: C₂₂H₂₅F₂N₂O₂ 387.187 9, 387.187 8.
5c	21	159-161	-156 (0.009)	(CDCl₃) δ 8.07 (d, J = 2.2 Hz, 1H), 7.83 (q, J = 8.8 Hz, 3H), 7.61 (dd, J = 8.8, 2.2 Hz, 1H), 7.55-7.44 (m, 2H), 4.05-4.01 (m, 1H), 3.31-3.23 (m, 1H), 3.03-3.00 (m, 1H), 2.94-2.91 (m, 2H), 2.77-2.74 (m, 1H), 2.67 (d, J = 13.6 Hz, 1H), 2.58-2.46 (m, 2H), 2.43-2.40 (m, 1H), 2.29-2.24 (m, 1H), 2.18-2.15 (m, 1H), 2.13-1.95 (m, 1H), 1.88-1.84 (m, 2H), 1.78-1.75 (m, 2H), 1.52-1.50 (m, 1H), 1.42 (d, J = 13.6 Hz, 1H), 1.10-0.99 (m, 2H).	(CDCl₃) δ 200.8, 170.4, 152.0, 133.7, 132.4, 131.6, 128.1, 127.9, 127.6, 127.0, 126.9, 126.1, 123.7, 121.3, 59.7, 57.7, 53.4, 52.4, 46.7, 46.4, 45.2, 37.9, 24.5, 22.3, 19.7, 18.5.	[M+H]⁺: C₂₆H₂₉N₂O₂ 401.222 4, 401.221 9.
5d	25	189-191	-131 (0.016)	(CDCl₃) δ 7.69 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H), 4.03-3.97 (m, 1H), 3.58 (s, 1H), 3.33 (s, 1H), 3.20-3.10 (m, 1H), 2.98 (d, J = 12.1 Hz, 1H), 2.81 (s, 1H), 2.67 (d, J = 13.9 Hz, 1H), 2.50-2.28 (m, 2H), 2.22 (s, 1H), 2.15-2.09 (m, 1H), 1.98 (d, J = 12.1 Hz, 1H), 1.93 (d, J = 13.9 Hz, 1H), 1.88-1.84 (m, 2H), 1.73-1.67 (m, 1H), 1.62-1.58 (m, 1H), 1.50-1.45 (m, 2H), 1.14-1.10 (m, 2H).	(CDCl₃) δ 201.2, 153.6, 139.5, 132.7 (2), 128.2 (2), 124.9, 98.5, 58.6, 54.4, 47.8, 47.2, 45.7, 34.2, 26.1, 25.5, 22.0, 21.3, 20.6, 19.4.	[M+H]⁺: C₂₁H₂₆BrN₂O₃S 465.084 2, 465.085 5.
5e	21	132-134	-27 (0.023)	(CDCl₃) δ 7.61 (dt, J = 7.7, 1.5 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.48-7.46 (m, 1H), 7.44 (d, J =1.5 Hz, 1H), 4.64 (d, J = 17.2 Hz, 1H), 4.40 (d, J = 17.2 Hz, 1H), 3.36-3.32 (m, 1H), 3.26 (d, J = 2.9 Hz, 1H), 3.19-3.05 (m, 2H), 2.92 (td, J = 13.6, 2.9 Hz, 1H), 2.81 (d, J = 13.6 Hz, 1H), 2.75 (s, 1H), 2.50-2.47 (m, 2H), 2.45-2.39 (m, 1H), 2.23-2.20 (m, 1H), 2.07-1.99 (m, 2H), 1.92 (dd, J = 13.1, 3.8 Hz, 1H), 1.89-1.84 (m, 2H), 1.82-1.74 (m, 1H), 1.62 (qt, J = 13.1, 3.8 Hz, 1H), 1.51-1.47 (m, 1H), 1.26-1.23 (m, 2H).	(CDCl₃) δ 196.1, 159.7, 139.4, 131.4, 130.5, 129.9, 129.7, 118.5, 113.2, 108.8, 58.3, 54.7, 53.1, 49.7, 47.0, 46.5, 32.2, 27.0, 25.1, 23.5, 21.1, 19.8, 19.6.	[M+H]⁺: C₂₃H₂₈N₃O 362.222 7, 362.224 6.

Compd.

Yield /%

mp /℃

$ {\left[\alpha \right]}_{589\ \mathrm{n}\mathrm{m}}^{25\ ^\circ {\rm{C}}} $

= (±) Value (c : g/100 mL, CH₃OH)

¹HNMR (600 MHz)

¹³C NMR (151 MHz)

HR-ESI-MS (m/z)

Formula Calcd. Found

172-173

+127 (0.011)

(CDCl₃) δ 6.03 (d, J = 2.1 Hz, 1H), 4.36 (d, J = 2.1 Hz, 1H), 4.05-3.96 (m, 1H), 3.93-3.86 (m, 1H), 3.86-3.79 (m, 2H), 3.76 (d, J = 13.7 Hz, 1H), 3.68 (s, 2H), 3.44-3.36 (m, 1H), 3.35 (s, 3H), 3.16-3.12 (m, 1H), 2.50-2.37 (m, 2H), 2.31-2.28 (m, 1H), 2.22-2.19 (m, 1H), 2.18-2.14 (m, 1H), 2.02-2.00 (m, 1H), 1.99-1.95 (m, 1H), 1.95-1.87 (m, 2H), 1.85-1.76 (m, 2H), 1.73 (d, J = 13.7 Hz, 1H), 1.48 (s, 9H).

(CDCl₃) δ 156.1, 136.1, 130.0, 80.8, 76.0, 68.9, 61.8, 60.1, 58.7, 43.4, 34.7, 29.6, 28.7, 28.5 (3), 27.6, 23.7, 22.9, 20.7, 17.8.

[M]⁺:
C₂₁H₃₅N₂O₂
347.269 3,
347.269 0.

175-176

+35 (0.011)

(DMSO-d₆) δ 7.93-7.88 (m, 2H), 7.88-7.81 (m, 2H), 6.02-5.82 (m, 1H), 4.05-3.89 (m, 1H), 3.87-3.82 (m, 1H), 3.50-3.46 (m, 2H), 3.33 (s, 3H), 3.28-3.24 (m, 1H), 3.20-3.17 (m, 1H), 3.16 (s, 1H), 3.13-3.08 (m, 1H), 2.42-2.30 (m, 1H), 2.27-2.06 (m, 2H), 2.02-1.89 (m, 2H), 1.85-1.82 (m, 1H), 1.75-1.65 (m, 2H), 1.59-1.55 (m, 2H), 1.53-1.47 (m, 1H), 1.43-1.38 (m, 1H), 1.30-1.20 (m, 1H), 0.86-0.83 (m, 1H).

(DMSO-d₆) δ 136.7, 135.5, 132.6 (2), 129.6 (2), 129.4, 127.5, 74.3, 67.5, 60.0, 58.7, 45.7, 44.6, 33.5, 30.8, 28.9, 27.3, 22.9, 21.7, 19.5, 17.1.

[M]⁺:
C₂₂H₃₀BrN₂O₂S 465.120 6,
465.119 7.

165-166

+30 (0.020)

(DMSO-d₆) δ 7.79-7.77 (m, J = 1.8 Hz, 1H), 7.75 (dd, J = 7.5, 1.6 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 5.89-5.80 (m, 1H), 4.11 (d, J = 13.9 Hz, 1H), 3.74-3.70 (m, 2H), 3.56-3.52 (m, 1H), 3.43 (s, 3H), 3.36-3.33 (m, 1H), 3.13 (s, 1H), 3.05 (d, J = 13.9 Hz, 1H), 2.97-2.95 (m, 1H), 2.90-2.85 (m, 1H), 2.73-2.63 (m, 1H), 2.55 (d, J = 4.8 Hz, 2H), 2.40-2.37 (m, 1H), 2.34-2.20 (m, 2H), 2.01 (t, J = 4.8 Hz, 2H), 1.94-1.90 (m, 1H), 1.85-1.76 (m, 2H), 1.72-1.66 (m, 1H), 1.58-1.55 (m, 2H), 1.42-1.39 (m, 1H).

(DMSO-d₆) δ 140.6, 138.0, 134.3, 132.5, 131.4, 130.1, 127.7, 119.4, 111.9, 68.9, 66.2, 64.6, 58.6, 57.2, 54.9, 52.6, 34.9, 34.5, 33.5, 28.7, 27.8, 24.2, 23.4, 20.3.

[M]⁺:
C₂₄H₃₂N₃
362.259 1,
362.258 4.

/(oil)

+31 (0.013)

(CDCl₃) δ 4.05-4.03 (m, 1H), 3.10-3.06 (m, 2H), 2.55-2.50 (m, 1H), 2.49-2.46 (m, 1H), 2.39-2.36 (m, Hz, 1H), 2.21-2.18 (m, 3H), 2.13-2.10 (m, 1H), 2.06 (s, 3H), 2.04-2.00 (m, 1H), 1.79-1.75 (m, 1H), 1.74-1.71 (m, 2H), 1.71-1.64 (m, 2H), 1.36 (s, 9H), 1.32-1.28 (m, 1H), 1.22-1.18 (m, 1H), 1.16-1.11 (m, 1H), 1.00-0.95 (m, 1H), 0.82-0.79 (m, 1H), 0.76-0.72 (m, 1H).

(CDCl₃) δ 153.8, 129.6, 129.4, 78.6, 59.5, 59.0, 44.6, 44.1, 35.2, 30.5, 30.0, 29.5, 27.7, 27.5, 27.4 (3), 25.2, 23.5, 20.6, 19.0.

[M+H]⁺:
C₂₁H₃₅N₂O₂
347.269 3,
347.270 6.

/(oil)

+126 (0.006)

(CDCl₃) δ 6.69-6.67 (m, 1H), 4.96 (br, 1H), 3.17-3.14 (m, 1H), 3.08-3.04 (m, 1H), 2.99-2.90 (m, 1H), 2.72-2.68 (m, 2H), 2.64-2.51 (m, 2H), 2.37-2.35 (m, 1H), 2.27-2.24 (m, 2H), 2.16-2.12 (m, 1H), 1.91 (d, J = 6.8 Hz, 2H), 1.88-1.85 (m, 1H), 1.86-1.80 (m, 1H), 1.61-1.57 (m, 2H), 1.53 (d, J = 6.8 Hz, 1H), 1.44-1.40 (m, 1H), 1.37 (s, 9H), 1.12-1.08 (m, 2H).

(CDCl₃) δ 155.1, 146.0, 139.4, 77.9, 54.4, 53.5, 52.4, 48.2, 42.9, 38.7, 35.5, 27.6, 27.5 (3), 26.4, 25.8, 24.7, 22.8, 18.0.

[M+H]⁺:
C₂₀H₃₃N₂O₃
349.248 6,
349.248 7.

136-137

+50 (0.008)

(CDCl₃) δ 7.41-7.31 (m, 2H), 6.86-6.84 (m, 1H), 6.78-6.74 (m, 1H), 3.43-3.32 (m, 1H), 3.22-3.18 (m, 2H), 2.73-2.65 (m, 2H), 2.62-2.57 (m, 2H), 2.41 (q, J = 3.3 Hz, 1H), 2.34-2.31 (m, 1H), 2.29-2.26 (m, 1H), 2.23-2.20 (m, 1H), 1.94 (d, J = 3.3 Hz, 2H), 1.91-1.89 (m, 1H), 1.87-1.82 (m, 1H), 1.71-1.67 (m, 2H), 1.63-1.60 (m, 1H), 1.42-1.39 (m, 1H), 1.19 (s, 1H), 1.14-1.08 (m, 2H).

(CDCl₃) δ 163.8, 162.8 (d, J = 12.1 Hz), 161.1 (d, J = 12.1 Hz), 147.9, 139.4, 137.4 (t, J = 6.0 Hz), 109.4 (d, J = 6.0 Hz), 109.2 (d, J = 6.0 Hz), 105.5 (t, J = 25.7 Hz), 54.3, 53.7, 48.6, 42.8, 37.1, 35.5, 28.7, 28.1, 26.4, 24.7, 24.2, 22.6, 18.1.

[M+H]⁺:
C₂₂H₂₇F₂N₂O₂
389.203 5,
389.205 0.

190-192

+153 (0.015)

(CDCl₃) δ 7.75 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H), 6.10-6.08 (m, 1H), 4.52-4.50 (m, 2H), 3.90-3.86 (m, 1H), 3.71-3.67 (m, 1H), 3.64 (d, J = 14.5 Hz, 1H), 3.56-3.54 (m, 2H), 3.46-3.37 (m, 1H), 3.10 (d, J = 14.5 Hz, 1H), 2.91 (s, 1H), 2.39 (s, 2H), 2.10-2.07 (m, 1H), 1.98-1.94 (m, 2H), 1.87 (s, 1H), 1.80 (s, 2H), 1.75-1.72 (m, 1H), 1.34-1.27 (m, 1H), 1.24-1.22 (m, 2H).

(CDCl₃) δ 138.8, 137.7, 132.5 (2), 130.6, 129.3 (2), 128.2, 68.6, 58.4, 57.3, 55.1, 54.6, 45.5, 42.5, 33.5, 33.2, 30.7, 23.8, 22.1, 18.4.

[M+H]⁺:
C₂₁H₂₈BrN₂O₃S
467.099 9,
467.100 1.

153-154

+28 (0.011)

(CDCl₃) δ 3.64-3.60 (m, 1H), 3.47 (s, 1H), 3.40-3.47 (m, 1H), 3.20-3.10 (m, 1H), 2.97-2.87 (m, 1H), 2.75-2.62 (m, 2H), 2.54-2.51 (m, 1H), 2.44-2.36 (m, 1H), 2.17-2.08 (m, 2H), 1.93 (s, 2H), 1.85-1.78 (m, 2H), 1.77-1.66 (m, 2H), 1.43 (s, 9H), 1.40-1.36 (m, 2H), 1.08-1.04 (m, 2H).

(CDCl₃) δ 200.7, 155.6, 151.9, 120.9, 80.9, 57.9, 53.5, 46.3, 45.5, 45.1, 32.5, 27.5, 27.2 (3), 25.9, 24.6, 21.3, 19.7, 18.5.

[M+H]⁺:
C₂₀H₃₁N₂O₃
347.232 9,
347.232 5.

128-130

+15 (0.014)

(CDCl₃) δ 7.49-7.32 (m, 2H), 6.95-6.85 (m, 1H), 5.18 (s, 1H), 3.80-3.78 (m, 1H), 3.62-3.60 (m, 1H), 3.50-3.47 (m, 1H), 3.37-3.35 (m, 2H), 3.31-3.28 (m, 1H), 3.19-3.17 (m, 1H), 3.10-3.07 (m, 1H), 2.47-2.44 (m, 1H), 2.35-2.32 (m, 1H), 2.30-2.24 (m, 1H), 2.19-2.16 (m, 1H), 2.13-2.08 (m, 1H), 1.99-1.94 (m, 1H), 1.95-1.86 (m, 1H), 1.77-1.74 (m, 1H), 1.71-1.66 (m, 1H), 1.65-1.60 (m, 1H), 1.57-1.54 (m, 2H).

(CDCl₃) δ 196.6, 168.4 (dt, J = 144.96, 3.02 Hz), 161.8 (dq, J = 249.15, 144.96 Hz, 2C), 152.9, 137.5 (dt, J = 12.08, 4.53 Hz), 125.2, 111.41 (dq, J = 58.89, 4.53 Hz, 2C), 106.4 (dt, J = 99.66, 25.67 Hz), 57.3, 55.8, 51.9, 47.8, 45.7, 29.6, 23.7, 22.4, 21.3, 19.8, 17.9, 17.4.

[M+H]⁺:
C₂₂H₂₅F₂N₂O₂
387.187 9,
387.187 8.

159-161

-156 (0.009)

(CDCl₃) δ 8.07 (d, J = 2.2 Hz, 1H), 7.83 (q, J = 8.8 Hz, 3H), 7.61 (dd, J = 8.8, 2.2 Hz, 1H), 7.55-7.44 (m, 2H), 4.05-4.01 (m, 1H), 3.31-3.23 (m, 1H), 3.03-3.00 (m, 1H), 2.94-2.91 (m, 2H), 2.77-2.74 (m, 1H), 2.67 (d, J = 13.6 Hz, 1H), 2.58-2.46 (m, 2H), 2.43-2.40 (m, 1H), 2.29-2.24 (m, 1H), 2.18-2.15 (m, 1H), 2.13-1.95 (m, 1H), 1.88-1.84 (m, 2H), 1.78-1.75 (m, 2H), 1.52-1.50 (m, 1H), 1.42 (d, J = 13.6 Hz, 1H), 1.10-0.99 (m, 2H).

(CDCl₃) δ 200.8, 170.4, 152.0, 133.7, 132.4, 131.6, 128.1, 127.9, 127.6, 127.0, 126.9, 126.1, 123.7, 121.3, 59.7, 57.7, 53.4, 52.4, 46.7, 46.4, 45.2, 37.9, 24.5, 22.3, 19.7, 18.5.

[M+H]⁺:
C₂₆H₂₉N₂O₂
401.222 4,
401.221 9.

189-191

-131 (0.016)

(CDCl₃) δ 7.69 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H), 4.03-3.97 (m, 1H), 3.58 (s, 1H), 3.33 (s, 1H), 3.20-3.10 (m, 1H), 2.98 (d, J = 12.1 Hz, 1H), 2.81 (s, 1H), 2.67 (d, J = 13.9 Hz, 1H), 2.50-2.28 (m, 2H), 2.22 (s, 1H), 2.15-2.09 (m, 1H), 1.98 (d, J = 12.1 Hz, 1H), 1.93 (d, J = 13.9 Hz, 1H), 1.88-1.84 (m, 2H), 1.73-1.67 (m, 1H), 1.62-1.58 (m, 1H), 1.50-1.45 (m, 2H), 1.14-1.10 (m, 2H).

(CDCl₃) δ 201.2, 153.6, 139.5, 132.7 (2), 128.2 (2), 124.9, 98.5, 58.6, 54.4, 47.8, 47.2, 45.7, 34.2, 26.1, 25.5, 22.0, 21.3, 20.6, 19.4.

[M+H]⁺:
C₂₁H₂₆BrN₂O₃S
465.084 2,
465.085 5.

132-134

-27 (0.023)

(CDCl₃) δ 7.61 (dt, J = 7.7, 1.5 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.48-7.46 (m, 1H), 7.44 (d, J =1.5 Hz, 1H), 4.64 (d, J = 17.2 Hz, 1H), 4.40 (d, J = 17.2 Hz, 1H), 3.36-3.32 (m, 1H), 3.26 (d, J = 2.9 Hz, 1H), 3.19-3.05 (m, 2H), 2.92 (td, J = 13.6, 2.9 Hz, 1H), 2.81 (d, J = 13.6 Hz, 1H), 2.75 (s, 1H), 2.50-2.47 (m, 2H), 2.45-2.39 (m, 1H), 2.23-2.20 (m, 1H), 2.07-1.99 (m, 2H), 1.92 (dd, J = 13.1, 3.8 Hz, 1H), 1.89-1.84 (m, 2H), 1.82-1.74 (m, 1H), 1.62 (qt, J = 13.1, 3.8 Hz, 1H), 1.51-1.47 (m, 1H), 1.26-1.23 (m, 2H).

(CDCl₃) δ 196.1, 159.7, 139.4, 131.4, 130.5, 129.9, 129.7, 118.5, 113.2, 108.8, 58.3, 54.7, 53.1, 49.7, 47.0, 46.5, 32.2, 27.0, 25.1, 23.5, 21.1, 19.8, 19.6.

[M+H]⁺:
C₂₃H₂₈N₃O
362.222 7,
362.224 6.

Compd.	Yield /%	mp /℃	$ {\left[\alpha \right]}_{589\ \mathrm{n}\mathrm{m}}^{25\ ^\circ {\rm{C}}} $= (±) Value (c : g/100 mL, CH₃OH)	¹HNMR (600 MHz)	¹³C NMR (151 MHz)	HR-ESI-MS (m/z)
2a	56	172-173	+127 (0.011)	(CDCl₃) δ 6.03 (d, J = 2.1 Hz, 1H), 4.36 (d, J = 2.1 Hz, 1H), 4.05-3.96 (m, 1H), 3.93-3.86 (m, 1H), 3.86-3.79 (m, 2H), 3.76 (d, J = 13.7 Hz, 1H), 3.68 (s, 2H), 3.44-3.36 (m, 1H), 3.35 (s, 3H), 3.16-3.12 (m, 1H), 2.50-2.37 (m, 2H), 2.31-2.28 (m, 1H), 2.22-2.19 (m, 1H), 2.18-2.14 (m, 1H), 2.02-2.00 (m, 1H), 1.99-1.95 (m, 1H), 1.95-1.87 (m, 2H), 1.85-1.76 (m, 2H), 1.73 (d, J = 13.7 Hz, 1H), 1.48 (s, 9H).	(CDCl₃) δ 156.1, 136.1, 130.0, 80.8, 76.0, 68.9, 61.8, 60.1, 58.7, 43.4, 34.7, 29.6, 28.7, 28.5 (3), 27.6, 23.7, 22.9, 20.7, 17.8.	[M]⁺: C₂₁H₃₅N₂O₂ 347.269 3, 347.269 0.
2b	24	175-176	+35 (0.011)	(DMSO-d₆) δ 7.93-7.88 (m, 2H), 7.88-7.81 (m, 2H), 6.02-5.82 (m, 1H), 4.05-3.89 (m, 1H), 3.87-3.82 (m, 1H), 3.50-3.46 (m, 2H), 3.33 (s, 3H), 3.28-3.24 (m, 1H), 3.20-3.17 (m, 1H), 3.16 (s, 1H), 3.13-3.08 (m, 1H), 2.42-2.30 (m, 1H), 2.27-2.06 (m, 2H), 2.02-1.89 (m, 2H), 1.85-1.82 (m, 1H), 1.75-1.65 (m, 2H), 1.59-1.55 (m, 2H), 1.53-1.47 (m, 1H), 1.43-1.38 (m, 1H), 1.30-1.20 (m, 1H), 0.86-0.83 (m, 1H).	(DMSO-d₆) δ 136.7, 135.5, 132.6 (2), 129.6 (2), 129.4, 127.5, 74.3, 67.5, 60.0, 58.7, 45.7, 44.6, 33.5, 30.8, 28.9, 27.3, 22.9, 21.7, 19.5, 17.1.	[M]⁺: C₂₂H₃₀BrN₂O₂S 465.120 6, 465.119 7.
2c	19	165-166	+30 (0.020)	(DMSO-d₆) δ 7.79-7.77 (m, J = 1.8 Hz, 1H), 7.75 (dd, J = 7.5, 1.6 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 5.89-5.80 (m, 1H), 4.11 (d, J = 13.9 Hz, 1H), 3.74-3.70 (m, 2H), 3.56-3.52 (m, 1H), 3.43 (s, 3H), 3.36-3.33 (m, 1H), 3.13 (s, 1H), 3.05 (d, J = 13.9 Hz, 1H), 2.97-2.95 (m, 1H), 2.90-2.85 (m, 1H), 2.73-2.63 (m, 1H), 2.55 (d, J = 4.8 Hz, 2H), 2.40-2.37 (m, 1H), 2.34-2.20 (m, 2H), 2.01 (t, J = 4.8 Hz, 2H), 1.94-1.90 (m, 1H), 1.85-1.76 (m, 2H), 1.72-1.66 (m, 1H), 1.58-1.55 (m, 2H), 1.42-1.39 (m, 1H).	(DMSO-d₆) δ 140.6, 138.0, 134.3, 132.5, 131.4, 130.1, 127.7, 119.4, 111.9, 68.9, 66.2, 64.6, 58.6, 57.2, 54.9, 52.6, 34.9, 34.5, 33.5, 28.7, 27.8, 24.2, 23.4, 20.3.	[M]⁺: C₂₄H₃₂N₃ 362.259 1, 362.258 4.
3	42	/(oil)	+31 (0.013)	(CDCl₃) δ 4.05-4.03 (m, 1H), 3.10-3.06 (m, 2H), 2.55-2.50 (m, 1H), 2.49-2.46 (m, 1H), 2.39-2.36 (m, Hz, 1H), 2.21-2.18 (m, 3H), 2.13-2.10 (m, 1H), 2.06 (s, 3H), 2.04-2.00 (m, 1H), 1.79-1.75 (m, 1H), 1.74-1.71 (m, 2H), 1.71-1.64 (m, 2H), 1.36 (s, 9H), 1.32-1.28 (m, 1H), 1.22-1.18 (m, 1H), 1.16-1.11 (m, 1H), 1.00-0.95 (m, 1H), 0.82-0.79 (m, 1H), 0.76-0.72 (m, 1H).	(CDCl₃) δ 153.8, 129.6, 129.4, 78.6, 59.5, 59.0, 44.6, 44.1, 35.2, 30.5, 30.0, 29.5, 27.7, 27.5, 27.4 (3), 25.2, 23.5, 20.6, 19.0.	[M+H]⁺: C₂₁H₃₅N₂O₂ 347.269 3, 347.270 6.
4a	36	/(oil)	+126 (0.006)	(CDCl₃) δ 6.69-6.67 (m, 1H), 4.96 (br, 1H), 3.17-3.14 (m, 1H), 3.08-3.04 (m, 1H), 2.99-2.90 (m, 1H), 2.72-2.68 (m, 2H), 2.64-2.51 (m, 2H), 2.37-2.35 (m, 1H), 2.27-2.24 (m, 2H), 2.16-2.12 (m, 1H), 1.91 (d, J = 6.8 Hz, 2H), 1.88-1.85 (m, 1H), 1.86-1.80 (m, 1H), 1.61-1.57 (m, 2H), 1.53 (d, J = 6.8 Hz, 1H), 1.44-1.40 (m, 1H), 1.37 (s, 9H), 1.12-1.08 (m, 2H).	(CDCl₃) δ 155.1, 146.0, 139.4, 77.9, 54.4, 53.5, 52.4, 48.2, 42.9, 38.7, 35.5, 27.6, 27.5 (3), 26.4, 25.8, 24.7, 22.8, 18.0.	[M+H]⁺: C₂₀H₃₃N₂O₃ 349.248 6, 349.248 7.
4b	37	136-137	+50 (0.008)	(CDCl₃) δ 7.41-7.31 (m, 2H), 6.86-6.84 (m, 1H), 6.78-6.74 (m, 1H), 3.43-3.32 (m, 1H), 3.22-3.18 (m, 2H), 2.73-2.65 (m, 2H), 2.62-2.57 (m, 2H), 2.41 (q, J = 3.3 Hz, 1H), 2.34-2.31 (m, 1H), 2.29-2.26 (m, 1H), 2.23-2.20 (m, 1H), 1.94 (d, J = 3.3 Hz, 2H), 1.91-1.89 (m, 1H), 1.87-1.82 (m, 1H), 1.71-1.67 (m, 2H), 1.63-1.60 (m, 1H), 1.42-1.39 (m, 1H), 1.19 (s, 1H), 1.14-1.08 (m, 2H).	(CDCl₃) δ 163.8, 162.8 (d, J = 12.1 Hz), 161.1 (d, J = 12.1 Hz), 147.9, 139.4, 137.4 (t, J = 6.0 Hz), 109.4 (d, J = 6.0 Hz), 109.2 (d, J = 6.0 Hz), 105.5 (t, J = 25.7 Hz), 54.3, 53.7, 48.6, 42.8, 37.1, 35.5, 28.7, 28.1, 26.4, 24.7, 24.2, 22.6, 18.1.	[M+H]⁺: C₂₂H₂₇F₂N₂O₂ 389.203 5, 389.205 0.
4c	42	190-192	+153 (0.015)	(CDCl₃) δ 7.75 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H), 6.10-6.08 (m, 1H), 4.52-4.50 (m, 2H), 3.90-3.86 (m, 1H), 3.71-3.67 (m, 1H), 3.64 (d, J = 14.5 Hz, 1H), 3.56-3.54 (m, 2H), 3.46-3.37 (m, 1H), 3.10 (d, J = 14.5 Hz, 1H), 2.91 (s, 1H), 2.39 (s, 2H), 2.10-2.07 (m, 1H), 1.98-1.94 (m, 2H), 1.87 (s, 1H), 1.80 (s, 2H), 1.75-1.72 (m, 1H), 1.34-1.27 (m, 1H), 1.24-1.22 (m, 2H).	(CDCl₃) δ 138.8, 137.7, 132.5 (2), 130.6, 129.3 (2), 128.2, 68.6, 58.4, 57.3, 55.1, 54.6, 45.5, 42.5, 33.5, 33.2, 30.7, 23.8, 22.1, 18.4.	[M+H]⁺: C₂₁H₂₈BrN₂O₃S 467.099 9, 467.100 1.
5a	29	153-154	+28 (0.011)	(CDCl₃) δ 3.64-3.60 (m, 1H), 3.47 (s, 1H), 3.40-3.47 (m, 1H), 3.20-3.10 (m, 1H), 2.97-2.87 (m, 1H), 2.75-2.62 (m, 2H), 2.54-2.51 (m, 1H), 2.44-2.36 (m, 1H), 2.17-2.08 (m, 2H), 1.93 (s, 2H), 1.85-1.78 (m, 2H), 1.77-1.66 (m, 2H), 1.43 (s, 9H), 1.40-1.36 (m, 2H), 1.08-1.04 (m, 2H).	(CDCl₃) δ 200.7, 155.6, 151.9, 120.9, 80.9, 57.9, 53.5, 46.3, 45.5, 45.1, 32.5, 27.5, 27.2 (3), 25.9, 24.6, 21.3, 19.7, 18.5.	[M+H]⁺: C₂₀H₃₁N₂O₃ 347.232 9, 347.232 5.
5b	23	128-130	+15 (0.014)	(CDCl₃) δ 7.49-7.32 (m, 2H), 6.95-6.85 (m, 1H), 5.18 (s, 1H), 3.80-3.78 (m, 1H), 3.62-3.60 (m, 1H), 3.50-3.47 (m, 1H), 3.37-3.35 (m, 2H), 3.31-3.28 (m, 1H), 3.19-3.17 (m, 1H), 3.10-3.07 (m, 1H), 2.47-2.44 (m, 1H), 2.35-2.32 (m, 1H), 2.30-2.24 (m, 1H), 2.19-2.16 (m, 1H), 2.13-2.08 (m, 1H), 1.99-1.94 (m, 1H), 1.95-1.86 (m, 1H), 1.77-1.74 (m, 1H), 1.71-1.66 (m, 1H), 1.65-1.60 (m, 1H), 1.57-1.54 (m, 2H).	(CDCl₃) δ 196.6, 168.4 (dt, J = 144.96, 3.02 Hz), 161.8 (dq, J = 249.15, 144.96 Hz, 2C), 152.9, 137.5 (dt, J = 12.08, 4.53 Hz), 125.2, 111.41 (dq, J = 58.89, 4.53 Hz, 2C), 106.4 (dt, J = 99.66, 25.67 Hz), 57.3, 55.8, 51.9, 47.8, 45.7, 29.6, 23.7, 22.4, 21.3, 19.8, 17.9, 17.4.	[M+H]⁺: C₂₂H₂₅F₂N₂O₂ 387.187 9, 387.187 8.
5c	21	159-161	-156 (0.009)	(CDCl₃) δ 8.07 (d, J = 2.2 Hz, 1H), 7.83 (q, J = 8.8 Hz, 3H), 7.61 (dd, J = 8.8, 2.2 Hz, 1H), 7.55-7.44 (m, 2H), 4.05-4.01 (m, 1H), 3.31-3.23 (m, 1H), 3.03-3.00 (m, 1H), 2.94-2.91 (m, 2H), 2.77-2.74 (m, 1H), 2.67 (d, J = 13.6 Hz, 1H), 2.58-2.46 (m, 2H), 2.43-2.40 (m, 1H), 2.29-2.24 (m, 1H), 2.18-2.15 (m, 1H), 2.13-1.95 (m, 1H), 1.88-1.84 (m, 2H), 1.78-1.75 (m, 2H), 1.52-1.50 (m, 1H), 1.42 (d, J = 13.6 Hz, 1H), 1.10-0.99 (m, 2H).	(CDCl₃) δ 200.8, 170.4, 152.0, 133.7, 132.4, 131.6, 128.1, 127.9, 127.6, 127.0, 126.9, 126.1, 123.7, 121.3, 59.7, 57.7, 53.4, 52.4, 46.7, 46.4, 45.2, 37.9, 24.5, 22.3, 19.7, 18.5.	[M+H]⁺: C₂₆H₂₉N₂O₂ 401.222 4, 401.221 9.
5d	25	189-191	-131 (0.016)	(CDCl₃) δ 7.69 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H), 4.03-3.97 (m, 1H), 3.58 (s, 1H), 3.33 (s, 1H), 3.20-3.10 (m, 1H), 2.98 (d, J = 12.1 Hz, 1H), 2.81 (s, 1H), 2.67 (d, J = 13.9 Hz, 1H), 2.50-2.28 (m, 2H), 2.22 (s, 1H), 2.15-2.09 (m, 1H), 1.98 (d, J = 12.1 Hz, 1H), 1.93 (d, J = 13.9 Hz, 1H), 1.88-1.84 (m, 2H), 1.73-1.67 (m, 1H), 1.62-1.58 (m, 1H), 1.50-1.45 (m, 2H), 1.14-1.10 (m, 2H).	(CDCl₃) δ 201.2, 153.6, 139.5, 132.7 (2), 128.2 (2), 124.9, 98.5, 58.6, 54.4, 47.8, 47.2, 45.7, 34.2, 26.1, 25.5, 22.0, 21.3, 20.6, 19.4.	[M+H]⁺: C₂₁H₂₆BrN₂O₃S 465.084 2, 465.085 5.
5e	21	132-134	-27 (0.023)	(CDCl₃) δ 7.61 (dt, J = 7.7, 1.5 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.48-7.46 (m, 1H), 7.44 (d, J =1.5 Hz, 1H), 4.64 (d, J = 17.2 Hz, 1H), 4.40 (d, J = 17.2 Hz, 1H), 3.36-3.32 (m, 1H), 3.26 (d, J = 2.9 Hz, 1H), 3.19-3.05 (m, 2H), 2.92 (td, J = 13.6, 2.9 Hz, 1H), 2.81 (d, J = 13.6 Hz, 1H), 2.75 (s, 1H), 2.50-2.47 (m, 2H), 2.45-2.39 (m, 1H), 2.23-2.20 (m, 1H), 2.07-1.99 (m, 2H), 1.92 (dd, J = 13.1, 3.8 Hz, 1H), 1.89-1.84 (m, 2H), 1.82-1.74 (m, 1H), 1.62 (qt, J = 13.1, 3.8 Hz, 1H), 1.51-1.47 (m, 1H), 1.26-1.23 (m, 2H).	(CDCl₃) δ 196.1, 159.7, 139.4, 131.4, 130.5, 129.9, 129.7, 118.5, 113.2, 108.8, 58.3, 54.7, 53.1, 49.7, 47.0, 46.5, 32.2, 27.0, 25.1, 23.5, 21.1, 19.8, 19.6.	[M+H]⁺: C₂₃H₂₈N₃O 362.222 7, 362.224 6.

Compd.

Yield /%

mp /℃

$ {\left[\alpha \right]}_{589\ \mathrm{n}\mathrm{m}}^{25\ ^\circ {\rm{C}}} $

= (±) Value (c : g/100 mL, CH₃OH)

¹HNMR (600 MHz)

¹³C NMR (151 MHz)

HR-ESI-MS (m/z)

Formula Calcd. Found

172-173

+127 (0.011)

(CDCl₃) δ 156.1, 136.1, 130.0, 80.8, 76.0, 68.9, 61.8, 60.1, 58.7, 43.4, 34.7, 29.6, 28.7, 28.5 (3), 27.6, 23.7, 22.9, 20.7, 17.8.

[M]⁺:
C₂₁H₃₅N₂O₂
347.269 3,
347.269 0.

175-176

+35 (0.011)

(DMSO-d₆) δ 136.7, 135.5, 132.6 (2), 129.6 (2), 129.4, 127.5, 74.3, 67.5, 60.0, 58.7, 45.7, 44.6, 33.5, 30.8, 28.9, 27.3, 22.9, 21.7, 19.5, 17.1.

[M]⁺:
C₂₂H₃₀BrN₂O₂S 465.120 6,
465.119 7.

165-166

+30 (0.020)

(DMSO-d₆) δ 140.6, 138.0, 134.3, 132.5, 131.4, 130.1, 127.7, 119.4, 111.9, 68.9, 66.2, 64.6, 58.6, 57.2, 54.9, 52.6, 34.9, 34.5, 33.5, 28.7, 27.8, 24.2, 23.4, 20.3.

[M]⁺:
C₂₄H₃₂N₃
362.259 1,
362.258 4.

/(oil)

+31 (0.013)

(CDCl₃) δ 153.8, 129.6, 129.4, 78.6, 59.5, 59.0, 44.6, 44.1, 35.2, 30.5, 30.0, 29.5, 27.7, 27.5, 27.4 (3), 25.2, 23.5, 20.6, 19.0.

[M+H]⁺:
C₂₁H₃₅N₂O₂
347.269 3,
347.270 6.

/(oil)

+126 (0.006)

(CDCl₃) δ 155.1, 146.0, 139.4, 77.9, 54.4, 53.5, 52.4, 48.2, 42.9, 38.7, 35.5, 27.6, 27.5 (3), 26.4, 25.8, 24.7, 22.8, 18.0.

[M+H]⁺:
C₂₀H₃₃N₂O₃
349.248 6,
349.248 7.

136-137

+50 (0.008)

[M+H]⁺:
C₂₂H₂₇F₂N₂O₂
389.203 5,
389.205 0.

190-192

+153 (0.015)

(CDCl₃) δ 138.8, 137.7, 132.5 (2), 130.6, 129.3 (2), 128.2, 68.6, 58.4, 57.3, 55.1, 54.6, 45.5, 42.5, 33.5, 33.2, 30.7, 23.8, 22.1, 18.4.

[M+H]⁺:
C₂₁H₂₈BrN₂O₃S
467.099 9,
467.100 1.

153-154

+28 (0.011)

(CDCl₃) δ 200.7, 155.6, 151.9, 120.9, 80.9, 57.9, 53.5, 46.3, 45.5, 45.1, 32.5, 27.5, 27.2 (3), 25.9, 24.6, 21.3, 19.7, 18.5.

[M+H]⁺:
C₂₀H₃₁N₂O₃
347.232 9,
347.232 5.

128-130

+15 (0.014)

[M+H]⁺:
C₂₂H₂₅F₂N₂O₂
387.187 9,
387.187 8.

159-161

-156 (0.009)

(CDCl₃) δ 200.8, 170.4, 152.0, 133.7, 132.4, 131.6, 128.1, 127.9, 127.6, 127.0, 126.9, 126.1, 123.7, 121.3, 59.7, 57.7, 53.4, 52.4, 46.7, 46.4, 45.2, 37.9, 24.5, 22.3, 19.7, 18.5.

[M+H]⁺:
C₂₆H₂₉N₂O₂
401.222 4,
401.221 9.

189-191

-131 (0.016)

(CDCl₃) δ 201.2, 153.6, 139.5, 132.7 (2), 128.2 (2), 124.9, 98.5, 58.6, 54.4, 47.8, 47.2, 45.7, 34.2, 26.1, 25.5, 22.0, 21.3, 20.6, 19.4.

[M+H]⁺:
C₂₁H₂₆BrN₂O₃S
465.084 2,
465.085 5.

132-134

-27 (0.023)

(CDCl₃) δ 196.1, 159.7, 139.4, 131.4, 130.5, 129.9, 129.7, 118.5, 113.2, 108.8, 58.3, 54.7, 53.1, 49.7, 47.0, 46.5, 32.2, 27.0, 25.1, 23.5, 21.1, 19.8, 19.6.

[M+H]⁺:
C₂₃H₂₈N₃O
362.222 7,
362.224 6.


2a		3.77 ± 0.17	> 200	> 53.1
2b		7.95 ± 3.72	> 200	> 25.2
2c		NA	> 200	-
3	-	9.58 ± 2.06	43.44 ± 1.06	5
4a		NA	> 200	-
4b		NA	186.84 ± 12.10	-
4c		NA	17.26 ± 0.49	-
5a		26.34 ± 6.75	103.90 ± 8.33	3.9
5b		NA	> 200	-
5c		6.41 ± 1.01	106.63 ± 3.14	17
5d		12.85 ± 2.52	> 200	> 15.6
5e		NA	> 200	-
MP	-	1.95 ± 0.02	40.88 ± 6.03	21

Compd.

EC₅₀/μmol·L^-1

CC₅₀/μmol·L^-1

3.77 ± 0.17

> 200

> 53.1

7.95 ± 3.72

> 200

> 25.2

> 200

9.58 ± 2.06

43.44 ± 1.06

> 200

186.84 ± 12.10

17.26 ± 0.49

26.34 ± 6.75

103.90 ± 8.33

3.9

> 200

6.41 ± 1.01

106.63 ± 3.14

12.85 ± 2.52

> 200

> 15.6

> 200

1.95 ± 0.02

40.88 ± 6.03


2a		3.77 ± 0.17	> 200	> 53.1
2b		7.95 ± 3.72	> 200	> 25.2
2c		NA	> 200	-
3	-	9.58 ± 2.06	43.44 ± 1.06	5
4a		NA	> 200	-
4b		NA	186.84 ± 12.10	-
4c		NA	17.26 ± 0.49	-
5a		26.34 ± 6.75	103.90 ± 8.33	3.9
5b		NA	> 200	-
5c		6.41 ± 1.01	106.63 ± 3.14	17
5d		12.85 ± 2.52	> 200	> 15.6
5e		NA	> 200	-
MP	-	1.95 ± 0.02	40.88 ± 6.03	21

Compd.

EC₅₀/μmol·L^-1

CC₅₀/μmol·L^-1

3.77 ± 0.17

> 200

> 53.1

7.95 ± 3.72

> 200

> 25.2

> 200

9.58 ± 2.06

43.44 ± 1.06

> 200

186.84 ± 12.10

17.26 ± 0.49

26.34 ± 6.75

103.90 ± 8.33

3.9

> 200

6.41 ± 1.01

106.63 ± 3.14

12.85 ± 2.52

> 200

> 15.6

> 200

1.95 ± 0.02

40.88 ± 6.03

Target	Docking score
TMPRSS2	-4.792	-4.550
SR-B1	-5.200	-4.682

Target

Docking score

TMPRSS2

-4.792

-4.550

SR-B1

-5.200

-4.682

Target	Docking score
TMPRSS2	-4.792	-4.550
SR-B1	-5.200	-4.682

Target

Docking score

TMPRSS2

-4.792

-4.550

SR-B1

-5.200

-4.682

不同母核结构苦豆碱衍生物合成及其抗冠状病毒活性研究

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孟润泽 , 公玥 , 施宇龙 , 王坤 , 彭宗根 , 宋丹青 ^*

药学学报 | 研究论文 2024,59(2): 404-412

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药学学报 | 研究论文 2024, 59(2): 404-412

不同母核结构苦豆碱衍生物合成及其抗冠状病毒活性研究

全屏

孟润泽, 公玥, 施宇龙, 王坤, 彭宗根, 宋丹青^*

作者信息

中国医学科学院、北京协和医学院医药生物技术研究所, 北京 100050

通讯作者:

^*宋丹青, Tel / Fax: 86-10-63165268, E-mail: songdanqingsdq@sina.com

Synthesis and evaluation for anti-HCoV-OC43 activity of novel aloperine derivatives with different core structures

Run-ze MENG, Yue GONG, Yu-long SHI, Kun WANG, Zong-gen PENG, Dan-qing SONG^*

Affiliations

Institute of Pharmaceutical Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

出版时间: 2024-02-12 doi: 10.16438/j.0513-4870.2023-1136

文章导航

摘要

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本研究设计合成了不同母核结构的12个全新苦豆碱衍生物, 其中十元大环骨架苦豆碱衍生物3通过季铵盐γ-H的霍夫曼消除后扩环获得, 结构经X-单晶确证。进而采用CCK-8法评价了目标物对抗人类β-冠状病毒HCoV-OC43的活性。结果显示, 季铵盐苦豆碱2a与化合物3均具有良好活性, 2a表现出最好抗病毒活性, EC₅₀值为3.77 μmol·L^-1, SI值大于53.1。Schrödinger分子对接结果显示, 化合物2a与3均可能通过直接靶向宿主TMPRSS2和SR-B1发挥抗冠状病毒作用。研究结果拓展了桥环骨架苦豆碱的结构类型及其抗冠状病毒用途, 为发展一类新型抗冠状病毒化合物提供了有益科学数据。

关键词

季铵盐苦豆碱 / 新型冠状病毒 / 十元环苦豆碱 / TMPRSS2 / SR-B1

Abstract

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In this study, we designed and synthesized 12 novel aloperine derivatives with different core structures. Among them, compound 3 with a ten-membered ring core was obtained through a special ring expansion reaction after γ-H Huffman elimination of quaternary ammonium salt, and the structure was verified by X-single crystal diffraction. Furthermore, their antiviral activity against human β-coronavirus HCoV-OC43 was evaluated by CCK-8 assay. Quaternary ammonium salt 2a and 3 had a good inhibitory effect against HCoV-OC43, and 2a had the highest anti-HCoV-OC43 activity with an EC₅₀ values of 3.77 μmol·L^-1 and a SI value of over 53.1. Schrӧdinger molecular docking results showed that both 2a and 3 might display their anti-HCoV-OC43 activity by directly acting on host TMPRSS2 and SR-B1. The results expanded the structural types of endocyclic aloperine and the function against coronavirus, and provided useful scientific data for the development of pharmaceutical applications of these compounds.

Key words

quaternary ammonium salt aloperine / SARS-CoV-2 / ten-membered ring aloperine / TMPRSS2 / SR-B1

引用本文

孟润泽, 公玥, 施宇龙, 王坤, 彭宗根, 宋丹青. 不同母核结构苦豆碱衍生物合成及其抗冠状病毒活性研究. 药学学报, 2024 , 59 (2) : 404 -412 . DOI: 10.16438/j.0513-4870.2023-1136

Run-ze MENG, Yue GONG, Yu-long SHI, Kun WANG, Zong-gen PENG, Dan-qing SONG. Synthesis and evaluation for anti-HCoV-OC43 activity of novel aloperine derivatives with different core structures[J]. Acta Pharmaceutica Sinica, 2024 , 59 (2) : 404 -412 . DOI: 10.16438/j.0513-4870.2023-1136

正文

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严重急性呼吸综合征冠状病毒2型(SARS-CoV-2) 对全球造成了重大健康威胁和社会经济问题^{[1, 2]}。尽管一些疫苗和抗病毒新药已批准用于防控新型冠状病毒, 但是由于病毒的快速频繁变异, 各种病毒变体如Delta (B.1.617.2) 变体和Omicron (BA.5) 变体不断产生, 导致疫苗和抗病毒药物的防控效果降低^[3-5]。近年来, 靶向宿主抗病毒药物以其广谱性、有效性、低耐药性和受病毒变异影响小等诸多优势而备受关注, 在病毒感染的控制和治疗中展示出广泛的应用前景^{[6, 7]}。因此, 研发小分子抗病毒药物, 特别是针对宿主靶点的广谱抗病毒药物用于病毒防控至关重要。

前期研究发现, 基于我国天然产物桥环骨架苦豆碱(aloperine, 图 1) 衍生的12N-取代苦豆碱类衍生物主要通过靶向宿主作用机制发挥广谱抗病毒活性, 包括HCV、埃博拉、马尔堡, 以及SARS-CoV-2^[8-10]。其中, 12N上的取代基可以连有多种不同的结构类型, 例如苄基、甲酰基及磺酰基。近期, 本课题组进一步证实了此类苦豆碱衍生物可直接靶向宿主的跨膜丝氨酸蛋白酶2 (transmembrane serine protease 2, TMPRSS2) 和B类1型清道夫受体(scavenger receptor class B type 1, SR-B1) 阻断病毒侵入阶段发挥抑制SARS-CoV-2作用^[11]。然而, 苦豆碱类的结构修饰目前仅限于苦豆碱的侧链取代, 对桥环苦豆碱母核的结构修饰却少有文献报道, 大大限制了苦豆碱类化合物的结构类型与药用探索。

据此, 本研究在前期工作的基础上, 保留了12N上的侧链取代基, 变换苦豆碱的母核结构, 以此丰富苦豆碱桥环骨架的结构类型。在合成12N-取代季铵盐苦豆碱(2a~2c) 过程中, 发现了具有十元大环骨架的苦豆碱衍生物(3)。又设计合成3个12N-取代-17(S)-羟基苦豆碱(4a~4c) 与5个12N-取代氧化苦豆碱(5a~5e), 共计12个全新的苦豆碱类衍生物(图 1)。继而, 采用CCK-8法在H460细胞上评价了它们对HCoV-OC43的抗病毒活性, 探究不同结构类型苦豆碱母核对新型冠状病毒的影响, 并对活性化合物作用机制进行了初步探讨。

结果与讨论

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1 化合物的合成

目标化合物的合成如路线1所示。以市售苦豆碱为初始原料, 在碱性条件下与二碳酸二叔丁酯和酰氯等试剂反应制备12N-取代苦豆碱1a~1d, 再与碘甲烷在碱性条件下反应生成12N-取代季铵盐苦豆碱2a~2c, 总产率为19%~56%。以化合物2a为原料, 在强碱性条件下被夺氢发生重排生成12N-叔丁氧甲酰基十元扩环苦豆碱3, 总产率为42%, 但当12N上连有其他类型基团时, 在各种碱性条件下均未获得扩环产物。以化合物1b和1d为原料, 经二氧化硒选择性氧化生成12N-取代羟基苦豆碱4b和4c, 总产率为36%~42%。同样二氧化硒氧化1a, 经双键迁移, 获得羟基取代产物4a, 再用二氧化锰氧化后得到12N-取代氧化苦豆碱5a, 经过盐酸水解得到中间体6, 后者在强碱作用下与酰氯、磺酰氯等试剂反应制备12N-取代氧化苦豆碱5b~5e, 总产率为21%~26%。

其中, 十元环苦豆碱3的结构进一步经X-单晶衍射结果证实。推测的生成机制如下(图 2), 首先化合物2a上11-位碳原子上的氢在正丁基锂的作用下被拔除, 11位形成的碳负离子与16、17上的双键形成p-π共轭, 电子游离到17位碳原子, 形成17位碳负离子, 同时双键发生迁移。17位电子会进攻处于1N-α位的6位碳原子, 发生类似于霍夫曼消除的C-N键的断裂, 最终形成化合物3。

进一步将化合物进行构象分析以及几何优化后, 在B3LYP/6-311G(d, p) 水平, 使用时间依赖性DFT (TDDFT) 在0.35 eV的半频带宽度下分别生成了化合物2c、4a、5e的ECD谱。三者分别代表了三类骨架结构, 计算出的ECD曲线与实验ECD光谱高度相似(图 3), 表明此类化合物构型即为预测构型。

所有化合物结构经¹H NMR、¹³C NMR以及HR-MS分析确证。目标化合物的收率、理化参数和波谱数据见表 1。

2 苦豆碱类衍生物抗冠状病毒构效关系及细胞毒性实验

以化合物molnupiravir (MP) 为阳性对照^{[12, 13]}, 以H460细胞为宿主, 选用与新冠病毒同属的人类β-冠状病毒HCoV-OC43感染, 用CCK-8法考察各个化合物的EC₅₀和CC₅₀。目标化合物的结构与活性结果见表 2。

活性结果显示, 季铵盐类母核结构对HCoV-OC43具有明显的抑制活性, 其中化合物2a和2b的EC₅₀值分别为3.77、7.95 μmol·L^-1。十元大环苦豆碱衍生物3显示中度活性, 其EC₅₀值为9.58 μmol·L^-1。3个17-OH苦豆碱化合物丧失了对HCoV-OC43的抑制活性。17-氧化苦豆碱5a、5c、5d对HCoV-OC43具有一定的抑制活性, EC₅₀值分别为26.34、6.41、12.85 μmol·L^-1。细胞毒性结果显示, 除化合物4c外, 其余化合物的CC₅₀值均高于阳性对照MP。并且季铵盐类母核化合物2a~2c的CC₅₀值均大于200 μmol·L^-1, 显示安全性较高。

鉴于化合物2a表现出的最低EC₅₀值以及化合物3的新颖结构, 将其作为代表性化合物展开下一步研究。

3 Schrӧdinger分子对接

鉴于苦豆碱类衍生物通过直接靶向TMPRSS2和SR-B1发挥抗冠状病毒作用^[11], 采用Schrödinger分子对接软件让化合物2a和3与可能的作用靶点TMPRSS2(PDB ID: 7MEQ) 和SR-B1进行分子对接。对接结果显示, 代表性化合物2a和3得分较好, 提示二者与TMPRSS2和SR-B1均可能有较高的亲和力, 从而发挥抗冠状病毒作用, 且将二者得分相比较, 化合物2a相较于化合物3有着更好的对接分数, 这一点也与EC₅₀值相对应(表 3)。

在此基础上, 采用Schrödinger和Photoshop 23.0.0将对接结果进行可视化分析。TMPRSS2的对接结果如图 4所示, 化合物2a可以与SER-441和HIS-296形成较强的氢键相互作用(图 4a、b); 而化合物3并未发现与前者类似的氢键结构, 却产生了与ASP-435的盐桥作用(图 4c、d)。

与SR-B1的对接结果如图 5所示, 化合物2a通过季铵盐阳离子会与PHE-208中的苯环Pi键形成配位作用(图 5a、b); 而化合物3由于十元环的存在会与周围的氨基酸形成广泛的疏水相互作用(图 5c、d)。

综上所述, 代表性化合物2a和3均可能通过直接靶向TMPRSS2和SR-B1发挥抗冠状病毒作用, 而且二者的结合模式也存在着很大的差异, 进一步提示了苦豆碱衍生物结构的多样性所导致的作用机制及结合模式的多样性, 值得进一步研究。

小结

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本研究设计合成了12个全新的苦豆碱类衍生物, 包含季铵盐苦豆碱、十元大环苦豆碱、17(S)-羟基苦豆碱、17-氧化苦豆碱。通过CCK-8法评价了其在H460细胞中对HCoV-OC43的抑制作用。其中代表性化合物2a表现出良好的抗冠状病毒活性和较低的细胞毒性, 表明季铵盐类母核结构相比于其他类型苦豆碱在抗冠状病毒活性和安全性上有着明显的优势。十元环苦豆碱3对HCoV-OC43有着明显的抑制作用, 具有很大的结构修饰潜力。分子对接结果显示了二者可能通过直接靶向TMPRSS2和SR-B1发挥其抗冠状病毒活性, 且二者与靶点的结合模式存在着一定的差异。研究结果拓展了桥环骨架苦豆碱的结构类型, 为苦豆碱类衍生物发展成一类抗新型冠状病毒化合物提供了有益的科学数据。

实验部分

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所有化学试剂和无水溶剂均从商业来源获得并且无需进一步纯化即可使用。使用MP90熔点仪获得熔点, 未进行校正(Mettler-Toledo, Greifensee, Switzerland)。以DMSO-d₆、CDCl₃为溶剂, 以Me₄Si为内标, 在Bruker Avance (600 MHz) 光谱仪(Varian, San Francisco, USA) 上记录¹H NMR和¹³C NMR波谱。在AutospecUltima-TOF光谱仪(Micromass UK Ltd, Manchester, UK) 上记录ESI高分辨率质谱(HR-MS)。Flash柱分离纯化用Combiflash Rf 200 (Teledyne, Nebraska, USA) 快速制备液相; 薄层色谱(TLC) 采用Merck 60 F254和国产GF254薄层色谱硅胶板; 所用试剂为乐研公司、泰坦公司、毕得公司、伊诺凯公司、通广和GENERAL REAGENT等国产分析纯试剂。

1 化学合成

1.1 12N-叔丁氧甲酰基季铵盐苦豆碱2a的合成

向苦豆碱(10 mmol) 的无水CH₂Cl₂ (100 mL) 溶液中缓慢加入K₂CO₃ (5 mmol) 和二碳酸二叔丁酯(15 mmol), 在0 ℃下搅拌直至升至室温, 再搅拌8 h。TLC监测反应完全后, 将反应液减压浓缩, 残余物用硅胶匀化, 以CH₂Cl₂和MeOH为流动相, 经Flash硅胶柱色谱纯化, 得到化合物1a。

向化合物1a (3 mmol) 的无水CH₂Cl₂ (10 mL) 溶液中加入K₂CO₃ (3 mmol) 和CH₃I (10 mmol), 加压反应, 80 ℃反应48 h。TLC监测反应完全后, 过滤除去K₂CO₃, 将反应液减压浓缩, 残余用硅胶匀化, 以CH₂Cl₂和MeOH为流动相, 经Flash硅胶柱色谱纯化, 得到目标化合物2a。

1.2 12N-叔丁氧甲酰基十元环苦豆碱3的合成

在氮气保护下, 向化合物2a (1 mmol) 中加入无水THF (10 mL), -30 ℃下缓慢加入n-C₄H₉Li (10 mmol), 反应3 h至反应液澄清, 加入CH₃OH (10 mL) 淬灭n-C₄H₉Li, 将反应液减压浓缩, 残余用硅胶匀化, 以CH₂Cl₂和MeOH为流动相, 经Flash硅胶柱色谱纯化, 得到目标化合物3。

1.3 12N-取代季铵盐苦豆碱2b和2c的合成

向苦豆碱(10 mmol) 的无水CH₂Cl₂ (50 mL) 溶液中缓慢加入K₂CO₃ (15 mmol) 和对溴苯磺酰氯或间氰基苄溴(12 mmol), 室温反应8 h。TLC监测反应完全后, 过滤除去K₂CO₃, 将反应液减压浓缩, 残余物用硅胶匀化, 以CH₂Cl₂和MeOH为流动相, 经Flash硅胶柱色谱纯化, 得到化合物1b和1c。

向化合物1b和1c (3 mmol) 的无水CH₂Cl₂ (10 mL) 溶液中加入K₂CO₃ (3 mmol) 和CH₃I (10 mmol), 加压反应, 80 ℃反应48 h。TLC监测反应完全后, 过滤除去K₂CO₃, 将反应液减压浓缩, 残余用硅胶匀化, 以CH₂Cl₂和MeOH为流动相, 经Flash硅胶柱色谱纯化, 得到目标化合物2b和2c。

1.4 12N-叔丁氧酰基羟基苦豆碱4a的合成

向1a (8 mmol) 的无水CH₂Cl₂ (50 mL) 溶液中缓慢加入SeO₂ (5 mmol), 室温搅拌12 h。TLC监测反应完全后, 将反应液减压浓缩, 残余物用硅胶匀化, 以CH₂Cl₂和MeOH为流动相, 经Flash硅胶柱色谱纯化, 得到化合物4a。

1.5 12N-取代羟基苦豆碱4b和4c的合成

向苦豆碱(10 mmol) 的无水CH₂Cl₂ (50 mL) 溶液中缓慢加入K₂CO₃ (15 mmol) 和对溴苯磺酰氯或2, 4-二氟苯甲酰氯(12 mmol), 室温反应8 h。TLC监测反应完全后, 过滤除去K₂CO₃, 将反应液减压浓缩, 残余物用硅胶匀化, 以CH₂Cl₂和MeOH为流动相, 经Flash硅胶柱色谱纯化, 得到化合物1b和1d。

接着向1b和1d (8 mmol) 的无水CH₂Cl₂ (50 mL) 溶液中缓慢加入SeO₂ (5 mmol), 室温搅拌12 h。TLC监测反应完全后, 将反应液减压浓缩, 残余物用硅胶匀化, 以CH₂Cl₂和MeOH为流动相, 经Flash硅胶柱色谱纯化, 得到目标化合物4b和4c。

1.6 12N-取代氧化苦豆碱5a~5e的合成

向4a (5 mmol) 的无水CH₂Cl₂ (30 mL) 溶液中缓慢加入MnO₂ (20 mmol), 室温反应12 h。TLC监测反应完全后, 过滤除去MnO₂, 将反应液减压浓缩, 残余用硅胶匀化, 以CH₂Cl₂和MeOH为流动相, 经Flash硅胶柱色谱纯化, 得到目标化合物5a。

向5a (5 mmol) 的无水THF (50 mL) 溶液中缓慢加入HCl (30 mmol), 边搅拌边加入, 室温反应0.5 h。加入氢氧化钠(35 mmol) 至溶液呈碱性, 过滤除去生成的NaCl, 然后将反应液减压浓缩, 加入CH₂Cl₂和水萃取反应物, 取有机层(下层) 溶液减压浓缩, 残余物用硅胶匀化, 以CH₂Cl₂和MeOH为流动相, 经Flash硅胶柱色谱纯化, 得到化合物6。

在氮气保护下, 向化合物6 (2 mmol) 的无水THF (200 mL) 溶液中缓慢加入n-C₄H₉Li (6 mmol), -30 ℃反应0.5 h。紧接着向反应液中加入卤代物, 继续-30 ℃反应2.5 h。然后加入CH₃OH (10 mL) 淬灭n-C₄H₉Li, 将反应液减压浓缩, 残余物用硅胶匀化, 以CH₂Cl₂和MeOH为流动相, 经Flash硅胶柱色谱纯化, 得到目标化合物5b~5e。

2 生物部分

以HCoV-OC43感染的H460细胞为模型, MP作为阳性对照药, 在病毒感染(MOI = 1.0) H460细胞(密度为每毫升1.5×10⁵个) 的同时将待测化合物不同浓度稀释液和DMSO溶剂对照加入至96孔板(Corning, Inc., Corning, NY) 中, 37 ℃、5% CO₂培养72 h。采用CCK-8法检测细胞在450 nm波长处的吸光度, 通过比较未感染病毒溶剂对照组、感染病毒溶剂对照组和感染病毒待测化合物组细胞的活力, 判断化合物的抗病毒作用, 通过比较DMSO溶剂对照组和待测化合物组细胞的活力, 判断化合物的细胞毒性。用Reed-Muench法计算待测化合物抗病毒的EC₅₀和CC₅₀。

3 分子对接

TMPRSS2蛋白结构来自PDB数据库(PDB ID: 7MEQ)。由于SR-B1的完整晶体蛋白结构并未被报道, 通过UniProt网站获得了人类SR-B1蛋白的氨基酸序列(序列编号: Q8WTV0), 然后通过美国国家生物信息中心(NCBI) 上的基本局部比对搜索工具(Basic Local Alignment Search Tool) 找到了与之序列最相近的已报道蛋白结构(PDB ID: 4Q4F)。通过Schrödinger Maestro Version 12.8.117进行同源模建, 得到了基本完整的SR-B1蛋白的三维结构, 以此作为对接的蛋白。

对接过程: 使用软件自带模块处理蛋白并进行能量最小化, 设置pH为7.4; 配体小分子均通过软件默认设置进行处理; TMPRSS2对接盒子选用其PDB蛋白结构中配体分子所处活性口袋, SR-B1选用整个蛋白作为对接盒子; 对接过程参数增添氢键优势, 其余选项均为默认设置。

致谢: 目标化合物的核磁共振氢谱、碳谱及高分辨质谱由中国医学科学院医药生物技术研究所分析测试中心测定。

作者贡献: 孟润泽负责目标化合物的合成、分子对接及初稿的撰写; 公玥负责测定目标化合物活性结果; 施宇龙负责试验方法的设计和部分化合物的合成与构型确证; 王坤负责部分化合物构型的确证; 彭宗根对生物实验部分进行了有益的指导; 宋丹青对实验过程中出现的问题及论文撰写提供了有益的指导, 并负责实验设计和把关、稿件修改等工作。

利益冲突: 所有作者均声明不存在利益冲突。

基金

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国家自然科学基金(81974494)
中国医学科学院医学与健康科技创新工程资助项目(2021-I2M-1-048)

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Shrestha LB, Foster C, Rawlinson W, et al. Evolution of the SARS-CoV-2 omicron variants BA. 1 to BA. 5: implications for immune escape and transmission [J]. Rev Med Virol, 2022, 32: e2381.

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Zhao HJ, Lu L, Peng Z, et al. SARS-CoV-2 Omicron variant shows less efficient replication and fusion activity when compared with Delta variant in TMPRSS2-expressed cells [J]. Emerg Microbes Infect, 2022, 11: 277-283.

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Kumar N, Sharma S, Kumar R, et al. Host-directed antiviral therapy [J]. Clin Microbiol Rev, 2020, 33: e00168-19.

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Santopolo S, Riccio A, Santoro MG. The biogenesis of SARS-CoV-2 spike glycoprotein: multiple targets for host-directed antiviral therapy [J]. Biochem Biophys Res Commun, 2021, 538: 80-87.

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Wang K, Wu JJ, Xin Z, et al. Discovery and evolution of 12N-substituted aloperine derivatives as anti-SARS-CoV-2 agents through targeting late entry stage [J]. Bioorg Chem, 2021, 115: 105196.

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Zhang X, Liu Q, Zhang N, et al. Discovery and evolution of aloperine derivatives as novel anti-filovirus agents through targeting entry stage [J]. Eur J Med Chem, 2018, 149: 45-55.

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Zhang X, Lv XQ, Tang S, et al. Discovery and evolution of aloperine derivatives as a new family of HCV inhibitors with novel mechanism [J]. Eur J Med Chem, 2018, 143: 1053-1065.

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Shi YL, Chen FB, Wu MY, et al. Chemical construction and anti-HCoV-OC43 evaluation of novel 10, 12-disubstituted aloperine derivatives as dual cofactor inhibitors of TMPRSS2 and SR-B1 [J]. Chin Chem Lett, 2023. DOI: 10.1016/j.cclet.2023.108792.

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Wen W, Chen C, Tang J, et al. Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and paxlovid) for COVID-19: a meta-analysis [J]. Ann Med, 2022, 54: 516-523.

2024年第59卷第2期

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doi: 10.16438/j.0513-4870.2023-1136

接收时间：2023-10-08
首发时间：2025-11-28
出版时间：2024-02-12

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收稿日期：2023-10-08
修回日期：2023-10-31

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国家自然科学基金(81974494)

中国医学科学院医学与健康科技创新工程资助项目(2021-I2M-1-048)

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中国医学科学院、北京协和医学院医药生物技术研究所, 北京 100050

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^*宋丹青, Tel / Fax: 86-10-63165268, E-mail: songdanqingsdq@sina.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Compd.	Yield /%	mp /℃	$ {\left[\alpha \right]}_{589\ \mathrm{n}\mathrm{m}}^{25\ ^\circ {\rm{C}}} $= (±) Value (c : g/100 mL, CH₃OH)	¹HNMR (600 MHz)	¹³C NMR (151 MHz)	HR-ESI-MS (m/z)
2a	56	172-173	+127 (0.011)	(CDCl₃) δ 6.03 (d, J = 2.1 Hz, 1H), 4.36 (d, J = 2.1 Hz, 1H), 4.05-3.96 (m, 1H), 3.93-3.86 (m, 1H), 3.86-3.79 (m, 2H), 3.76 (d, J = 13.7 Hz, 1H), 3.68 (s, 2H), 3.44-3.36 (m, 1H), 3.35 (s, 3H), 3.16-3.12 (m, 1H), 2.50-2.37 (m, 2H), 2.31-2.28 (m, 1H), 2.22-2.19 (m, 1H), 2.18-2.14 (m, 1H), 2.02-2.00 (m, 1H), 1.99-1.95 (m, 1H), 1.95-1.87 (m, 2H), 1.85-1.76 (m, 2H), 1.73 (d, J = 13.7 Hz, 1H), 1.48 (s, 9H).	(CDCl₃) δ 156.1, 136.1, 130.0, 80.8, 76.0, 68.9, 61.8, 60.1, 58.7, 43.4, 34.7, 29.6, 28.7, 28.5 (3), 27.6, 23.7, 22.9, 20.7, 17.8.	[M]⁺: C₂₁H₃₅N₂O₂ 347.269 3, 347.269 0.
2b	24	175-176	+35 (0.011)	(DMSO-d₆) δ 7.93-7.88 (m, 2H), 7.88-7.81 (m, 2H), 6.02-5.82 (m, 1H), 4.05-3.89 (m, 1H), 3.87-3.82 (m, 1H), 3.50-3.46 (m, 2H), 3.33 (s, 3H), 3.28-3.24 (m, 1H), 3.20-3.17 (m, 1H), 3.16 (s, 1H), 3.13-3.08 (m, 1H), 2.42-2.30 (m, 1H), 2.27-2.06 (m, 2H), 2.02-1.89 (m, 2H), 1.85-1.82 (m, 1H), 1.75-1.65 (m, 2H), 1.59-1.55 (m, 2H), 1.53-1.47 (m, 1H), 1.43-1.38 (m, 1H), 1.30-1.20 (m, 1H), 0.86-0.83 (m, 1H).	(DMSO-d₆) δ 136.7, 135.5, 132.6 (2), 129.6 (2), 129.4, 127.5, 74.3, 67.5, 60.0, 58.7, 45.7, 44.6, 33.5, 30.8, 28.9, 27.3, 22.9, 21.7, 19.5, 17.1.	[M]⁺: C₂₂H₃₀BrN₂O₂S 465.120 6, 465.119 7.
2c	19	165-166	+30 (0.020)	(DMSO-d₆) δ 7.79-7.77 (m, J = 1.8 Hz, 1H), 7.75 (dd, J = 7.5, 1.6 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 5.89-5.80 (m, 1H), 4.11 (d, J = 13.9 Hz, 1H), 3.74-3.70 (m, 2H), 3.56-3.52 (m, 1H), 3.43 (s, 3H), 3.36-3.33 (m, 1H), 3.13 (s, 1H), 3.05 (d, J = 13.9 Hz, 1H), 2.97-2.95 (m, 1H), 2.90-2.85 (m, 1H), 2.73-2.63 (m, 1H), 2.55 (d, J = 4.8 Hz, 2H), 2.40-2.37 (m, 1H), 2.34-2.20 (m, 2H), 2.01 (t, J = 4.8 Hz, 2H), 1.94-1.90 (m, 1H), 1.85-1.76 (m, 2H), 1.72-1.66 (m, 1H), 1.58-1.55 (m, 2H), 1.42-1.39 (m, 1H).	(DMSO-d₆) δ 140.6, 138.0, 134.3, 132.5, 131.4, 130.1, 127.7, 119.4, 111.9, 68.9, 66.2, 64.6, 58.6, 57.2, 54.9, 52.6, 34.9, 34.5, 33.5, 28.7, 27.8, 24.2, 23.4, 20.3.	[M]⁺: C₂₄H₃₂N₃ 362.259 1, 362.258 4.
3	42	/(oil)	+31 (0.013)	(CDCl₃) δ 4.05-4.03 (m, 1H), 3.10-3.06 (m, 2H), 2.55-2.50 (m, 1H), 2.49-2.46 (m, 1H), 2.39-2.36 (m, Hz, 1H), 2.21-2.18 (m, 3H), 2.13-2.10 (m, 1H), 2.06 (s, 3H), 2.04-2.00 (m, 1H), 1.79-1.75 (m, 1H), 1.74-1.71 (m, 2H), 1.71-1.64 (m, 2H), 1.36 (s, 9H), 1.32-1.28 (m, 1H), 1.22-1.18 (m, 1H), 1.16-1.11 (m, 1H), 1.00-0.95 (m, 1H), 0.82-0.79 (m, 1H), 0.76-0.72 (m, 1H).	(CDCl₃) δ 153.8, 129.6, 129.4, 78.6, 59.5, 59.0, 44.6, 44.1, 35.2, 30.5, 30.0, 29.5, 27.7, 27.5, 27.4 (3), 25.2, 23.5, 20.6, 19.0.	[M+H]⁺: C₂₁H₃₅N₂O₂ 347.269 3, 347.270 6.
4a	36	/(oil)	+126 (0.006)	(CDCl₃) δ 6.69-6.67 (m, 1H), 4.96 (br, 1H), 3.17-3.14 (m, 1H), 3.08-3.04 (m, 1H), 2.99-2.90 (m, 1H), 2.72-2.68 (m, 2H), 2.64-2.51 (m, 2H), 2.37-2.35 (m, 1H), 2.27-2.24 (m, 2H), 2.16-2.12 (m, 1H), 1.91 (d, J = 6.8 Hz, 2H), 1.88-1.85 (m, 1H), 1.86-1.80 (m, 1H), 1.61-1.57 (m, 2H), 1.53 (d, J = 6.8 Hz, 1H), 1.44-1.40 (m, 1H), 1.37 (s, 9H), 1.12-1.08 (m, 2H).	(CDCl₃) δ 155.1, 146.0, 139.4, 77.9, 54.4, 53.5, 52.4, 48.2, 42.9, 38.7, 35.5, 27.6, 27.5 (3), 26.4, 25.8, 24.7, 22.8, 18.0.	[M+H]⁺: C₂₀H₃₃N₂O₃ 349.248 6, 349.248 7.
4b	37	136-137	+50 (0.008)	(CDCl₃) δ 7.41-7.31 (m, 2H), 6.86-6.84 (m, 1H), 6.78-6.74 (m, 1H), 3.43-3.32 (m, 1H), 3.22-3.18 (m, 2H), 2.73-2.65 (m, 2H), 2.62-2.57 (m, 2H), 2.41 (q, J = 3.3 Hz, 1H), 2.34-2.31 (m, 1H), 2.29-2.26 (m, 1H), 2.23-2.20 (m, 1H), 1.94 (d, J = 3.3 Hz, 2H), 1.91-1.89 (m, 1H), 1.87-1.82 (m, 1H), 1.71-1.67 (m, 2H), 1.63-1.60 (m, 1H), 1.42-1.39 (m, 1H), 1.19 (s, 1H), 1.14-1.08 (m, 2H).	(CDCl₃) δ 163.8, 162.8 (d, J = 12.1 Hz), 161.1 (d, J = 12.1 Hz), 147.9, 139.4, 137.4 (t, J = 6.0 Hz), 109.4 (d, J = 6.0 Hz), 109.2 (d, J = 6.0 Hz), 105.5 (t, J = 25.7 Hz), 54.3, 53.7, 48.6, 42.8, 37.1, 35.5, 28.7, 28.1, 26.4, 24.7, 24.2, 22.6, 18.1.	[M+H]⁺: C₂₂H₂₇F₂N₂O₂ 389.203 5, 389.205 0.
4c	42	190-192	+153 (0.015)	(CDCl₃) δ 7.75 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H), 6.10-6.08 (m, 1H), 4.52-4.50 (m, 2H), 3.90-3.86 (m, 1H), 3.71-3.67 (m, 1H), 3.64 (d, J = 14.5 Hz, 1H), 3.56-3.54 (m, 2H), 3.46-3.37 (m, 1H), 3.10 (d, J = 14.5 Hz, 1H), 2.91 (s, 1H), 2.39 (s, 2H), 2.10-2.07 (m, 1H), 1.98-1.94 (m, 2H), 1.87 (s, 1H), 1.80 (s, 2H), 1.75-1.72 (m, 1H), 1.34-1.27 (m, 1H), 1.24-1.22 (m, 2H).	(CDCl₃) δ 138.8, 137.7, 132.5 (2), 130.6, 129.3 (2), 128.2, 68.6, 58.4, 57.3, 55.1, 54.6, 45.5, 42.5, 33.5, 33.2, 30.7, 23.8, 22.1, 18.4.	[M+H]⁺: C₂₁H₂₈BrN₂O₃S 467.099 9, 467.100 1.
5a	29	153-154	+28 (0.011)	(CDCl₃) δ 3.64-3.60 (m, 1H), 3.47 (s, 1H), 3.40-3.47 (m, 1H), 3.20-3.10 (m, 1H), 2.97-2.87 (m, 1H), 2.75-2.62 (m, 2H), 2.54-2.51 (m, 1H), 2.44-2.36 (m, 1H), 2.17-2.08 (m, 2H), 1.93 (s, 2H), 1.85-1.78 (m, 2H), 1.77-1.66 (m, 2H), 1.43 (s, 9H), 1.40-1.36 (m, 2H), 1.08-1.04 (m, 2H).	(CDCl₃) δ 200.7, 155.6, 151.9, 120.9, 80.9, 57.9, 53.5, 46.3, 45.5, 45.1, 32.5, 27.5, 27.2 (3), 25.9, 24.6, 21.3, 19.7, 18.5.	[M+H]⁺: C₂₀H₃₁N₂O₃ 347.232 9, 347.232 5.
5b	23	128-130	+15 (0.014)	(CDCl₃) δ 7.49-7.32 (m, 2H), 6.95-6.85 (m, 1H), 5.18 (s, 1H), 3.80-3.78 (m, 1H), 3.62-3.60 (m, 1H), 3.50-3.47 (m, 1H), 3.37-3.35 (m, 2H), 3.31-3.28 (m, 1H), 3.19-3.17 (m, 1H), 3.10-3.07 (m, 1H), 2.47-2.44 (m, 1H), 2.35-2.32 (m, 1H), 2.30-2.24 (m, 1H), 2.19-2.16 (m, 1H), 2.13-2.08 (m, 1H), 1.99-1.94 (m, 1H), 1.95-1.86 (m, 1H), 1.77-1.74 (m, 1H), 1.71-1.66 (m, 1H), 1.65-1.60 (m, 1H), 1.57-1.54 (m, 2H).	(CDCl₃) δ 196.6, 168.4 (dt, J = 144.96, 3.02 Hz), 161.8 (dq, J = 249.15, 144.96 Hz, 2C), 152.9, 137.5 (dt, J = 12.08, 4.53 Hz), 125.2, 111.41 (dq, J = 58.89, 4.53 Hz, 2C), 106.4 (dt, J = 99.66, 25.67 Hz), 57.3, 55.8, 51.9, 47.8, 45.7, 29.6, 23.7, 22.4, 21.3, 19.8, 17.9, 17.4.	[M+H]⁺: C₂₂H₂₅F₂N₂O₂ 387.187 9, 387.187 8.
5c	21	159-161	-156 (0.009)	(CDCl₃) δ 8.07 (d, J = 2.2 Hz, 1H), 7.83 (q, J = 8.8 Hz, 3H), 7.61 (dd, J = 8.8, 2.2 Hz, 1H), 7.55-7.44 (m, 2H), 4.05-4.01 (m, 1H), 3.31-3.23 (m, 1H), 3.03-3.00 (m, 1H), 2.94-2.91 (m, 2H), 2.77-2.74 (m, 1H), 2.67 (d, J = 13.6 Hz, 1H), 2.58-2.46 (m, 2H), 2.43-2.40 (m, 1H), 2.29-2.24 (m, 1H), 2.18-2.15 (m, 1H), 2.13-1.95 (m, 1H), 1.88-1.84 (m, 2H), 1.78-1.75 (m, 2H), 1.52-1.50 (m, 1H), 1.42 (d, J = 13.6 Hz, 1H), 1.10-0.99 (m, 2H).	(CDCl₃) δ 200.8, 170.4, 152.0, 133.7, 132.4, 131.6, 128.1, 127.9, 127.6, 127.0, 126.9, 126.1, 123.7, 121.3, 59.7, 57.7, 53.4, 52.4, 46.7, 46.4, 45.2, 37.9, 24.5, 22.3, 19.7, 18.5.	[M+H]⁺: C₂₆H₂₉N₂O₂ 401.222 4, 401.221 9.
5d	25	189-191	-131 (0.016)	(CDCl₃) δ 7.69 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H), 4.03-3.97 (m, 1H), 3.58 (s, 1H), 3.33 (s, 1H), 3.20-3.10 (m, 1H), 2.98 (d, J = 12.1 Hz, 1H), 2.81 (s, 1H), 2.67 (d, J = 13.9 Hz, 1H), 2.50-2.28 (m, 2H), 2.22 (s, 1H), 2.15-2.09 (m, 1H), 1.98 (d, J = 12.1 Hz, 1H), 1.93 (d, J = 13.9 Hz, 1H), 1.88-1.84 (m, 2H), 1.73-1.67 (m, 1H), 1.62-1.58 (m, 1H), 1.50-1.45 (m, 2H), 1.14-1.10 (m, 2H).	(CDCl₃) δ 201.2, 153.6, 139.5, 132.7 (2), 128.2 (2), 124.9, 98.5, 58.6, 54.4, 47.8, 47.2, 45.7, 34.2, 26.1, 25.5, 22.0, 21.3, 20.6, 19.4.	[M+H]⁺: C₂₁H₂₆BrN₂O₃S 465.084 2, 465.085 5.
5e	21	132-134	-27 (0.023)	(CDCl₃) δ 7.61 (dt, J = 7.7, 1.5 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.48-7.46 (m, 1H), 7.44 (d, J =1.5 Hz, 1H), 4.64 (d, J = 17.2 Hz, 1H), 4.40 (d, J = 17.2 Hz, 1H), 3.36-3.32 (m, 1H), 3.26 (d, J = 2.9 Hz, 1H), 3.19-3.05 (m, 2H), 2.92 (td, J = 13.6, 2.9 Hz, 1H), 2.81 (d, J = 13.6 Hz, 1H), 2.75 (s, 1H), 2.50-2.47 (m, 2H), 2.45-2.39 (m, 1H), 2.23-2.20 (m, 1H), 2.07-1.99 (m, 2H), 1.92 (dd, J = 13.1, 3.8 Hz, 1H), 1.89-1.84 (m, 2H), 1.82-1.74 (m, 1H), 1.62 (qt, J = 13.1, 3.8 Hz, 1H), 1.51-1.47 (m, 1H), 1.26-1.23 (m, 2H).	(CDCl₃) δ 196.1, 159.7, 139.4, 131.4, 130.5, 129.9, 129.7, 118.5, 113.2, 108.8, 58.3, 54.7, 53.1, 49.7, 47.0, 46.5, 32.2, 27.0, 25.1, 23.5, 21.1, 19.8, 19.6.	[M+H]⁺: C₂₃H₂₈N₃O 362.222 7, 362.224 6.

Compd.

Yield /%

mp /℃

$ {\left[\alpha \right]}_{589\ \mathrm{n}\mathrm{m}}^{25\ ^\circ {\rm{C}}} $

= (±) Value (c : g/100 mL, CH₃OH)

¹HNMR (600 MHz)

¹³C NMR (151 MHz)

HR-ESI-MS (m/z)

Formula Calcd. Found

172-173

+127 (0.011)

(CDCl₃) δ 156.1, 136.1, 130.0, 80.8, 76.0, 68.9, 61.8, 60.1, 58.7, 43.4, 34.7, 29.6, 28.7, 28.5 (3), 27.6, 23.7, 22.9, 20.7, 17.8.

[M]⁺:
C₂₁H₃₅N₂O₂
347.269 3,
347.269 0.

175-176

+35 (0.011)

(DMSO-d₆) δ 136.7, 135.5, 132.6 (2), 129.6 (2), 129.4, 127.5, 74.3, 67.5, 60.0, 58.7, 45.7, 44.6, 33.5, 30.8, 28.9, 27.3, 22.9, 21.7, 19.5, 17.1.

[M]⁺:
C₂₂H₃₀BrN₂O₂S 465.120 6,
465.119 7.

165-166

+30 (0.020)

(DMSO-d₆) δ 140.6, 138.0, 134.3, 132.5, 131.4, 130.1, 127.7, 119.4, 111.9, 68.9, 66.2, 64.6, 58.6, 57.2, 54.9, 52.6, 34.9, 34.5, 33.5, 28.7, 27.8, 24.2, 23.4, 20.3.

[M]⁺:
C₂₄H₃₂N₃
362.259 1,
362.258 4.

/(oil)

+31 (0.013)

(CDCl₃) δ 153.8, 129.6, 129.4, 78.6, 59.5, 59.0, 44.6, 44.1, 35.2, 30.5, 30.0, 29.5, 27.7, 27.5, 27.4 (3), 25.2, 23.5, 20.6, 19.0.

[M+H]⁺:
C₂₁H₃₅N₂O₂
347.269 3,
347.270 6.

/(oil)

+126 (0.006)

(CDCl₃) δ 155.1, 146.0, 139.4, 77.9, 54.4, 53.5, 52.4, 48.2, 42.9, 38.7, 35.5, 27.6, 27.5 (3), 26.4, 25.8, 24.7, 22.8, 18.0.

[M+H]⁺:
C₂₀H₃₃N₂O₃
349.248 6,
349.248 7.

136-137

+50 (0.008)

[M+H]⁺:
C₂₂H₂₇F₂N₂O₂
389.203 5,
389.205 0.

190-192

+153 (0.015)

(CDCl₃) δ 138.8, 137.7, 132.5 (2), 130.6, 129.3 (2), 128.2, 68.6, 58.4, 57.3, 55.1, 54.6, 45.5, 42.5, 33.5, 33.2, 30.7, 23.8, 22.1, 18.4.

[M+H]⁺:
C₂₁H₂₈BrN₂O₃S
467.099 9,
467.100 1.

153-154

+28 (0.011)

(CDCl₃) δ 200.7, 155.6, 151.9, 120.9, 80.9, 57.9, 53.5, 46.3, 45.5, 45.1, 32.5, 27.5, 27.2 (3), 25.9, 24.6, 21.3, 19.7, 18.5.

[M+H]⁺:
C₂₀H₃₁N₂O₃
347.232 9,
347.232 5.

128-130

+15 (0.014)

[M+H]⁺:
C₂₂H₂₅F₂N₂O₂
387.187 9,
387.187 8.

159-161

-156 (0.009)

(CDCl₃) δ 200.8, 170.4, 152.0, 133.7, 132.4, 131.6, 128.1, 127.9, 127.6, 127.0, 126.9, 126.1, 123.7, 121.3, 59.7, 57.7, 53.4, 52.4, 46.7, 46.4, 45.2, 37.9, 24.5, 22.3, 19.7, 18.5.

[M+H]⁺:
C₂₆H₂₉N₂O₂
401.222 4,
401.221 9.

189-191

-131 (0.016)

(CDCl₃) δ 201.2, 153.6, 139.5, 132.7 (2), 128.2 (2), 124.9, 98.5, 58.6, 54.4, 47.8, 47.2, 45.7, 34.2, 26.1, 25.5, 22.0, 21.3, 20.6, 19.4.

[M+H]⁺:
C₂₁H₂₆BrN₂O₃S
465.084 2,
465.085 5.

132-134

-27 (0.023)

(CDCl₃) δ 196.1, 159.7, 139.4, 131.4, 130.5, 129.9, 129.7, 118.5, 113.2, 108.8, 58.3, 54.7, 53.1, 49.7, 47.0, 46.5, 32.2, 27.0, 25.1, 23.5, 21.1, 19.8, 19.6.

[M+H]⁺:
C₂₃H₂₈N₃O
362.222 7,
362.224 6.


2a		3.77 ± 0.17	> 200	> 53.1
2b		7.95 ± 3.72	> 200	> 25.2
2c		NA	> 200	-
3	-	9.58 ± 2.06	43.44 ± 1.06	5
4a		NA	> 200	-
4b		NA	186.84 ± 12.10	-
4c		NA	17.26 ± 0.49	-
5a		26.34 ± 6.75	103.90 ± 8.33	3.9
5b		NA	> 200	-
5c		6.41 ± 1.01	106.63 ± 3.14	17
5d		12.85 ± 2.52	> 200	> 15.6
5e		NA	> 200	-
MP	-	1.95 ± 0.02	40.88 ± 6.03	21

Compd.

EC₅₀/μmol·L^-1

CC₅₀/μmol·L^-1

3.77 ± 0.17

> 200

> 53.1

7.95 ± 3.72

> 200

> 25.2

> 200

9.58 ± 2.06

43.44 ± 1.06

> 200

186.84 ± 12.10

17.26 ± 0.49

26.34 ± 6.75

103.90 ± 8.33

3.9

> 200

6.41 ± 1.01

106.63 ± 3.14

12.85 ± 2.52

> 200

> 15.6

> 200

1.95 ± 0.02

40.88 ± 6.03

Target	Docking score
TMPRSS2	-4.792	-4.550
SR-B1	-5.200	-4.682

Target

Docking score

TMPRSS2

-4.792

-4.550

SR-B1

-5.200

-4.682