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5a	CH₃	CH₃	47	171-174
5b	CH₃	C₂H₅	54	154-156
5c	CH₃		62	201-203
5d	CH₃		83	211-213
5e	CH₃		86	221-222
5f	CH₃		90	225-228
5g	CH₃		87	214-217
5h	F	CH₃	49	186-188
5i	F	C₂H₅	66	167-169
5j	F		82	205-206
5k	F		88	204-206
5l	F		85	221-223
5m	F		91	228-230
5n	F		87	197-199
5o	Cl	CH₃	49	186-189
5p	Cl	C₂H₅	77	152-155
5q	Cl		72	202-204
5r	Cl		83	218-220
5s	Cl		86	226-227
5t	Cl		92	238-240
5u	Cl		84	199-200

Compd.

R₁

R₂

Yield/%

mp/℃

CH₃

171-174

CH₃

C₂H₅

154-156

CH₃

201-203

CH₃

211-213

CH₃

221-222

CH₃

225-228

CH₃

214-217

CH₃

186-188

C₂H₅

167-169

205-206

204-206

221-223

228-230

197-199

CH₃

186-189

C₂H₅

152-155

202-204

218-220

226-227

238-240

199-200


5a	CH₃	CH₃	47	171-174
5b	CH₃	C₂H₅	54	154-156
5c	CH₃		62	201-203
5d	CH₃		83	211-213
5e	CH₃		86	221-222
5f	CH₃		90	225-228
5g	CH₃		87	214-217
5h	F	CH₃	49	186-188
5i	F	C₂H₅	66	167-169
5j	F		82	205-206
5k	F		88	204-206
5l	F		85	221-223
5m	F		91	228-230
5n	F		87	197-199
5o	Cl	CH₃	49	186-189
5p	Cl	C₂H₅	77	152-155
5q	Cl		72	202-204
5r	Cl		83	218-220
5s	Cl		86	226-227
5t	Cl		92	238-240
5u	Cl		84	199-200

Compd.

R₁

R₂

Yield/%

mp/℃

CH₃

171-174

CH₃

C₂H₅

154-156

CH₃

201-203

CH₃

211-213

CH₃

221-222

CH₃

225-228

CH₃

214-217

CH₃

186-188

C₂H₅

167-169

205-206

204-206

221-223

228-230

197-199

CH₃

186-189

C₂H₅

152-155

202-204

218-220

226-227

238-240

199-200

Compd.	¹H NMR, ¹³C NMR and HR-MS
5a	¹H NMR (600 MHz, CDCl₃) δ 12.02 (d, J = 10.9 Hz, 1H, -NH-), 7.87 (d, J = 1.7 Hz, 1H, Ar-H), 7.75 (d, J = 10.9 Hz, 1H, =CH-), 7.23 (d, J = 8.0 Hz, 1H, Ar-H), 7.21 (dd, J = 8.0, 1.7 Hz, 1H, Ar-H), 3.77 (s, 2H, -S-CH₂-), 2.69 (s, 3H, -CH₃), 2.37 (s, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 187.99, 163.39, 158.68, 138.77, 136.81, 135.79, 133.80, 133.31, 129.59, 127.97, 107.31, 31.65, 20.97, 15.96. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₄H₁₄N₃OS₂: 304.057 28; Found: 304.057 06.
5b	¹H NMR (600 MHz, CDCl₃) δ 12.03 (d, J = 10.9 Hz, 1H, -NH-), 7.87 (d, J = 1.8 Hz, 1H, Ar-H), 7.76 (d, J = 10.9 Hz, 1H, =CH-), 7.23 (d, J = 8.0 Hz, 1H, Ar-H), 7.21 (dd, J = 8.0, 1.8 Hz, 1H, Ar-H), 3.77 (s, 2H, -S-CH₂-), 3.04 (q, J = 7.6 Hz, 2H, -CH₂CH₃), 2.37 (s, 3H, -CH₃), 1.40 (t, J = 7.6 Hz, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 187.94, 165.56, 163.04, 138.86, 136.79, 135.77, 133.77, 133.32, 129.59, 127.96, 107.20, 31.65, 24.11, 20.97, 14.03. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₅H₁₆N₃OS₂: 318.072 93; Found: 318.072 79.
5c	¹H NMR (600 MHz, CDCl₃) δ 12.16 (d, J = 10.8 Hz, 1H, -NH-), 7.89 (d, J = 1.7 Hz, 1H, Ar-H), 7.87 (m, 2H, Ar-H), 7.81 (d, J = 10.8 Hz, 1H, =CH-), 7.49-7.44 (m, 3H, Ar-H), 7.24 (d, J = 8.0 Hz, 1H, Ar-H), 7.22 (dd, J = 8.0, 1.7 Hz, 1H, Ar-H), 3.80 (s, 2H, -S-CH₂-), 2.38 (s, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 188.02, 162.83, 161.84, 138.48, 136.90, 135.82, 133.83, 133.32, 130.76, 130.22, 129.65, 129.12, 127.97, 127.36, 107.80, 31.69, 20.90. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₃H₁₁FN₃OS₂: 366.072 93; Found: 366.072 88.
5d	¹H NMR (600 MHz, CDCl₃) δ 12.18 (d, J = 10.8 Hz, 1H, -NH-), 7.89 (d, J = 1.4 Hz, 1H, Ar-H), 7.83-7.80 (m, 1H, =CH-, 2H, Ar-H), 7.45 (d, J = 8.5 Hz, 2H, Ar-H), 7.25 (d, J = 8.0 Hz, 1H, Ar-H), 7.23 (dd, J = 8.0, 1.4 Hz, 1H, Ar-H), 3.80 (s, 2H, -S-CH₂-), 2.38 (s, 3H, -CH₃).¹³C NMR (151 MHz, CDCl₃) δ 188.11, 162.99, 160.84, 138.27, 136.90, 136.86, 135.87, 133.92, 133.25, 129.66, 129.42, 128.68, 128.47, 128.00, 108.03, 31.69, 20.93. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₉H₁₅ClN₃OS₂: 400.033 96; Found: 400.034 07.
5e	¹H NMR (600 MHz, CDCl₃) δ 12.19 (d, J = 10.8 Hz, 1H, -NH-), 8.30-8.26 (m, 1H, Ar-H), 7.89 (d, J = 1.7 Hz, 1H, Ar-H), 7.83 (d, J = 10.8 Hz, 1H, =CH-), 7.53-7.50 (m, 1H, Ar-H), 7.44-7.40 (m, 2H, Ar-H), 7.24 (d, J = 8.0 Hz, 1H, Ar-H), 7.22 (dd, J = 8.0, 1.7 Hz, 1H, Ar-H), 3.81 (s, 2H, -S-CH₂-), 2.38 (s, 3H, -CH₃).¹³C NMR (151 MHz, CDCl₃) δ 188.02, 164.68, 157.36, 138.48, 136.83, 135.85, 133.87, 133.29, 131.95, 131.37, 130.74, 130.53, 129.68, 128.95, 127.99, 127.37, 107.90, 31.73, 20.97. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₉H₁₅ClN₃OS₂: 400.033 96; Found: 400.034 07.
5f	¹H NMR (600 MHz, CDCl₃) δ 12.26 (d, J = 10.6 Hz, 1H, -NH-), 8.34 (d, J = 8.6 Hz, 2H, Ar-H), 8.06 (d, J = 8.6 Hz, 2H, Ar-H), 7.89 (s, 1H, Ar-H), 7.82 (d, J = 10.6 Hz, 1H, =CH-), 7.25-7.22 (m, 2H, Ar-H), 3.81 (s, 2H, -S-CH₂-), 2.39 (s, 3H, -CH₃).¹³C NMR (151 MHz, CDCl₃) δ 188.25, 164.08, 159.24, 148.87, 137.73, 136.99, 135.95, 135.85, 134.09, 133.12, 129.72, 128.04, 127.93, 124.44, 108.76, 31.69, 20.92. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₉H₁₅N₄O₃S₂: 411.058 55; Found: 411.058 43.
5g	¹H NMR (600 MHz, CDCl₃) δ 12.22 (d, J = 10.7 Hz, 1H, -NH-), 8.00 (d, J = 7.7 Hz, 2H, Ar-H), 7.89 (s, 1H, Ar-H), 7.82 (d, J = 10.7 Hz, 1H, =CH-), 7.74 (d, J = 7.7 Hz, 2H, Ar-H), 7.25-7.21 (m, 2H, Ar-H), 3.81 (s, 2H, -S-CH₂-), 2.38 (s, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 188.18, 163.52, 160.35, 138.04, 136.95, 135.90, 133.99, 133.20, 132.76, 132.54, 132.33, 132.10, 129.69, 128.05, 128.02, 127.55, 126.39, 126.19, 126.17, 126.14, 126.12, 124.58, 122.77, 120.97, 108.35, 31.70, 20.99. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₂₀H₁₅F₃N₃OS₂: 434.060 31; Found: 434.060 22.
5h	¹H NMR (600 MHz, CDCl₃) δ 11.95 (d, J = 11.0 Hz, 1H, -NH-), 7.82 (d, J = 11.0 Hz, 1H, =CH-), 7.75 (dd, J = 9.3, 2.9 Hz, 1H, Ar-H), 7.31 (dd, J = 8.6, 5.0 Hz, 1H, Ar-H), 7.12 (td, J = 8.2, 2.9 Hz, 1H, Ar-H), 3.79 (s, 2H, -S-CH₂-), 2.70 (s, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 186.67, 163.15, 161.90, 160.27, 159.03, 139.50, 135.32, 135.31, 135.04, 134.99, 129.70, 129.66, 120.41, 120.26, 115.69, 115.54, 106.44, 31.58, 15.98. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₃H₁₁FN₃OS₂: 308.032 21; Found: 308.032 10.
5i	¹H NMR (600 MHz, CDCl₃) δ 12.10 (d, J = 10.8 Hz, 1H, -NH-), 7.93-7.86 (m, 3H, Ar-H), 7.77 (dd, J = 9.2, 2.9 Hz, 1H, =CH-), 7.50-7.46 (m, 4H, Ar-H), 7.33 (dd, J = 8.6, 5.0 Hz, 1H, Ar-H), 7.14 (td, J = 8.2, 2.9 Hz, 1H, Ar-H), 3.82 (d, J = 0.7 Hz, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.77, 162.55, 160.91, 160.30, 158.45, 139.22, 136.55, 136.53, 135.37, 134.91, 134.38, 134.36, 133.17, 133.08, 131.93, 130.92, 130.06, 129.69, 129.19, 128.15, 127.39, 126.27, 126.24, 120.50, 120.35, 115.60, 115.05, 107.53, 31.64. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₃FN₃OS₂: 370.047 86; Found: 370.047 96.
5j	¹H NMR (600 MHz, CDCl₃) δ 12.10 (d, J = 10.8 Hz, 1H, -NH-), 7.93-7.86 (m, 3H, Ar-H), 7.77 (dd, J = 9.2, 2.9 Hz, 1H, =CH-), 7.50-7.46 (m, 4H, Ar-H), 7.33 (dd, J = 8.6, 5.0 Hz, 1H, Ar-H), 7.14 (td, J = 8.2, 2.9 Hz, 1H, Ar-H), 3.82 (d, J = 0.7 Hz, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.77, 162.55, 160.91, 160.30, 158.45, 139.22, 136.55, 136.53, 135.37, 134.91, 134.38, 134.36, 133.17, 133.08, 131.93, 130.92, 130.06, 129.69, 129.19, 128.15, 127.39, 126.27, 126.24, 120.50, 120.35, 115.60, 115.05, 107.53, 31.64. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₃FN₃OS₂: 370.047 86; Found: 370.047 96.
5k	¹H NMR (600 MHz, CDCl₃) δ 12.10 (d, J = 10.9 Hz, 1H, -NH-), 7.87 (d, J = 10.9 Hz, 1H, =CH-), 7.81 (d, J = 8.5 Hz, 2H, Ar-H), 7.77 (dd, J = 9.2, 2.9 Hz, 1H, Ar-H), 7.46 (d, J = 8.5 Hz, 2H, Ar-H), 7.33 (dd, J = 8.6, 4.9 Hz, 1H, Ar-H), 7.14 (td, J = 8.2, 2.9 Hz, 1H, Ar-H), 3.82 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.80, 162.74, 161.95, 161.18, 160.32, 139.00, 136.98, 135.41, 135.39, 134.96, 134.92, 129.73, 129.68, 129.46, 128.58, 128.50, 120.53, 120.38, 115.76, 115.61, 107.16, 31.63. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₂ClFN₃OS₂: 404.008 89; Found: 404.008 80.
5l	¹H NMR (600 MHz, CDCl₃) δ 12.13 (d, J = 11.0 Hz, 1H, -NH-), 8.29-8.26 (m, 1H, Ar-H), 7.90 (d, J = 11.0 Hz, 1H, =CH-), 7.78 (dd, J = 9.2, 2.9 Hz, 1H, Ar-H), 7.54-7.51 (m, 1H, Ar-H), 7.44-7.41 (m, 2H, Ar-H), 7.33 (dd, J = 8.6, 5.0 Hz, 1H, Ar-H), 7.15-7.12 (m, 1H, Ar-H), 3.83 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.72, 164.42, 161.93, 160.30, 157.67, 139.21, 135.34, 135.32, 135.02, 134.98, 131.98, 131.46, 130.74, 130.55, 129.72, 129.68, 128.86, 127.40, 120.48, 120.33, 115.79, 115.63, 107.01, 31.66. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₈H₁₁ClFN₃NaOS₂: 425.990 83; Found: 425.991 40.
5m	¹H NMR (600 MHz, CDCl₃) δ 12.19 (d, J = 10.8 Hz, 1H, -NH-), 8.35 (d, J = 7.8 Hz, 2H, Ar-H), 8.07 (d, J = 8.1 Hz, 2H, Ar-H), 7.90 (d, J = 10.8 Hz, 1H, =CH-), 7.78 (d, J = 9.1 Hz, 1H, Ar-H), 7.38-7.31 (m, 1H, Ar-H), 7.16 (t, J = 8.1 Hz, 1H, Ar-H), 3.84 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, DMSO-d₆) δ 184.36, 164.68, 161.89, 159.97, 159.40, 137.25, 135.50, 134.33, 133.89, 133.82, 133.06, 130.71, 130.49, 129.94, 128.23, 127.97, 126.70, 126.68, 126.65, 125.27, 123.47, 111.40, 26.63. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₂FN₄O₃S₂: 415.0334 67; Found: 415.0334 79.
5n	¹H NMR (600 MHz, CDCl₃) δ 12.14 (d, J = 10.8 Hz, 1H, -NH-), 8.00 (d, J = 8.2 Hz, 2H, Ar-H), 7.89 (d, J = 10.8 Hz, 1H, =CH-), 7.77 (dd, J = 9.2, 2.9 Hz, 1H, Ar-H), 7.74 (d, J = 8.2 Hz, 2H, Ar-H), 7.33 (dd, J = 8.6, 4.9 Hz, 1H, Ar-H), 7.14 (td, J = 8.2, 2.9 Hz, 1H, Ar-H), 3.83 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.90, 163.28, 161.94, 160.67, 160.30, 138.78, 135.44, 135.42, 134.89, 134.85, 133.30, 132.82, 132.60, 132.39, 132.17, 129.78, 129.74, 127.58, 126.36, 126.23, 126.21, 126.19, 126.16, 124.55, 122.75, 120.95, 120.69, 120.49, 115.79, 115.64, 107.43, 31.64. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₉H₁₁F₄N₃NaOS₂: 460.017 19; Found: 460.017 31.
5o	¹H NMR (600 MHz, CDCl₃) δ 11.95 (d, J = 10.8 Hz, 1H, -NH-), 8.02 (d, J = 2.4 Hz, 1H, Ar-H), 7.81 (d, J = 10.8 Hz, 1H, =CH-), 7.34 (dd, J = 8.4, 2.4 Hz, 1H, Ar-H), 7.28 (d, J = 8.4 Hz, 1H, Ar-H), 3.79 (s, 2H, -S-CH₂-), 2.70 (s, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 186.44, 163.13, 159.06, 139.58, 138.55, 134.58, 132.54, 131.94, 129.34, 129.05, 106.26, 31.46, 15.99. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₃H₁₁ClN₃OS₂: 324.002 66; Found: 324.002 46.
5p	¹H NMR (600 MHz, CDCl₃) δ 11.98 (d, J = 10.9 Hz, 1H, -NH-), 8.02 (d, J = 2.4 Hz, 1H, Ar-H), 7.83 (d, J = 10.9 Hz, 1H, =CH-), 7.34 (dd, J = 8.4, 2.4 Hz, 1H, Ar-H), 7.28 (d, J = 8.4 Hz, 1H, Ar-H), 3.79 (s, 2H, -S-CH₂-), 3.05 (q, J = 7.6 Hz, 2H, -CH₂CH₃), 1.41 (t, J = 7.6 Hz, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 186.43, 165.95, 162.78, 139.65, 138.54, 134.61, 132.53, 131.94, 129.33, 129.05, 106.19, 31.47, 24.12, 14.03. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₄H₁₃ClN₃OS₂: 338.018 31; Found: 338.018 11.
5q	¹H NMR (600 MHz, CDCl₃) δ 12.09 (d, J = 10.8 Hz, 1H, -NH-), 8.04 (s, 1H, Ar-H), 7.88 (m, 1H, =CH-, 2H, Ar-H), 7.49 (m, 3H, Ar-H) 7.35 (d, J = 8.4 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz, 1H, Ar-H), 3.82 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.09, 162.57, 159.31, 139.30, 138.59, 134.57, 132.64, 132.01, 130.93, 130.05, 129.37, 129.19, 129.12, 127.39, 108.84, 31.52. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₂ClN₃OS₂: 386.018 31; Found: 386.018 16.
5r	¹H NMR (600 MHz, CDCl₃) δ 12.10 (d, J = 10.7 Hz, 1H, -NH-), 8.04 (d, J = 2.4 Hz, 1H, Ar-H), 7.87 (d, J = 10.7 Hz, 1H, =CH-), 7.81 (d, J = 8.6 Hz, 2H, Ar-H), 7.46 (d, J = 8.6 Hz, 2H, Ar-H), 7.35 (dd, J = 8.4, 2.4 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz, 2H, Ar-H), 3.82 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.61, 162.74, 161.27, 139.06, 138.63, 138.54, 136.98, 134.50, 132.69, 132.03, 129.47, 129.38, 129.12, 128.50, 106.98, 31.50, 18.42. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₂Cl₂N₃OS₂: 419.979 34; Found: 419.979 92.
5s	¹H NMR (600 MHz, CDCl₃) δ 12.12 (d, J = 10.8 Hz, 1H, -NH-), 8.28 (d, J = 6.0 Hz, 1H, Ar-H), 8.05 (s, 1H, Ar-H), 7.89 (d, J = 10.8 Hz, 1H, =CH-), 7.52 (d, J = 6.0 Hz, 1H, Ar-H), 7.45-7.40 (m, 2H, Ar-H), 7.35 (d, J = 8.4 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz, 1H, Ar-H), 3.83 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.49, 164.40, 157.69, 139.28, 138.58, 134.60, 132.60, 132.03, 132.02, 131.43, 130.76, 130.54, 129.33, 129.15, 128.90, 127.37, 106.87, 31.53. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₂Cl₂N₃OS₂: 419.979 34; Found: 419.979 92.
5t	¹H NMR (600 MHz, CDCl₃) δ 12.18 (d, J = 10.8 Hz, 1H, -NH-), 8.35 (d, J = 7.6 Hz, 2H, Ar-H), 8.07 (d, J = 7.6 Hz, 2H), 8.05 (s, 1H, Ar-H), 7.91 (d, J = 10.8 Hz, 1H, =CH-), 7.37 (d, J = 8.2 Hz, 1H, Ar-H), 7.30 (d, J = 8.2 Hz, 1H, Ar-H), 3.84 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, DMSO-d₆) δ 183.06, 165.12, 159.55, 148.61, 139.54, 136.20, 134.51, 132.62, 130.86, 130.30, 128.87, 128.41, 128.26, 128.10, 124.95, 110.55, 26.22. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₁ClN₄O₃S₂: 431.003 93; Found: 431.004 05.
5u	¹H NMR (600 MHz, CDCl₃) δ 12.14 (d, J = 10.8 Hz, 1H, -NH-), 8.04 (d, J = 2.4 Hz, 1H, Ar-H), 8.00 (d, J = 8.1 Hz, 2H, Ar-H), 7.88 (d, J = 10.8 Hz, 1H, =CH-), 7.74 (d, J = 8.1 Hz, 2H, Ar-H), 7.36 (dd, J = 8.4, 2.4 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz, 1H, Ar-H), 3.83 (s, 1H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.64, 163.27, 160.69, 138.88, 134.42, 133.27, 132.80, 132.75, 132.58, 132.37, 132.14, 132.03, 129.40, 129.13, 128.39, 127.56, 126.35, 126.22, 126.20, 126.18, 126.15, 124.55, 122.74, 120.94, 107.23, 31.50. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₉H₁₁ClF₃N₃OS₂: 475.987 57; Found: 475.987 09.

Compd.

¹H NMR, ¹³C NMR and HR-MS

¹H NMR (600 MHz, CDCl₃) δ 12.02 (d, J = 10.9 Hz, 1H, -NH-), 7.87 (d, J = 1.7 Hz, 1H, Ar-H), 7.75 (d, J = 10.9 Hz, 1H, =CH-), 7.23 (d, J = 8.0 Hz, 1H, Ar-H), 7.21 (dd, J = 8.0, 1.7 Hz, 1H, Ar-H), 3.77 (s, 2H, -S-CH₂-), 2.69 (s, 3H, -CH₃), 2.37 (s, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 187.99, 163.39, 158.68, 138.77, 136.81, 135.79, 133.80, 133.31, 129.59, 127.97, 107.31, 31.65, 20.97, 15.96. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₄H₁₄N₃OS₂: 304.057 28; Found: 304.057 06.

¹H NMR (600 MHz, CDCl₃) δ 12.03 (d, J = 10.9 Hz, 1H, -NH-), 7.87 (d, J = 1.8 Hz, 1H, Ar-H), 7.76 (d, J = 10.9 Hz, 1H, =CH-), 7.23 (d, J = 8.0 Hz, 1H, Ar-H), 7.21 (dd, J = 8.0, 1.8 Hz, 1H, Ar-H), 3.77 (s, 2H, -S-CH₂-), 3.04 (q, J = 7.6 Hz, 2H, -CH₂CH₃), 2.37 (s, 3H, -CH₃), 1.40 (t, J = 7.6 Hz, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 187.94, 165.56, 163.04, 138.86, 136.79, 135.77, 133.77, 133.32, 129.59, 127.96, 107.20, 31.65, 24.11, 20.97, 14.03. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₅H₁₆N₃OS₂: 318.072 93; Found: 318.072 79.

¹H NMR (600 MHz, CDCl₃) δ 12.16 (d, J = 10.8 Hz, 1H, -NH-), 7.89 (d, J = 1.7 Hz, 1H, Ar-H), 7.87 (m, 2H, Ar-H), 7.81 (d, J = 10.8 Hz, 1H, =CH-), 7.49-7.44 (m, 3H, Ar-H), 7.24 (d, J = 8.0 Hz, 1H, Ar-H), 7.22 (dd, J = 8.0, 1.7 Hz, 1H, Ar-H), 3.80 (s, 2H, -S-CH₂-), 2.38 (s, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 188.02, 162.83, 161.84, 138.48, 136.90, 135.82, 133.83, 133.32, 130.76, 130.22, 129.65, 129.12, 127.97, 127.36, 107.80, 31.69, 20.90. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₃H₁₁FN₃OS₂: 366.072 93; Found: 366.072 88.

¹H NMR (600 MHz, CDCl₃) δ 12.18 (d, J = 10.8 Hz, 1H, -NH-), 7.89 (d, J = 1.4 Hz, 1H, Ar-H), 7.83-7.80 (m, 1H, =CH-, 2H, Ar-H), 7.45 (d, J = 8.5 Hz, 2H, Ar-H), 7.25 (d, J = 8.0 Hz, 1H, Ar-H), 7.23 (dd, J = 8.0, 1.4 Hz, 1H, Ar-H), 3.80 (s, 2H, -S-CH₂-), 2.38 (s, 3H, -CH₃).¹³C NMR (151 MHz, CDCl₃) δ 188.11, 162.99, 160.84, 138.27, 136.90, 136.86, 135.87, 133.92, 133.25, 129.66, 129.42, 128.68, 128.47, 128.00, 108.03, 31.69, 20.93. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₉H₁₅ClN₃OS₂: 400.033 96; Found: 400.034 07.

¹H NMR (600 MHz, CDCl₃) δ 12.19 (d, J = 10.8 Hz, 1H, -NH-), 8.30-8.26 (m, 1H, Ar-H), 7.89 (d, J = 1.7 Hz, 1H, Ar-H), 7.83 (d, J = 10.8 Hz, 1H, =CH-), 7.53-7.50 (m, 1H, Ar-H), 7.44-7.40 (m, 2H, Ar-H), 7.24 (d, J = 8.0 Hz, 1H, Ar-H), 7.22 (dd, J = 8.0, 1.7 Hz, 1H, Ar-H), 3.81 (s, 2H, -S-CH₂-), 2.38 (s, 3H, -CH₃).¹³C NMR (151 MHz, CDCl₃) δ 188.02, 164.68, 157.36, 138.48, 136.83, 135.85, 133.87, 133.29, 131.95, 131.37, 130.74, 130.53, 129.68, 128.95, 127.99, 127.37, 107.90, 31.73, 20.97. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₉H₁₅ClN₃OS₂: 400.033 96; Found: 400.034 07.

¹H NMR (600 MHz, CDCl₃) δ 12.26 (d, J = 10.6 Hz, 1H, -NH-), 8.34 (d, J = 8.6 Hz, 2H, Ar-H), 8.06 (d, J = 8.6 Hz, 2H, Ar-H), 7.89 (s, 1H, Ar-H), 7.82 (d, J = 10.6 Hz, 1H, =CH-), 7.25-7.22 (m, 2H, Ar-H), 3.81 (s, 2H, -S-CH₂-), 2.39 (s, 3H, -CH₃).¹³C NMR (151 MHz, CDCl₃) δ 188.25, 164.08, 159.24, 148.87, 137.73, 136.99, 135.95, 135.85, 134.09, 133.12, 129.72, 128.04, 127.93, 124.44, 108.76, 31.69, 20.92. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₉H₁₅N₄O₃S₂: 411.058 55; Found: 411.058 43.

¹H NMR (600 MHz, CDCl₃) δ 12.22 (d, J = 10.7 Hz, 1H, -NH-), 8.00 (d, J = 7.7 Hz, 2H, Ar-H), 7.89 (s, 1H, Ar-H), 7.82 (d, J = 10.7 Hz, 1H, =CH-), 7.74 (d, J = 7.7 Hz, 2H, Ar-H), 7.25-7.21 (m, 2H, Ar-H), 3.81 (s, 2H, -S-CH₂-), 2.38 (s, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 188.18, 163.52, 160.35, 138.04, 136.95, 135.90, 133.99, 133.20, 132.76, 132.54, 132.33, 132.10, 129.69, 128.05, 128.02, 127.55, 126.39, 126.19, 126.17, 126.14, 126.12, 124.58, 122.77, 120.97, 108.35, 31.70, 20.99. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₂₀H₁₅F₃N₃OS₂: 434.060 31; Found: 434.060 22.

¹H NMR (600 MHz, CDCl₃) δ 11.95 (d, J = 11.0 Hz, 1H, -NH-), 7.82 (d, J = 11.0 Hz, 1H, =CH-), 7.75 (dd, J = 9.3, 2.9 Hz, 1H, Ar-H), 7.31 (dd, J = 8.6, 5.0 Hz, 1H, Ar-H), 7.12 (td, J = 8.2, 2.9 Hz, 1H, Ar-H), 3.79 (s, 2H, -S-CH₂-), 2.70 (s, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 186.67, 163.15, 161.90, 160.27, 159.03, 139.50, 135.32, 135.31, 135.04, 134.99, 129.70, 129.66, 120.41, 120.26, 115.69, 115.54, 106.44, 31.58, 15.98. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₃H₁₁FN₃OS₂: 308.032 21; Found: 308.032 10.

¹H NMR (600 MHz, CDCl₃) δ 12.10 (d, J = 10.8 Hz, 1H, -NH-), 7.93-7.86 (m, 3H, Ar-H), 7.77 (dd, J = 9.2, 2.9 Hz, 1H, =CH-), 7.50-7.46 (m, 4H, Ar-H), 7.33 (dd, J = 8.6, 5.0 Hz, 1H, Ar-H), 7.14 (td, J = 8.2, 2.9 Hz, 1H, Ar-H), 3.82 (d, J = 0.7 Hz, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.77, 162.55, 160.91, 160.30, 158.45, 139.22, 136.55, 136.53, 135.37, 134.91, 134.38, 134.36, 133.17, 133.08, 131.93, 130.92, 130.06, 129.69, 129.19, 128.15, 127.39, 126.27, 126.24, 120.50, 120.35, 115.60, 115.05, 107.53, 31.64. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₃FN₃OS₂: 370.047 86; Found: 370.047 96.

¹H NMR (600 MHz, CDCl₃) δ 12.10 (d, J = 10.9 Hz, 1H, -NH-), 7.87 (d, J = 10.9 Hz, 1H, =CH-), 7.81 (d, J = 8.5 Hz, 2H, Ar-H), 7.77 (dd, J = 9.2, 2.9 Hz, 1H, Ar-H), 7.46 (d, J = 8.5 Hz, 2H, Ar-H), 7.33 (dd, J = 8.6, 4.9 Hz, 1H, Ar-H), 7.14 (td, J = 8.2, 2.9 Hz, 1H, Ar-H), 3.82 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.80, 162.74, 161.95, 161.18, 160.32, 139.00, 136.98, 135.41, 135.39, 134.96, 134.92, 129.73, 129.68, 129.46, 128.58, 128.50, 120.53, 120.38, 115.76, 115.61, 107.16, 31.63. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₂ClFN₃OS₂: 404.008 89; Found: 404.008 80.

¹H NMR (600 MHz, CDCl₃) δ 12.13 (d, J = 11.0 Hz, 1H, -NH-), 8.29-8.26 (m, 1H, Ar-H), 7.90 (d, J = 11.0 Hz, 1H, =CH-), 7.78 (dd, J = 9.2, 2.9 Hz, 1H, Ar-H), 7.54-7.51 (m, 1H, Ar-H), 7.44-7.41 (m, 2H, Ar-H), 7.33 (dd, J = 8.6, 5.0 Hz, 1H, Ar-H), 7.15-7.12 (m, 1H, Ar-H), 3.83 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.72, 164.42, 161.93, 160.30, 157.67, 139.21, 135.34, 135.32, 135.02, 134.98, 131.98, 131.46, 130.74, 130.55, 129.72, 129.68, 128.86, 127.40, 120.48, 120.33, 115.79, 115.63, 107.01, 31.66. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₈H₁₁ClFN₃NaOS₂: 425.990 83; Found: 425.991 40.

¹H NMR (600 MHz, CDCl₃) δ 12.19 (d, J = 10.8 Hz, 1H, -NH-), 8.35 (d, J = 7.8 Hz, 2H, Ar-H), 8.07 (d, J = 8.1 Hz, 2H, Ar-H), 7.90 (d, J = 10.8 Hz, 1H, =CH-), 7.78 (d, J = 9.1 Hz, 1H, Ar-H), 7.38-7.31 (m, 1H, Ar-H), 7.16 (t, J = 8.1 Hz, 1H, Ar-H), 3.84 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, DMSO-d₆) δ 184.36, 164.68, 161.89, 159.97, 159.40, 137.25, 135.50, 134.33, 133.89, 133.82, 133.06, 130.71, 130.49, 129.94, 128.23, 127.97, 126.70, 126.68, 126.65, 125.27, 123.47, 111.40, 26.63. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₂FN₄O₃S₂: 415.0334 67; Found: 415.0334 79.

¹H NMR (600 MHz, CDCl₃) δ 12.14 (d, J = 10.8 Hz, 1H, -NH-), 8.00 (d, J = 8.2 Hz, 2H, Ar-H), 7.89 (d, J = 10.8 Hz, 1H, =CH-), 7.77 (dd, J = 9.2, 2.9 Hz, 1H, Ar-H), 7.74 (d, J = 8.2 Hz, 2H, Ar-H), 7.33 (dd, J = 8.6, 4.9 Hz, 1H, Ar-H), 7.14 (td, J = 8.2, 2.9 Hz, 1H, Ar-H), 3.83 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.90, 163.28, 161.94, 160.67, 160.30, 138.78, 135.44, 135.42, 134.89, 134.85, 133.30, 132.82, 132.60, 132.39, 132.17, 129.78, 129.74, 127.58, 126.36, 126.23, 126.21, 126.19, 126.16, 124.55, 122.75, 120.95, 120.69, 120.49, 115.79, 115.64, 107.43, 31.64. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₉H₁₁F₄N₃NaOS₂: 460.017 19; Found: 460.017 31.

¹H NMR (600 MHz, CDCl₃) δ 11.95 (d, J = 10.8 Hz, 1H, -NH-), 8.02 (d, J = 2.4 Hz, 1H, Ar-H), 7.81 (d, J = 10.8 Hz, 1H, =CH-), 7.34 (dd, J = 8.4, 2.4 Hz, 1H, Ar-H), 7.28 (d, J = 8.4 Hz, 1H, Ar-H), 3.79 (s, 2H, -S-CH₂-), 2.70 (s, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 186.44, 163.13, 159.06, 139.58, 138.55, 134.58, 132.54, 131.94, 129.34, 129.05, 106.26, 31.46, 15.99. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₃H₁₁ClN₃OS₂: 324.002 66; Found: 324.002 46.

¹H NMR (600 MHz, CDCl₃) δ 11.98 (d, J = 10.9 Hz, 1H, -NH-), 8.02 (d, J = 2.4 Hz, 1H, Ar-H), 7.83 (d, J = 10.9 Hz, 1H, =CH-), 7.34 (dd, J = 8.4, 2.4 Hz, 1H, Ar-H), 7.28 (d, J = 8.4 Hz, 1H, Ar-H), 3.79 (s, 2H, -S-CH₂-), 3.05 (q, J = 7.6 Hz, 2H, -CH₂CH₃), 1.41 (t, J = 7.6 Hz, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 186.43, 165.95, 162.78, 139.65, 138.54, 134.61, 132.53, 131.94, 129.33, 129.05, 106.19, 31.47, 24.12, 14.03. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₄H₁₃ClN₃OS₂: 338.018 31; Found: 338.018 11.

¹H NMR (600 MHz, CDCl₃) δ 12.09 (d, J = 10.8 Hz, 1H, -NH-), 8.04 (s, 1H, Ar-H), 7.88 (m, 1H, =CH-, 2H, Ar-H), 7.49 (m, 3H, Ar-H) 7.35 (d, J = 8.4 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz, 1H, Ar-H), 3.82 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.09, 162.57, 159.31, 139.30, 138.59, 134.57, 132.64, 132.01, 130.93, 130.05, 129.37, 129.19, 129.12, 127.39, 108.84, 31.52. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₂ClN₃OS₂: 386.018 31; Found: 386.018 16.

¹H NMR (600 MHz, CDCl₃) δ 12.10 (d, J = 10.7 Hz, 1H, -NH-), 8.04 (d, J = 2.4 Hz, 1H, Ar-H), 7.87 (d, J = 10.7 Hz, 1H, =CH-), 7.81 (d, J = 8.6 Hz, 2H, Ar-H), 7.46 (d, J = 8.6 Hz, 2H, Ar-H), 7.35 (dd, J = 8.4, 2.4 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz, 2H, Ar-H), 3.82 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.61, 162.74, 161.27, 139.06, 138.63, 138.54, 136.98, 134.50, 132.69, 132.03, 129.47, 129.38, 129.12, 128.50, 106.98, 31.50, 18.42. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₂Cl₂N₃OS₂: 419.979 34; Found: 419.979 92.

¹H NMR (600 MHz, CDCl₃) δ 12.12 (d, J = 10.8 Hz, 1H, -NH-), 8.28 (d, J = 6.0 Hz, 1H, Ar-H), 8.05 (s, 1H, Ar-H), 7.89 (d, J = 10.8 Hz, 1H, =CH-), 7.52 (d, J = 6.0 Hz, 1H, Ar-H), 7.45-7.40 (m, 2H, Ar-H), 7.35 (d, J = 8.4 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz, 1H, Ar-H), 3.83 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.49, 164.40, 157.69, 139.28, 138.58, 134.60, 132.60, 132.03, 132.02, 131.43, 130.76, 130.54, 129.33, 129.15, 128.90, 127.37, 106.87, 31.53. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₂Cl₂N₃OS₂: 419.979 34; Found: 419.979 92.

¹H NMR (600 MHz, CDCl₃) δ 12.18 (d, J = 10.8 Hz, 1H, -NH-), 8.35 (d, J = 7.6 Hz, 2H, Ar-H), 8.07 (d, J = 7.6 Hz, 2H), 8.05 (s, 1H, Ar-H), 7.91 (d, J = 10.8 Hz, 1H, =CH-), 7.37 (d, J = 8.2 Hz, 1H, Ar-H), 7.30 (d, J = 8.2 Hz, 1H, Ar-H), 3.84 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, DMSO-d₆) δ 183.06, 165.12, 159.55, 148.61, 139.54, 136.20, 134.51, 132.62, 130.86, 130.30, 128.87, 128.41, 128.26, 128.10, 124.95, 110.55, 26.22. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₁ClN₄O₃S₂: 431.003 93; Found: 431.004 05.

¹H NMR (600 MHz, CDCl₃) δ 12.14 (d, J = 10.8 Hz, 1H, -NH-), 8.04 (d, J = 2.4 Hz, 1H, Ar-H), 8.00 (d, J = 8.1 Hz, 2H, Ar-H), 7.88 (d, J = 10.8 Hz, 1H, =CH-), 7.74 (d, J = 8.1 Hz, 2H, Ar-H), 7.36 (dd, J = 8.4, 2.4 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz, 1H, Ar-H), 3.83 (s, 1H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.64, 163.27, 160.69, 138.88, 134.42, 133.27, 132.80, 132.75, 132.58, 132.37, 132.14, 132.03, 129.40, 129.13, 128.39, 127.56, 126.35, 126.22, 126.20, 126.18, 126.15, 124.55, 122.74, 120.94, 107.23, 31.50. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₉H₁₁ClF₃N₃OS₂: 475.987 57; Found: 475.987 09.

Compd.	¹H NMR, ¹³C NMR and HR-MS
5a	¹H NMR (600 MHz, CDCl₃) δ 12.02 (d, J = 10.9 Hz, 1H, -NH-), 7.87 (d, J = 1.7 Hz, 1H, Ar-H), 7.75 (d, J = 10.9 Hz, 1H, =CH-), 7.23 (d, J = 8.0 Hz, 1H, Ar-H), 7.21 (dd, J = 8.0, 1.7 Hz, 1H, Ar-H), 3.77 (s, 2H, -S-CH₂-), 2.69 (s, 3H, -CH₃), 2.37 (s, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 187.99, 163.39, 158.68, 138.77, 136.81, 135.79, 133.80, 133.31, 129.59, 127.97, 107.31, 31.65, 20.97, 15.96. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₄H₁₄N₃OS₂: 304.057 28; Found: 304.057 06.
5b	¹H NMR (600 MHz, CDCl₃) δ 12.03 (d, J = 10.9 Hz, 1H, -NH-), 7.87 (d, J = 1.8 Hz, 1H, Ar-H), 7.76 (d, J = 10.9 Hz, 1H, =CH-), 7.23 (d, J = 8.0 Hz, 1H, Ar-H), 7.21 (dd, J = 8.0, 1.8 Hz, 1H, Ar-H), 3.77 (s, 2H, -S-CH₂-), 3.04 (q, J = 7.6 Hz, 2H, -CH₂CH₃), 2.37 (s, 3H, -CH₃), 1.40 (t, J = 7.6 Hz, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 187.94, 165.56, 163.04, 138.86, 136.79, 135.77, 133.77, 133.32, 129.59, 127.96, 107.20, 31.65, 24.11, 20.97, 14.03. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₅H₁₆N₃OS₂: 318.072 93; Found: 318.072 79.
5c	¹H NMR (600 MHz, CDCl₃) δ 12.16 (d, J = 10.8 Hz, 1H, -NH-), 7.89 (d, J = 1.7 Hz, 1H, Ar-H), 7.87 (m, 2H, Ar-H), 7.81 (d, J = 10.8 Hz, 1H, =CH-), 7.49-7.44 (m, 3H, Ar-H), 7.24 (d, J = 8.0 Hz, 1H, Ar-H), 7.22 (dd, J = 8.0, 1.7 Hz, 1H, Ar-H), 3.80 (s, 2H, -S-CH₂-), 2.38 (s, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 188.02, 162.83, 161.84, 138.48, 136.90, 135.82, 133.83, 133.32, 130.76, 130.22, 129.65, 129.12, 127.97, 127.36, 107.80, 31.69, 20.90. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₃H₁₁FN₃OS₂: 366.072 93; Found: 366.072 88.
5d	¹H NMR (600 MHz, CDCl₃) δ 12.18 (d, J = 10.8 Hz, 1H, -NH-), 7.89 (d, J = 1.4 Hz, 1H, Ar-H), 7.83-7.80 (m, 1H, =CH-, 2H, Ar-H), 7.45 (d, J = 8.5 Hz, 2H, Ar-H), 7.25 (d, J = 8.0 Hz, 1H, Ar-H), 7.23 (dd, J = 8.0, 1.4 Hz, 1H, Ar-H), 3.80 (s, 2H, -S-CH₂-), 2.38 (s, 3H, -CH₃).¹³C NMR (151 MHz, CDCl₃) δ 188.11, 162.99, 160.84, 138.27, 136.90, 136.86, 135.87, 133.92, 133.25, 129.66, 129.42, 128.68, 128.47, 128.00, 108.03, 31.69, 20.93. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₉H₁₅ClN₃OS₂: 400.033 96; Found: 400.034 07.
5e	¹H NMR (600 MHz, CDCl₃) δ 12.19 (d, J = 10.8 Hz, 1H, -NH-), 8.30-8.26 (m, 1H, Ar-H), 7.89 (d, J = 1.7 Hz, 1H, Ar-H), 7.83 (d, J = 10.8 Hz, 1H, =CH-), 7.53-7.50 (m, 1H, Ar-H), 7.44-7.40 (m, 2H, Ar-H), 7.24 (d, J = 8.0 Hz, 1H, Ar-H), 7.22 (dd, J = 8.0, 1.7 Hz, 1H, Ar-H), 3.81 (s, 2H, -S-CH₂-), 2.38 (s, 3H, -CH₃).¹³C NMR (151 MHz, CDCl₃) δ 188.02, 164.68, 157.36, 138.48, 136.83, 135.85, 133.87, 133.29, 131.95, 131.37, 130.74, 130.53, 129.68, 128.95, 127.99, 127.37, 107.90, 31.73, 20.97. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₉H₁₅ClN₃OS₂: 400.033 96; Found: 400.034 07.
5f	¹H NMR (600 MHz, CDCl₃) δ 12.26 (d, J = 10.6 Hz, 1H, -NH-), 8.34 (d, J = 8.6 Hz, 2H, Ar-H), 8.06 (d, J = 8.6 Hz, 2H, Ar-H), 7.89 (s, 1H, Ar-H), 7.82 (d, J = 10.6 Hz, 1H, =CH-), 7.25-7.22 (m, 2H, Ar-H), 3.81 (s, 2H, -S-CH₂-), 2.39 (s, 3H, -CH₃).¹³C NMR (151 MHz, CDCl₃) δ 188.25, 164.08, 159.24, 148.87, 137.73, 136.99, 135.95, 135.85, 134.09, 133.12, 129.72, 128.04, 127.93, 124.44, 108.76, 31.69, 20.92. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₉H₁₅N₄O₃S₂: 411.058 55; Found: 411.058 43.
5g	¹H NMR (600 MHz, CDCl₃) δ 12.22 (d, J = 10.7 Hz, 1H, -NH-), 8.00 (d, J = 7.7 Hz, 2H, Ar-H), 7.89 (s, 1H, Ar-H), 7.82 (d, J = 10.7 Hz, 1H, =CH-), 7.74 (d, J = 7.7 Hz, 2H, Ar-H), 7.25-7.21 (m, 2H, Ar-H), 3.81 (s, 2H, -S-CH₂-), 2.38 (s, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 188.18, 163.52, 160.35, 138.04, 136.95, 135.90, 133.99, 133.20, 132.76, 132.54, 132.33, 132.10, 129.69, 128.05, 128.02, 127.55, 126.39, 126.19, 126.17, 126.14, 126.12, 124.58, 122.77, 120.97, 108.35, 31.70, 20.99. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₂₀H₁₅F₃N₃OS₂: 434.060 31; Found: 434.060 22.
5h	¹H NMR (600 MHz, CDCl₃) δ 11.95 (d, J = 11.0 Hz, 1H, -NH-), 7.82 (d, J = 11.0 Hz, 1H, =CH-), 7.75 (dd, J = 9.3, 2.9 Hz, 1H, Ar-H), 7.31 (dd, J = 8.6, 5.0 Hz, 1H, Ar-H), 7.12 (td, J = 8.2, 2.9 Hz, 1H, Ar-H), 3.79 (s, 2H, -S-CH₂-), 2.70 (s, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 186.67, 163.15, 161.90, 160.27, 159.03, 139.50, 135.32, 135.31, 135.04, 134.99, 129.70, 129.66, 120.41, 120.26, 115.69, 115.54, 106.44, 31.58, 15.98. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₃H₁₁FN₃OS₂: 308.032 21; Found: 308.032 10.
5i	¹H NMR (600 MHz, CDCl₃) δ 12.10 (d, J = 10.8 Hz, 1H, -NH-), 7.93-7.86 (m, 3H, Ar-H), 7.77 (dd, J = 9.2, 2.9 Hz, 1H, =CH-), 7.50-7.46 (m, 4H, Ar-H), 7.33 (dd, J = 8.6, 5.0 Hz, 1H, Ar-H), 7.14 (td, J = 8.2, 2.9 Hz, 1H, Ar-H), 3.82 (d, J = 0.7 Hz, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.77, 162.55, 160.91, 160.30, 158.45, 139.22, 136.55, 136.53, 135.37, 134.91, 134.38, 134.36, 133.17, 133.08, 131.93, 130.92, 130.06, 129.69, 129.19, 128.15, 127.39, 126.27, 126.24, 120.50, 120.35, 115.60, 115.05, 107.53, 31.64. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₃FN₃OS₂: 370.047 86; Found: 370.047 96.
5j	¹H NMR (600 MHz, CDCl₃) δ 12.10 (d, J = 10.8 Hz, 1H, -NH-), 7.93-7.86 (m, 3H, Ar-H), 7.77 (dd, J = 9.2, 2.9 Hz, 1H, =CH-), 7.50-7.46 (m, 4H, Ar-H), 7.33 (dd, J = 8.6, 5.0 Hz, 1H, Ar-H), 7.14 (td, J = 8.2, 2.9 Hz, 1H, Ar-H), 3.82 (d, J = 0.7 Hz, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.77, 162.55, 160.91, 160.30, 158.45, 139.22, 136.55, 136.53, 135.37, 134.91, 134.38, 134.36, 133.17, 133.08, 131.93, 130.92, 130.06, 129.69, 129.19, 128.15, 127.39, 126.27, 126.24, 120.50, 120.35, 115.60, 115.05, 107.53, 31.64. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₃FN₃OS₂: 370.047 86; Found: 370.047 96.
5k	¹H NMR (600 MHz, CDCl₃) δ 12.10 (d, J = 10.9 Hz, 1H, -NH-), 7.87 (d, J = 10.9 Hz, 1H, =CH-), 7.81 (d, J = 8.5 Hz, 2H, Ar-H), 7.77 (dd, J = 9.2, 2.9 Hz, 1H, Ar-H), 7.46 (d, J = 8.5 Hz, 2H, Ar-H), 7.33 (dd, J = 8.6, 4.9 Hz, 1H, Ar-H), 7.14 (td, J = 8.2, 2.9 Hz, 1H, Ar-H), 3.82 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.80, 162.74, 161.95, 161.18, 160.32, 139.00, 136.98, 135.41, 135.39, 134.96, 134.92, 129.73, 129.68, 129.46, 128.58, 128.50, 120.53, 120.38, 115.76, 115.61, 107.16, 31.63. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₂ClFN₃OS₂: 404.008 89; Found: 404.008 80.
5l	¹H NMR (600 MHz, CDCl₃) δ 12.13 (d, J = 11.0 Hz, 1H, -NH-), 8.29-8.26 (m, 1H, Ar-H), 7.90 (d, J = 11.0 Hz, 1H, =CH-), 7.78 (dd, J = 9.2, 2.9 Hz, 1H, Ar-H), 7.54-7.51 (m, 1H, Ar-H), 7.44-7.41 (m, 2H, Ar-H), 7.33 (dd, J = 8.6, 5.0 Hz, 1H, Ar-H), 7.15-7.12 (m, 1H, Ar-H), 3.83 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.72, 164.42, 161.93, 160.30, 157.67, 139.21, 135.34, 135.32, 135.02, 134.98, 131.98, 131.46, 130.74, 130.55, 129.72, 129.68, 128.86, 127.40, 120.48, 120.33, 115.79, 115.63, 107.01, 31.66. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₈H₁₁ClFN₃NaOS₂: 425.990 83; Found: 425.991 40.
5m	¹H NMR (600 MHz, CDCl₃) δ 12.19 (d, J = 10.8 Hz, 1H, -NH-), 8.35 (d, J = 7.8 Hz, 2H, Ar-H), 8.07 (d, J = 8.1 Hz, 2H, Ar-H), 7.90 (d, J = 10.8 Hz, 1H, =CH-), 7.78 (d, J = 9.1 Hz, 1H, Ar-H), 7.38-7.31 (m, 1H, Ar-H), 7.16 (t, J = 8.1 Hz, 1H, Ar-H), 3.84 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, DMSO-d₆) δ 184.36, 164.68, 161.89, 159.97, 159.40, 137.25, 135.50, 134.33, 133.89, 133.82, 133.06, 130.71, 130.49, 129.94, 128.23, 127.97, 126.70, 126.68, 126.65, 125.27, 123.47, 111.40, 26.63. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₂FN₄O₃S₂: 415.0334 67; Found: 415.0334 79.
5n	¹H NMR (600 MHz, CDCl₃) δ 12.14 (d, J = 10.8 Hz, 1H, -NH-), 8.00 (d, J = 8.2 Hz, 2H, Ar-H), 7.89 (d, J = 10.8 Hz, 1H, =CH-), 7.77 (dd, J = 9.2, 2.9 Hz, 1H, Ar-H), 7.74 (d, J = 8.2 Hz, 2H, Ar-H), 7.33 (dd, J = 8.6, 4.9 Hz, 1H, Ar-H), 7.14 (td, J = 8.2, 2.9 Hz, 1H, Ar-H), 3.83 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.90, 163.28, 161.94, 160.67, 160.30, 138.78, 135.44, 135.42, 134.89, 134.85, 133.30, 132.82, 132.60, 132.39, 132.17, 129.78, 129.74, 127.58, 126.36, 126.23, 126.21, 126.19, 126.16, 124.55, 122.75, 120.95, 120.69, 120.49, 115.79, 115.64, 107.43, 31.64. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₉H₁₁F₄N₃NaOS₂: 460.017 19; Found: 460.017 31.
5o	¹H NMR (600 MHz, CDCl₃) δ 11.95 (d, J = 10.8 Hz, 1H, -NH-), 8.02 (d, J = 2.4 Hz, 1H, Ar-H), 7.81 (d, J = 10.8 Hz, 1H, =CH-), 7.34 (dd, J = 8.4, 2.4 Hz, 1H, Ar-H), 7.28 (d, J = 8.4 Hz, 1H, Ar-H), 3.79 (s, 2H, -S-CH₂-), 2.70 (s, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 186.44, 163.13, 159.06, 139.58, 138.55, 134.58, 132.54, 131.94, 129.34, 129.05, 106.26, 31.46, 15.99. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₃H₁₁ClN₃OS₂: 324.002 66; Found: 324.002 46.
5p	¹H NMR (600 MHz, CDCl₃) δ 11.98 (d, J = 10.9 Hz, 1H, -NH-), 8.02 (d, J = 2.4 Hz, 1H, Ar-H), 7.83 (d, J = 10.9 Hz, 1H, =CH-), 7.34 (dd, J = 8.4, 2.4 Hz, 1H, Ar-H), 7.28 (d, J = 8.4 Hz, 1H, Ar-H), 3.79 (s, 2H, -S-CH₂-), 3.05 (q, J = 7.6 Hz, 2H, -CH₂CH₃), 1.41 (t, J = 7.6 Hz, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 186.43, 165.95, 162.78, 139.65, 138.54, 134.61, 132.53, 131.94, 129.33, 129.05, 106.19, 31.47, 24.12, 14.03. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₄H₁₃ClN₃OS₂: 338.018 31; Found: 338.018 11.
5q	¹H NMR (600 MHz, CDCl₃) δ 12.09 (d, J = 10.8 Hz, 1H, -NH-), 8.04 (s, 1H, Ar-H), 7.88 (m, 1H, =CH-, 2H, Ar-H), 7.49 (m, 3H, Ar-H) 7.35 (d, J = 8.4 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz, 1H, Ar-H), 3.82 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.09, 162.57, 159.31, 139.30, 138.59, 134.57, 132.64, 132.01, 130.93, 130.05, 129.37, 129.19, 129.12, 127.39, 108.84, 31.52. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₂ClN₃OS₂: 386.018 31; Found: 386.018 16.
5r	¹H NMR (600 MHz, CDCl₃) δ 12.10 (d, J = 10.7 Hz, 1H, -NH-), 8.04 (d, J = 2.4 Hz, 1H, Ar-H), 7.87 (d, J = 10.7 Hz, 1H, =CH-), 7.81 (d, J = 8.6 Hz, 2H, Ar-H), 7.46 (d, J = 8.6 Hz, 2H, Ar-H), 7.35 (dd, J = 8.4, 2.4 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz, 2H, Ar-H), 3.82 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.61, 162.74, 161.27, 139.06, 138.63, 138.54, 136.98, 134.50, 132.69, 132.03, 129.47, 129.38, 129.12, 128.50, 106.98, 31.50, 18.42. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₂Cl₂N₃OS₂: 419.979 34; Found: 419.979 92.
5s	¹H NMR (600 MHz, CDCl₃) δ 12.12 (d, J = 10.8 Hz, 1H, -NH-), 8.28 (d, J = 6.0 Hz, 1H, Ar-H), 8.05 (s, 1H, Ar-H), 7.89 (d, J = 10.8 Hz, 1H, =CH-), 7.52 (d, J = 6.0 Hz, 1H, Ar-H), 7.45-7.40 (m, 2H, Ar-H), 7.35 (d, J = 8.4 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz, 1H, Ar-H), 3.83 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.49, 164.40, 157.69, 139.28, 138.58, 134.60, 132.60, 132.03, 132.02, 131.43, 130.76, 130.54, 129.33, 129.15, 128.90, 127.37, 106.87, 31.53. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₂Cl₂N₃OS₂: 419.979 34; Found: 419.979 92.
5t	¹H NMR (600 MHz, CDCl₃) δ 12.18 (d, J = 10.8 Hz, 1H, -NH-), 8.35 (d, J = 7.6 Hz, 2H, Ar-H), 8.07 (d, J = 7.6 Hz, 2H), 8.05 (s, 1H, Ar-H), 7.91 (d, J = 10.8 Hz, 1H, =CH-), 7.37 (d, J = 8.2 Hz, 1H, Ar-H), 7.30 (d, J = 8.2 Hz, 1H, Ar-H), 3.84 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, DMSO-d₆) δ 183.06, 165.12, 159.55, 148.61, 139.54, 136.20, 134.51, 132.62, 130.86, 130.30, 128.87, 128.41, 128.26, 128.10, 124.95, 110.55, 26.22. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₁ClN₄O₃S₂: 431.003 93; Found: 431.004 05.
5u	¹H NMR (600 MHz, CDCl₃) δ 12.14 (d, J = 10.8 Hz, 1H, -NH-), 8.04 (d, J = 2.4 Hz, 1H, Ar-H), 8.00 (d, J = 8.1 Hz, 2H, Ar-H), 7.88 (d, J = 10.8 Hz, 1H, =CH-), 7.74 (d, J = 8.1 Hz, 2H, Ar-H), 7.36 (dd, J = 8.4, 2.4 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz, 1H, Ar-H), 3.83 (s, 1H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.64, 163.27, 160.69, 138.88, 134.42, 133.27, 132.80, 132.75, 132.58, 132.37, 132.14, 132.03, 129.40, 129.13, 128.39, 127.56, 126.35, 126.22, 126.20, 126.18, 126.15, 124.55, 122.74, 120.94, 107.23, 31.50. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₉H₁₁ClF₃N₃OS₂: 475.987 57; Found: 475.987 09.

Compd.

¹H NMR, ¹³C NMR and HR-MS

Compd.	C.c.	R.c.	V.m.	A.n.
5a	128	64	64	128
5b	128	-	-	128
5c	64	128	-	-
5d	128	128	16	128
5e	-	128	-	-
5f	-	-	64	-
5g	-	128	16	128
5h	128	128	32	-
5i	128	-	128	128
5j	64	32	32	64
5k	-	128	64	-
5l	-	128	-	128
5m	-	-	128	128
5n	64	16	64	128
5o	128	16	128	-
5p	32	64	32	128
5q	-	128	-	128
5r	64	128	32	128
5s	-	64	32	128
5t	128	64	64	64
5u	128	-	128	128
Carbendazim	-	64	32	128
AmphotericinB	< 2	< 2	< 2	< 2

Compd.

C.c.

R.c.

V.m.

A.n.

128

Carbendazim

128

AmphotericinB

< 2

Compd.	C.c.	R.c.	V.m.	A.n.
5a	128	64	64	128
5b	128	-	-	128
5c	64	128	-	-
5d	128	128	16	128
5e	-	128	-	-
5f	-	-	64	-
5g	-	128	16	128
5h	128	128	32	-
5i	128	-	128	128
5j	64	32	32	64
5k	-	128	64	-
5l	-	128	-	128
5m	-	-	128	128
5n	64	16	64	128
5o	128	16	128	-
5p	32	64	32	128
5q	-	128	-	128
5r	64	128	32	128
5s	-	64	32	128
5t	128	64	64	64
5u	128	-	128	128
Carbendazim	-	64	32	128
AmphotericinB	< 2	< 2	< 2	< 2

Compd.

C.c.

R.c.

V.m.

A.n.

128

Carbendazim

128

AmphotericinB

< 2

Compd.	C.n.	C.a.	A.f.	M.r.	T.m.	E.f.	C-Score
5a	32	32	16	64	64	32	6.090 0
5b	64	64	32	16	128	32	5.712 4
5c	64	128	128	128	128	-	5.221 5
5d	128	-	128	-	128	128	5.484 9
5e	128	128	32	64	-	-	5.271 2
5f	64	128	128	-	-	128	5.170 0
5g	128	128	128	-	-	128	5.642 5
5h	16	8	16	32	32	16	6.992 8
5i	32	16	16	16	64	32	6.232 1
5j	64	32	32	128	128	64	5.695 6
5k	32	128	64	64	128	128	5.400 7
5l	64	128	32	128	64	128	5.199 1
5m	128	-	128	128	-	128	5.072 8
5n	64	64	128	128	-	128	5.352 0
5o	32	16	16	64	64	64	6.210 5
5p	64	32	32	16	64	32	6.118 7
5q	64	128	32	64	128	64	5.277 5
5r	64	64	128	128	64	32	5.171 8
5s	64	128	64	128	-	128	5.028 7
5t	128	128	64	128	-	128	5.932 6
5u	128	128	64	64	128	128	5.277 5
Fluconazole	32	64	32	128	-	32	7.623 1
Amphotericin B	< 2	< 2	< 2	< 2	< 2	< 2	-

Compd.

C.n.

C.a.

A.f.

M.r.

T.m.

E.f.

C-Score

6.090 0

128

5.712 4

128

5.221 5

128

5.484 9

128

5.271 2

128

5.170 0

128

5.642 5

6.992 8

6.232 1

128

5.695 6

128

5.400 7

128

5.199 1

128

5.072 8

128

5.352 0

6.210 5

6.118 7

128

5.277 5

128

5.171 8

128

5.028 7

128

5.932 6

128

5.277 5

Fluconazole

128

7.623 1

Amphotericin B

< 2

Compd.	C.n.	C.a.	A.f.	M.r.	T.m.	E.f.	C-Score
5a	32	32	16	64	64	32	6.090 0
5b	64	64	32	16	128	32	5.712 4
5c	64	128	128	128	128	-	5.221 5
5d	128	-	128	-	128	128	5.484 9
5e	128	128	32	64	-	-	5.271 2
5f	64	128	128	-	-	128	5.170 0
5g	128	128	128	-	-	128	5.642 5
5h	16	8	16	32	32	16	6.992 8
5i	32	16	16	16	64	32	6.232 1
5j	64	32	32	128	128	64	5.695 6
5k	32	128	64	64	128	128	5.400 7
5l	64	128	32	128	64	128	5.199 1
5m	128	-	128	128	-	128	5.072 8
5n	64	64	128	128	-	128	5.352 0
5o	32	16	16	64	64	64	6.210 5
5p	64	32	32	16	64	32	6.118 7
5q	64	128	32	64	128	64	5.277 5
5r	64	64	128	128	64	32	5.171 8
5s	64	128	64	128	-	128	5.028 7
5t	128	128	64	128	-	128	5.932 6
5u	128	128	64	64	128	128	5.277 5
Fluconazole	32	64	32	128	-	32	7.623 1
Amphotericin B	< 2	< 2	< 2	< 2	< 2	< 2	-

Compd.

C.n.

C.a.

A.f.

M.r.

T.m.

E.f.

C-Score

6.090 0

128

5.712 4

128

5.221 5

128

5.484 9

128

5.271 2

128

5.170 0

128

5.642 5

6.992 8

6.232 1

128

5.695 6

128

5.400 7

128

5.199 1

128

5.072 8

128

5.352 0

6.210 5

6.118 7

128

5.277 5

128

5.171 8

128

5.028 7

128

5.932 6

128

5.277 5

Fluconazole

128

7.623 1

Amphotericin B

< 2

(E)-3-{[(1, 3, 4-噻二唑-2-基)氨基]亚甲基}-硫色满-4-酮类化合物的合成、抗真菌活性测定及分子对接研究

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李生彬 ¹ , 齐慧 ¹ , 张超超 ¹ , 刘振明 ³ , 宋亚丽 ¹^,^* , 乔晓强 ¹^,²^,^*

药学学报 | 研究论文 2018,53(9): 1518-1525

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药学学报 | 研究论文 2018, 53(9): 1518-1525

(E)-3-{[(1, 3, 4-噻二唑-2-基)氨基]亚甲基}-硫色满-4-酮类化合物的合成、抗真菌活性测定及分子对接研究

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李生彬¹, 齐慧¹, 张超超¹, 刘振明³, 宋亚丽¹^,^*, 乔晓强¹^,²^,^*

作者信息

1.河北大学药学院, 河北省药物质量分析控制重点实验室, 河北保定 071002

2.河北大学药物化学与分子诊断教育部重点实验室, 河北保定 071002

3.北京大学药学院天然药物及仿生药物国家重点实验室药物设计中心, 北京 100191

通讯作者:

* 宋亚丽, Tel/Fax:13483283338, E-mail:yalisong@hbu.edu.cn;

乔晓强, Tel/Fax:15903120430, E-mail:xiaoqiao@hbu.edu.cn

Synthesis, antifungal activity and molecular docking of (E)-3-(((1, 3, 4-thiadiazol-2-yl)amino)methylene)-thiochroman-4-ones

Sheng-bin LI¹, Hui QI¹, Chao-chao ZHANG¹, Zhen-ming LIU³, Ya-li SONG¹^,^*, Xiao-qiang QIAO¹^,²^,^*

Affiliations

1. Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding 071002, China

2. Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding 071002, China

3. Drug Design Center, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China

出版时间: 2018-09-12 doi: 10.16438/j.0513-4870.2018-0310

文章导航

摘要

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1，3，4-噻二唑和硫色满酮是具有广泛生物活性的杂环，为寻找具有抗真菌生物活性的新颖化合物，本文合成了21个含有1，3，4-噻二唑片段的硫色满酮类衍生物。所合成的化合物经HR-MS、¹H NMR、¹³C NMR和1D-noesy等方法进行了结构表征。采用微量稀释法对所合成的化合物进行抗真菌活性的测定，测试结果表明，化合物5j对辣椒炭疽病菌、小麦纹枯病菌、花生冠腐病菌的抑制活性均优于阳性对照药物多菌灵。化合物5h对白色念珠菌和烟曲霉的最小抑菌浓度分别为8 μg·mL^-1和16 μg·mL^-1，优于阳性对照药物氟康唑。利用分子对接方法研究了含1，3，4-噻二唑片段的硫色满酮类化合物与白色念珠菌的甾醇14α-去甲基化酶（sterol 14α-demethylase，CYP51）作用模式，为进一步的结构改造提供了依据。

关键词

抗菌活性 / 硫色满酮 / 噻二唑

Abstract

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Thiochromanones and 1, 3, 4-thiadazoles as heterocyclic compounds have broad biological activities. In order to find novel compounds with antifungal activity, we synthesized a novel series of (E)-3-(((1, 3, 4-thiadiazol-2-yl) amino)methylene)-thiochroman-4-ones. Structures of these compounds were established by HR-MS, ¹H NMR, ¹³C NMR and 1D-noesy. All of the synthesized compounds were screened for antifungal activity by using an established agar double dilution method (plate method) against ten fungi species in vitro. Compound 5j showed significant inhibitory activity to Colletotrichum capsici, Rhizoctonia cerealis and Aspergillus niger compared with that of the positive control carbendazim. Compounds 5h exhibited better antifungal activity to Canidia albicans and Aspergillus funigatus than the positive control fluconazole, in which the minimum inhibition concentration can reach 8 μg·mL^-1 and 16 μg·mL^-1. Moreover, the molecular docking method was used to study the interaction mode of compound 5h and CYP51, and the results will be helpful for designing of CYP51 inhibitors in the future.

Key words

antifungal activity / thiochromanone / 1, 3, 4-thiadiazol

引用本文

李生彬, 齐慧, 张超超, 刘振明, 宋亚丽, 乔晓强. (E)-3-{[(1, 3, 4-噻二唑-2-基)氨基]亚甲基}-硫色满-4-酮类化合物的合成、抗真菌活性测定及分子对接研究. 药学学报, 2018 , 53 (9) : 1518 -1525 . DOI: 10.16438/j.0513-4870.2018-0310

Sheng-bin LI, Hui QI, Chao-chao ZHANG, Zhen-ming LIU, Ya-li SONG, Xiao-qiang QIAO. Synthesis, antifungal activity and molecular docking of (E)-3-(((1, 3, 4-thiadiazol-2-yl)amino)methylene)-thiochroman-4-ones[J]. Acta Pharmaceutica Sinica, 2018 , 53 (9) : 1518 -1525 . DOI: 10.16438/j.0513-4870.2018-0310

正文

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真菌是一类分布十分广泛的真核细胞生物, 它们与人类关系密切, 其中许多真菌对人类是有益的, 然而还有些真菌可侵犯动植物及人类, 引起各种真菌病^{[1, 2]}。虽然人们对于一些结构新颖、活性突出的抗真菌药物需求量巨大, 但是抗真菌药物的发展依然十分缓慢^{[3, 4]}。甾醇14α-去甲基化酶(sterol 14α- demethylase, CYP51)是生物甾醇合成过程中的一个关键酶, 为细胞色素P450超家族的主要成员之一^[5]。其主要功能是催化羊毛甾醇14α-位的甲基离去^[6]。一旦此酶缺乏或其功能受到抑制, 生物体就无法合成甾醇, 细胞膜无法合成, 最终细胞因失去细胞膜而死亡^[7]。自然界中, CYP51广泛存在于植物、真菌、哺乳动物体内, 是氮唑类抗真菌药物的靶标酶, 在药物的设计和研发中占有重要地位^{[8, 9]}。

噻二唑类化合物是由包括氢键结合域、硫原子和双电子供体氮系统组成的五元杂环类化合物, 表现出广泛的生物活性^[10]。噻二唑类在自然界中存在以下4种异构体形式:分别是1, 2, 3-噻二唑、1, 2, 5-噻二唑、1, 2, 4-噻二唑和1, 3, 4-噻二唑^{[11, 12]}。其中, 1, 3, 4-噻二唑类的化合物对各种病原体显示出广谱的活性^[13]。这些化合物通过竞争性抑制真菌甾醇生物合成中的关键酶CYP51发挥作用^[14]。CYP51的选择性抑制会引起麦角甾醇的消耗以及羊毛甾醇和其他14-甲基甾醇的积累, 导致真菌细胞的生长抑制^{[15, 16]}。

鉴于1, 3, 4-噻二唑和硫色满酮杂环类化合物均具有良好生物活性^[17], 根据药物设计的生物活性基团拼接原理^[18-20], 设计了一系列的(E)-3-{[(1, 3, 4-噻二唑-2-基)氨基]亚甲基}-硫色满-4-酮类衍生物, 采用微量稀释法评价其抗真菌活性, 得出初步构效关系, 并通过分子对接探讨该类化合物与白色念珠菌的甾醇14α-去甲基化酶的结合方式, 为进一步结构改造提供依据^{[21, 22]}。

结果与讨论

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1 化合物的合成及结构鉴定

本文以5a为例, 由化合物3、4合成化合物5a的过程中(合成路线1), 考察了不同催化剂、溶剂对反应速率的影响。

以乙醇作溶剂, 考察了三乙胺、氢氧化钠、醋酸、盐酸等不同催化剂对产率的影响, 结果表明, 盐酸作催化剂时产率最高为83%。接着在盐酸作催化剂的条件下, 考察了乙醇、水、二氯甲烷等溶剂对反应产率的影响, 结果当乙醇作溶剂时, 产率最高。合成的最佳反应条件确定为:乙醇为溶剂, 盐酸为催化剂。

目标化合物经过HR-MS、¹H NMR、¹³C NMR等方法进行了表征, 理化数据见表 1、2。1D-noesy谱图中-S-CH₂- (δ_H 3.81)和-C=CH- (δ_H 7.83) (化合物5h)之间存在NOE效应, 说明化合物的双键为E构型。

2 抗植物病原真菌活性测定

以辣椒炭疽病菌(Colletotrichum capsici, C.c.)、小麦纹枯病菌(Rhizoctonia cerealis, R.c.)、苹果树腐烂病(Valsa mali, V.m.)、花生冠腐病菌(Aspergillus niger, A.n.)为供试菌。对合成的目标化合物5a~5u的抑菌活性进行初步筛选, 结果见表 3。结果表明化合物5n、5o对R.c.抗菌活性优于阳性对照多菌灵(carbendazim, CBD), 最小抑菌浓度均为16 μg·mL^-1。化合物5j对C.c.、R.c.、A.n.的抗菌活性也优于阳性对照多菌灵; 5p对R.c.、V.m.、A.n.抗菌活性与阳性对照多菌灵相当。化合物5a、5d、5r和5t表现出一定的抗菌活性, 但是, 所有化合物的活性均显著低于两性霉素B (amphotericin B, AmB)。

3 抗动物病原真菌活性测定

以新生隐球菌(Cryptococcus neoformans, C.n.)、白色念珠菌(Canidia albicans, C.a.)、烟曲霉(Aspergillus funigatus, A.f.)、絮状表皮癣菌(Epidermophyton floccosum, E.f.)、总状毛霉菌(Mucor racemosus, M.r.)和须癣毛癣菌(Trichophyton mentagrophytes, T.m.)为供试对象, 对合成的目标化合物5a~5u进行抑菌活性测试, 结果见表 4, 总体来看, 化合物对C.n.、C.a.和A.f.的抗菌活性要优于M.r.、T.m.和E.f.。化合物5h抗菌活性最强, 对C.a.最小抑菌浓度为8 μg·mL^-1, 对C.n.、A.f.、E.f.最小抑菌浓度为16 μg·mL^-1; 其次是5i, 对C.a.、A.f.和M.r.的最小抑菌浓度均为16 μg·mL^-1; 化合物5o对C.a.、A.f.最小抑菌浓度均为16 μg·mL^-1; 化合物5a对A.f.的最小抑菌浓度为16 μg·mL^-1, 对C.a.最小抑菌浓度为32 μg·mL^-1, 均优于阳性对照氟康唑。其余化合物对被试菌株也表现出一定的抗菌活性, 但所有化合物的抗真菌活性均显著低于两性霉素B。

R₂为烷烃时的抗菌活性优于芳香烃, 可能的原因为芳香烃空间位阻大, 无法进入活性口袋, 从而使化合物无法与作用靶点进行结合, 分子对接结果也证明了这点。另外, 当硫色满酮的苯环上带有吸电子取代基时(如氟、氯)、1, 3, 4-噻二唑的2位为供电子取代基时(如甲基或乙基), 化合物表现出较好的抗菌活性, 这对进一步设计工作具有指导意义。

4 分子对接研究

目标化合物5a~5u、阳性对照氟康唑分别与白色念珠菌的甾醇14α-去甲基化酶(ID: 5TZ1)的对接结果见表 4。对接结果表明:化合物的对接打分值(C-score)与其抗真菌活性大体相一致。

图 1、图 2和图 3为半柔性分子对接研究得到的5h、5c和氟康唑分别与CYP51活性位点的相互作用模式。从图中可以看出, 当R₂位为烷烃时(图 1), 化合物可以与CYP51的血红素铁原子形成配位结合, 而当R₂位为芳香烃时(图 2), 可能是因为苯环的空间位阻过大, 导致化合物无法与靶点的血红素铁原子形成配位结合。

同时, 分子对接研究表明, 化合物与CYP51主要通过氢键、疏水和范德华力相互作用。另外, 噻二唑环上的氮原子能与CYP51上的血红素铁原子形成配位结合, 说明化合物中噻二唑环为抗真菌活性的主要基团。硫色满酮基位于由LEU-121、TYR-122、MET-508和SER-378等氨基酸残基组成的疏水空穴中, 并形成较强的疏水相互作用, 硫色满酮环中的–C=O基团还能与TYR-118残基形成氢键, 说明–C=O基团在化合物的抗菌活性中也起关键作用。这与阳性对照氟康唑作用模式(图 3)基本相似。活性数据和对接结果表明此类化合物的抑菌作用可能与抑制CYP51有关。

结论

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本文设计合成了21个未见文献报道的含1, 3, 4-噻二唑片段的硫色满酮衍生物。采用微量稀释法对目标化合物进行抗真菌活性的测试。结果表明化合物5n、5o对R.c.抗菌活性优于阳性对照多菌灵, 最小抑菌浓度均为16 μg·mL^-1。化合物5j对C.c.、R.c.、A.n.的抗菌活性也优于阳性对照多菌灵; 化合物5a、5h、5i和5o对A.f.、C.a.的抗菌活性(MIC: 8~32 μg·mL^-1)要优于阳性对照氟康唑(MIC: 32~64 μg·mL^-1), 其余化合物的抗菌活性较弱。分子对接研究结果表明, 含1, 3, 4-噻二唑片段的硫色满酮衍生物与阳性对照氟康唑的作用模式相似, 说明噻二唑类化合物的抑菌作用可能与抑制CYP51有关。

实验部分

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¹H NMR, ¹³C NMR和1D-noesy由Bruker AVIII- 600 MHz核磁共振波谱仪完成; HR-MS由Bruker apex ultra 7.0 T傅里叶变换离子回旋共振质谱仪得到; 中间体的MS由Agilent LC/MSD Trap XCT液质联用仪获得; 熔点由SGW X-4显微熔点仪测定。其他试剂和溶剂未经特别说明均为国产或进口分析纯。

1 化合物合成

1.1 化合物2的合成

将取代苯硫酚0.1 mol和β-氯丙酸0.12 mol置于500 mL圆底烧瓶中, 加入含0.24 mol氢氧化钠的溶液300 mL, 充分搅拌均匀, 100 ℃反应。TLC跟踪监测, 待反应完全后冷至室温, 用稀盐酸调节pH 1, 析出大量白色沉淀, 抽滤, 大量水洗滤饼, 用乙醇/水重结晶(1:1), 得化合物1a~1c, 收率为72%~85%。化合物的数据与文献^[23]一致。

按1 g化合物1用4 mL浓硫酸的比例将化合物1溶于浓硫酸中, 室温放置12 h, 冰解, 析出大量浅黄色固体, 抽滤, 水洗至中性。用50%乙醇重结晶, 得到化合物2a~2c。收率为80%~85%, 化合物的数据与文献^[23]一致。

1.2 化合物3的合成

取氢化钠0.15 mol溶于甲酸乙酯150 mL中, 用恒压滴液漏斗向其中缓慢滴加0.05 mol化合物2的甲酸乙酯溶液, 30 min滴完, 在冰浴条件下搅拌, 反应12 h。反应液用水萃取3次, 合并水相然后用浓盐酸调节pH 2~3, 静止12 h析出大量沉淀。抽滤水洗得到化合物3a~3c, 产率72%~82%。化合物的数据与文献^[24]一致。

1.3 化合物4的合成

当R₂为甲基、乙基等脂肪族取代基时:取氨基硫脲0.11 mol、有机酸0.11 mol和浓盐酸30 mL加入到50 mL圆底烧瓶中, 搅拌回流3 h, 冷却至室温, 用氢氧化钠调pH 8~9, 冷却析出大量白色沉淀, 抽滤, 水洗得到化合物4a、4b, 产率75%~85%。化合物的数据与文献^[25]报道一致。

当R₂为苯基、对氯苯基等芳香族取代基时:将氨基硫脲0.11 mol和取代苯甲酸0.11 mol先加入到100 mL烧瓶中, 然后在搅拌条件下加入三氯氧磷12 mL, 在80 ℃回流反应2 h, 冷却至室温, 在冰水浴下, 缓缓滴加水15 mL, 0.5 h加毕。然后再在110 ℃回流反应5 h, 冷却, 倒入80 mL冰水中, 搅拌出现沉淀。在冰水浴下用氢氧化钠调pH 8~9, 抽滤, 水洗, 干燥, 得粗品。用DMF和H₂O (1:2)混合溶液重结晶得到化合物4c~4g, 产率70%~88%。化合物的数据与文献^[26]报道一致。

1.4 目标化合物5a~5u的合成

取化合物3 (0.01 mol)、化合物4 (0.01 mol)和浓盐酸0.5 mL加入到20 mL乙醇溶液中, 加热回流7~8 h, TLC监测(乙酸乙酯:石油醚=3:5), 反应结束后冷却至室温, 反应液用200目硅胶色谱(乙酸乙酯:石油醚=1:3)纯化, 即得目标产物5a~5u, 产率在47%~92%。

2 抗真菌活性测试

本实验受试动物病原真菌目前保存于河北省药物质量分析控制重点实验室, 植物病原真菌目前保存于河北大学药物化学与分子诊断教育部重点实验室。阳性对照品氟康唑购于山东绿因药业有限公司, 两性霉素B来自大连美仑生物技术有限公司, 阳性对照品多菌灵由江苏泰仓农化有限公司提供。本实验采用微量稀释法分别对4种植物病原真菌和6种动物病原真菌进行活性测试^[27]。将目标化合物分别用二甲基亚砜溶解, 配制成样品储备液。采用倍比稀释法稀释样品, 得到一系列质量浓度分别是128、64、32、16、8、4和2μg·mL^-1样品溶液。对照品的稀释方法同上。用血球计数法将受试菌的菌悬液浓度配成1×10⁵ CFU·mL^-1。将样品溶液100 μL及菌悬液100 μL加到96孔板中(每种菌同时作一空白对照), 混匀后植物病原真菌恒温28 ℃培养3~6天, 动物病原真菌恒温35 ℃培养2~7天, 以无菌生长的最低浓度为最小抑菌浓度(MIC值)。

3 分子对接研究

分子对接研究运用Sybyl-X2.0中的Surlex-Dock模块进行分析, 靶标蛋白白色念珠菌的甾醇14α-去甲基化酶(sterol 14α-demethylase, CYP51)的晶体结构(ID: 5TZ1)从蛋白数据库(Protein Data Bank, PDB)中获得。对接时设定对接模式为Surflex-Dock (SFXC), 对受体蛋白进行整体分析、残基修正、加氢加电荷、删除配体等处理。设定距离配体分子5Å范围以内的所有氨基酸残基为活性口袋进行对接叠合。然后基于Sybyl-X2.0软件的Surflex-Dock program模块将化合物和氟康唑分别与CYP51的晶体结构进行对接, 并对配体与受体对接模式进行分析。

基金

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国家自然科学基金资助项目(21675039)
中国博士后科学基金资助项目(2016M591401)
河北省青年拔尖人才项目
河北省自然科学基金资助项目(B2018201269)
河北大学杰出青年科学基金资助项目(2015JQ06)

参考文献

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2018年第53卷第9期

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doi: 10.16438/j.0513-4870.2018-0310

接收时间：2018-04-09
首发时间：2026-01-15
出版时间：2018-09-12

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收稿日期：2018-04-09
修回日期：2018-06-14

基金

国家自然科学基金资助项目(21675039)

中国博士后科学基金资助项目(2016M591401)

河北省青年拔尖人才项目

河北省自然科学基金资助项目(B2018201269)

河北大学杰出青年科学基金资助项目(2015JQ06)

作者信息

1.河北大学药学院, 河北省药物质量分析控制重点实验室, 河北保定 071002

2.河北大学药物化学与分子诊断教育部重点实验室, 河北保定 071002

3.北京大学药学院天然药物及仿生药物国家重点实验室药物设计中心, 北京 100191

通讯作者:

* 宋亚丽, Tel/Fax:13483283338, E-mail:yalisong@hbu.edu.cn;

乔晓强, Tel/Fax:15903120430, E-mail:xiaoqiao@hbu.edu.cn

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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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5a	CH₃	CH₃	47	171-174
5b	CH₃	C₂H₅	54	154-156
5c	CH₃		62	201-203
5d	CH₃		83	211-213
5e	CH₃		86	221-222
5f	CH₃		90	225-228
5g	CH₃		87	214-217
5h	F	CH₃	49	186-188
5i	F	C₂H₅	66	167-169
5j	F		82	205-206
5k	F		88	204-206
5l	F		85	221-223
5m	F		91	228-230
5n	F		87	197-199
5o	Cl	CH₃	49	186-189
5p	Cl	C₂H₅	77	152-155
5q	Cl		72	202-204
5r	Cl		83	218-220
5s	Cl		86	226-227
5t	Cl		92	238-240
5u	Cl		84	199-200

Compd.

R₁

R₂

Yield/%

mp/℃

CH₃

171-174

CH₃

C₂H₅

154-156

CH₃

201-203

CH₃

211-213

CH₃

221-222

CH₃

225-228

CH₃

214-217

CH₃

186-188

C₂H₅

167-169

205-206

204-206

221-223

228-230

197-199

CH₃

186-189

C₂H₅

152-155

202-204

218-220

226-227

238-240

199-200

Compd.	¹H NMR, ¹³C NMR and HR-MS
5a	¹H NMR (600 MHz, CDCl₃) δ 12.02 (d, J = 10.9 Hz, 1H, -NH-), 7.87 (d, J = 1.7 Hz, 1H, Ar-H), 7.75 (d, J = 10.9 Hz, 1H, =CH-), 7.23 (d, J = 8.0 Hz, 1H, Ar-H), 7.21 (dd, J = 8.0, 1.7 Hz, 1H, Ar-H), 3.77 (s, 2H, -S-CH₂-), 2.69 (s, 3H, -CH₃), 2.37 (s, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 187.99, 163.39, 158.68, 138.77, 136.81, 135.79, 133.80, 133.31, 129.59, 127.97, 107.31, 31.65, 20.97, 15.96. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₄H₁₄N₃OS₂: 304.057 28; Found: 304.057 06.
5b	¹H NMR (600 MHz, CDCl₃) δ 12.03 (d, J = 10.9 Hz, 1H, -NH-), 7.87 (d, J = 1.8 Hz, 1H, Ar-H), 7.76 (d, J = 10.9 Hz, 1H, =CH-), 7.23 (d, J = 8.0 Hz, 1H, Ar-H), 7.21 (dd, J = 8.0, 1.8 Hz, 1H, Ar-H), 3.77 (s, 2H, -S-CH₂-), 3.04 (q, J = 7.6 Hz, 2H, -CH₂CH₃), 2.37 (s, 3H, -CH₃), 1.40 (t, J = 7.6 Hz, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 187.94, 165.56, 163.04, 138.86, 136.79, 135.77, 133.77, 133.32, 129.59, 127.96, 107.20, 31.65, 24.11, 20.97, 14.03. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₅H₁₆N₃OS₂: 318.072 93; Found: 318.072 79.
5c	¹H NMR (600 MHz, CDCl₃) δ 12.16 (d, J = 10.8 Hz, 1H, -NH-), 7.89 (d, J = 1.7 Hz, 1H, Ar-H), 7.87 (m, 2H, Ar-H), 7.81 (d, J = 10.8 Hz, 1H, =CH-), 7.49-7.44 (m, 3H, Ar-H), 7.24 (d, J = 8.0 Hz, 1H, Ar-H), 7.22 (dd, J = 8.0, 1.7 Hz, 1H, Ar-H), 3.80 (s, 2H, -S-CH₂-), 2.38 (s, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 188.02, 162.83, 161.84, 138.48, 136.90, 135.82, 133.83, 133.32, 130.76, 130.22, 129.65, 129.12, 127.97, 127.36, 107.80, 31.69, 20.90. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₃H₁₁FN₃OS₂: 366.072 93; Found: 366.072 88.
5d	¹H NMR (600 MHz, CDCl₃) δ 12.18 (d, J = 10.8 Hz, 1H, -NH-), 7.89 (d, J = 1.4 Hz, 1H, Ar-H), 7.83-7.80 (m, 1H, =CH-, 2H, Ar-H), 7.45 (d, J = 8.5 Hz, 2H, Ar-H), 7.25 (d, J = 8.0 Hz, 1H, Ar-H), 7.23 (dd, J = 8.0, 1.4 Hz, 1H, Ar-H), 3.80 (s, 2H, -S-CH₂-), 2.38 (s, 3H, -CH₃).¹³C NMR (151 MHz, CDCl₃) δ 188.11, 162.99, 160.84, 138.27, 136.90, 136.86, 135.87, 133.92, 133.25, 129.66, 129.42, 128.68, 128.47, 128.00, 108.03, 31.69, 20.93. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₉H₁₅ClN₃OS₂: 400.033 96; Found: 400.034 07.
5e	¹H NMR (600 MHz, CDCl₃) δ 12.19 (d, J = 10.8 Hz, 1H, -NH-), 8.30-8.26 (m, 1H, Ar-H), 7.89 (d, J = 1.7 Hz, 1H, Ar-H), 7.83 (d, J = 10.8 Hz, 1H, =CH-), 7.53-7.50 (m, 1H, Ar-H), 7.44-7.40 (m, 2H, Ar-H), 7.24 (d, J = 8.0 Hz, 1H, Ar-H), 7.22 (dd, J = 8.0, 1.7 Hz, 1H, Ar-H), 3.81 (s, 2H, -S-CH₂-), 2.38 (s, 3H, -CH₃).¹³C NMR (151 MHz, CDCl₃) δ 188.02, 164.68, 157.36, 138.48, 136.83, 135.85, 133.87, 133.29, 131.95, 131.37, 130.74, 130.53, 129.68, 128.95, 127.99, 127.37, 107.90, 31.73, 20.97. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₉H₁₅ClN₃OS₂: 400.033 96; Found: 400.034 07.
5f	¹H NMR (600 MHz, CDCl₃) δ 12.26 (d, J = 10.6 Hz, 1H, -NH-), 8.34 (d, J = 8.6 Hz, 2H, Ar-H), 8.06 (d, J = 8.6 Hz, 2H, Ar-H), 7.89 (s, 1H, Ar-H), 7.82 (d, J = 10.6 Hz, 1H, =CH-), 7.25-7.22 (m, 2H, Ar-H), 3.81 (s, 2H, -S-CH₂-), 2.39 (s, 3H, -CH₃).¹³C NMR (151 MHz, CDCl₃) δ 188.25, 164.08, 159.24, 148.87, 137.73, 136.99, 135.95, 135.85, 134.09, 133.12, 129.72, 128.04, 127.93, 124.44, 108.76, 31.69, 20.92. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₉H₁₅N₄O₃S₂: 411.058 55; Found: 411.058 43.
5g	¹H NMR (600 MHz, CDCl₃) δ 12.22 (d, J = 10.7 Hz, 1H, -NH-), 8.00 (d, J = 7.7 Hz, 2H, Ar-H), 7.89 (s, 1H, Ar-H), 7.82 (d, J = 10.7 Hz, 1H, =CH-), 7.74 (d, J = 7.7 Hz, 2H, Ar-H), 7.25-7.21 (m, 2H, Ar-H), 3.81 (s, 2H, -S-CH₂-), 2.38 (s, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 188.18, 163.52, 160.35, 138.04, 136.95, 135.90, 133.99, 133.20, 132.76, 132.54, 132.33, 132.10, 129.69, 128.05, 128.02, 127.55, 126.39, 126.19, 126.17, 126.14, 126.12, 124.58, 122.77, 120.97, 108.35, 31.70, 20.99. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₂₀H₁₅F₃N₃OS₂: 434.060 31; Found: 434.060 22.
5h	¹H NMR (600 MHz, CDCl₃) δ 11.95 (d, J = 11.0 Hz, 1H, -NH-), 7.82 (d, J = 11.0 Hz, 1H, =CH-), 7.75 (dd, J = 9.3, 2.9 Hz, 1H, Ar-H), 7.31 (dd, J = 8.6, 5.0 Hz, 1H, Ar-H), 7.12 (td, J = 8.2, 2.9 Hz, 1H, Ar-H), 3.79 (s, 2H, -S-CH₂-), 2.70 (s, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 186.67, 163.15, 161.90, 160.27, 159.03, 139.50, 135.32, 135.31, 135.04, 134.99, 129.70, 129.66, 120.41, 120.26, 115.69, 115.54, 106.44, 31.58, 15.98. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₃H₁₁FN₃OS₂: 308.032 21; Found: 308.032 10.
5i	¹H NMR (600 MHz, CDCl₃) δ 12.10 (d, J = 10.8 Hz, 1H, -NH-), 7.93-7.86 (m, 3H, Ar-H), 7.77 (dd, J = 9.2, 2.9 Hz, 1H, =CH-), 7.50-7.46 (m, 4H, Ar-H), 7.33 (dd, J = 8.6, 5.0 Hz, 1H, Ar-H), 7.14 (td, J = 8.2, 2.9 Hz, 1H, Ar-H), 3.82 (d, J = 0.7 Hz, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.77, 162.55, 160.91, 160.30, 158.45, 139.22, 136.55, 136.53, 135.37, 134.91, 134.38, 134.36, 133.17, 133.08, 131.93, 130.92, 130.06, 129.69, 129.19, 128.15, 127.39, 126.27, 126.24, 120.50, 120.35, 115.60, 115.05, 107.53, 31.64. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₃FN₃OS₂: 370.047 86; Found: 370.047 96.
5j	¹H NMR (600 MHz, CDCl₃) δ 12.10 (d, J = 10.8 Hz, 1H, -NH-), 7.93-7.86 (m, 3H, Ar-H), 7.77 (dd, J = 9.2, 2.9 Hz, 1H, =CH-), 7.50-7.46 (m, 4H, Ar-H), 7.33 (dd, J = 8.6, 5.0 Hz, 1H, Ar-H), 7.14 (td, J = 8.2, 2.9 Hz, 1H, Ar-H), 3.82 (d, J = 0.7 Hz, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.77, 162.55, 160.91, 160.30, 158.45, 139.22, 136.55, 136.53, 135.37, 134.91, 134.38, 134.36, 133.17, 133.08, 131.93, 130.92, 130.06, 129.69, 129.19, 128.15, 127.39, 126.27, 126.24, 120.50, 120.35, 115.60, 115.05, 107.53, 31.64. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₃FN₃OS₂: 370.047 86; Found: 370.047 96.
5k	¹H NMR (600 MHz, CDCl₃) δ 12.10 (d, J = 10.9 Hz, 1H, -NH-), 7.87 (d, J = 10.9 Hz, 1H, =CH-), 7.81 (d, J = 8.5 Hz, 2H, Ar-H), 7.77 (dd, J = 9.2, 2.9 Hz, 1H, Ar-H), 7.46 (d, J = 8.5 Hz, 2H, Ar-H), 7.33 (dd, J = 8.6, 4.9 Hz, 1H, Ar-H), 7.14 (td, J = 8.2, 2.9 Hz, 1H, Ar-H), 3.82 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.80, 162.74, 161.95, 161.18, 160.32, 139.00, 136.98, 135.41, 135.39, 134.96, 134.92, 129.73, 129.68, 129.46, 128.58, 128.50, 120.53, 120.38, 115.76, 115.61, 107.16, 31.63. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₂ClFN₃OS₂: 404.008 89; Found: 404.008 80.
5l	¹H NMR (600 MHz, CDCl₃) δ 12.13 (d, J = 11.0 Hz, 1H, -NH-), 8.29-8.26 (m, 1H, Ar-H), 7.90 (d, J = 11.0 Hz, 1H, =CH-), 7.78 (dd, J = 9.2, 2.9 Hz, 1H, Ar-H), 7.54-7.51 (m, 1H, Ar-H), 7.44-7.41 (m, 2H, Ar-H), 7.33 (dd, J = 8.6, 5.0 Hz, 1H, Ar-H), 7.15-7.12 (m, 1H, Ar-H), 3.83 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.72, 164.42, 161.93, 160.30, 157.67, 139.21, 135.34, 135.32, 135.02, 134.98, 131.98, 131.46, 130.74, 130.55, 129.72, 129.68, 128.86, 127.40, 120.48, 120.33, 115.79, 115.63, 107.01, 31.66. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₈H₁₁ClFN₃NaOS₂: 425.990 83; Found: 425.991 40.
5m	¹H NMR (600 MHz, CDCl₃) δ 12.19 (d, J = 10.8 Hz, 1H, -NH-), 8.35 (d, J = 7.8 Hz, 2H, Ar-H), 8.07 (d, J = 8.1 Hz, 2H, Ar-H), 7.90 (d, J = 10.8 Hz, 1H, =CH-), 7.78 (d, J = 9.1 Hz, 1H, Ar-H), 7.38-7.31 (m, 1H, Ar-H), 7.16 (t, J = 8.1 Hz, 1H, Ar-H), 3.84 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, DMSO-d₆) δ 184.36, 164.68, 161.89, 159.97, 159.40, 137.25, 135.50, 134.33, 133.89, 133.82, 133.06, 130.71, 130.49, 129.94, 128.23, 127.97, 126.70, 126.68, 126.65, 125.27, 123.47, 111.40, 26.63. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₂FN₄O₃S₂: 415.0334 67; Found: 415.0334 79.
5n	¹H NMR (600 MHz, CDCl₃) δ 12.14 (d, J = 10.8 Hz, 1H, -NH-), 8.00 (d, J = 8.2 Hz, 2H, Ar-H), 7.89 (d, J = 10.8 Hz, 1H, =CH-), 7.77 (dd, J = 9.2, 2.9 Hz, 1H, Ar-H), 7.74 (d, J = 8.2 Hz, 2H, Ar-H), 7.33 (dd, J = 8.6, 4.9 Hz, 1H, Ar-H), 7.14 (td, J = 8.2, 2.9 Hz, 1H, Ar-H), 3.83 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.90, 163.28, 161.94, 160.67, 160.30, 138.78, 135.44, 135.42, 134.89, 134.85, 133.30, 132.82, 132.60, 132.39, 132.17, 129.78, 129.74, 127.58, 126.36, 126.23, 126.21, 126.19, 126.16, 124.55, 122.75, 120.95, 120.69, 120.49, 115.79, 115.64, 107.43, 31.64. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₉H₁₁F₄N₃NaOS₂: 460.017 19; Found: 460.017 31.
5o	¹H NMR (600 MHz, CDCl₃) δ 11.95 (d, J = 10.8 Hz, 1H, -NH-), 8.02 (d, J = 2.4 Hz, 1H, Ar-H), 7.81 (d, J = 10.8 Hz, 1H, =CH-), 7.34 (dd, J = 8.4, 2.4 Hz, 1H, Ar-H), 7.28 (d, J = 8.4 Hz, 1H, Ar-H), 3.79 (s, 2H, -S-CH₂-), 2.70 (s, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 186.44, 163.13, 159.06, 139.58, 138.55, 134.58, 132.54, 131.94, 129.34, 129.05, 106.26, 31.46, 15.99. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₃H₁₁ClN₃OS₂: 324.002 66; Found: 324.002 46.
5p	¹H NMR (600 MHz, CDCl₃) δ 11.98 (d, J = 10.9 Hz, 1H, -NH-), 8.02 (d, J = 2.4 Hz, 1H, Ar-H), 7.83 (d, J = 10.9 Hz, 1H, =CH-), 7.34 (dd, J = 8.4, 2.4 Hz, 1H, Ar-H), 7.28 (d, J = 8.4 Hz, 1H, Ar-H), 3.79 (s, 2H, -S-CH₂-), 3.05 (q, J = 7.6 Hz, 2H, -CH₂CH₃), 1.41 (t, J = 7.6 Hz, 3H, -CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 186.43, 165.95, 162.78, 139.65, 138.54, 134.61, 132.53, 131.94, 129.33, 129.05, 106.19, 31.47, 24.12, 14.03. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₄H₁₃ClN₃OS₂: 338.018 31; Found: 338.018 11.
5q	¹H NMR (600 MHz, CDCl₃) δ 12.09 (d, J = 10.8 Hz, 1H, -NH-), 8.04 (s, 1H, Ar-H), 7.88 (m, 1H, =CH-, 2H, Ar-H), 7.49 (m, 3H, Ar-H) 7.35 (d, J = 8.4 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz, 1H, Ar-H), 3.82 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.09, 162.57, 159.31, 139.30, 138.59, 134.57, 132.64, 132.01, 130.93, 130.05, 129.37, 129.19, 129.12, 127.39, 108.84, 31.52. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₂ClN₃OS₂: 386.018 31; Found: 386.018 16.
5r	¹H NMR (600 MHz, CDCl₃) δ 12.10 (d, J = 10.7 Hz, 1H, -NH-), 8.04 (d, J = 2.4 Hz, 1H, Ar-H), 7.87 (d, J = 10.7 Hz, 1H, =CH-), 7.81 (d, J = 8.6 Hz, 2H, Ar-H), 7.46 (d, J = 8.6 Hz, 2H, Ar-H), 7.35 (dd, J = 8.4, 2.4 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz, 2H, Ar-H), 3.82 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.61, 162.74, 161.27, 139.06, 138.63, 138.54, 136.98, 134.50, 132.69, 132.03, 129.47, 129.38, 129.12, 128.50, 106.98, 31.50, 18.42. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₂Cl₂N₃OS₂: 419.979 34; Found: 419.979 92.
5s	¹H NMR (600 MHz, CDCl₃) δ 12.12 (d, J = 10.8 Hz, 1H, -NH-), 8.28 (d, J = 6.0 Hz, 1H, Ar-H), 8.05 (s, 1H, Ar-H), 7.89 (d, J = 10.8 Hz, 1H, =CH-), 7.52 (d, J = 6.0 Hz, 1H, Ar-H), 7.45-7.40 (m, 2H, Ar-H), 7.35 (d, J = 8.4 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz, 1H, Ar-H), 3.83 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.49, 164.40, 157.69, 139.28, 138.58, 134.60, 132.60, 132.03, 132.02, 131.43, 130.76, 130.54, 129.33, 129.15, 128.90, 127.37, 106.87, 31.53. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₂Cl₂N₃OS₂: 419.979 34; Found: 419.979 92.
5t	¹H NMR (600 MHz, CDCl₃) δ 12.18 (d, J = 10.8 Hz, 1H, -NH-), 8.35 (d, J = 7.6 Hz, 2H, Ar-H), 8.07 (d, J = 7.6 Hz, 2H), 8.05 (s, 1H, Ar-H), 7.91 (d, J = 10.8 Hz, 1H, =CH-), 7.37 (d, J = 8.2 Hz, 1H, Ar-H), 7.30 (d, J = 8.2 Hz, 1H, Ar-H), 3.84 (s, 2H, -S-CH₂-). ¹³C NMR (151 MHz, DMSO-d₆) δ 183.06, 165.12, 159.55, 148.61, 139.54, 136.20, 134.51, 132.62, 130.86, 130.30, 128.87, 128.41, 128.26, 128.10, 124.95, 110.55, 26.22. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₈H₁₁ClN₄O₃S₂: 431.003 93; Found: 431.004 05.
5u	¹H NMR (600 MHz, CDCl₃) δ 12.14 (d, J = 10.8 Hz, 1H, -NH-), 8.04 (d, J = 2.4 Hz, 1H, Ar-H), 8.00 (d, J = 8.1 Hz, 2H, Ar-H), 7.88 (d, J = 10.8 Hz, 1H, =CH-), 7.74 (d, J = 8.1 Hz, 2H, Ar-H), 7.36 (dd, J = 8.4, 2.4 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz, 1H, Ar-H), 3.83 (s, 1H, -S-CH₂-). ¹³C NMR (151 MHz, CDCl₃) δ 186.64, 163.27, 160.69, 138.88, 134.42, 133.27, 132.80, 132.75, 132.58, 132.37, 132.14, 132.03, 129.40, 129.13, 128.39, 127.56, 126.35, 126.22, 126.20, 126.18, 126.15, 124.55, 122.74, 120.94, 107.23, 31.50. HR-MS (ESI⁺) [M+H]⁺: Calcd. for C₁₉H₁₁ClF₃N₃OS₂: 475.987 57; Found: 475.987 09.

Compd.

¹H NMR, ¹³C NMR and HR-MS

Compd.	C.c.	R.c.	V.m.	A.n.
5a	128	64	64	128
5b	128	-	-	128
5c	64	128	-	-
5d	128	128	16	128
5e	-	128	-	-
5f	-	-	64	-
5g	-	128	16	128
5h	128	128	32	-
5i	128	-	128	128
5j	64	32	32	64
5k	-	128	64	-
5l	-	128	-	128
5m	-	-	128	128
5n	64	16	64	128
5o	128	16	128	-
5p	32	64	32	128
5q	-	128	-	128
5r	64	128	32	128
5s	-	64	32	128
5t	128	64	64	64
5u	128	-	128	128
Carbendazim	-	64	32	128
AmphotericinB	< 2	< 2	< 2	< 2

Compd.

C.c.

R.c.

V.m.

A.n.

128

Carbendazim

128

AmphotericinB

< 2

Compd.	C.n.	C.a.	A.f.	M.r.	T.m.	E.f.	C-Score
5a	32	32	16	64	64	32	6.090 0
5b	64	64	32	16	128	32	5.712 4
5c	64	128	128	128	128	-	5.221 5
5d	128	-	128	-	128	128	5.484 9
5e	128	128	32	64	-	-	5.271 2
5f	64	128	128	-	-	128	5.170 0
5g	128	128	128	-	-	128	5.642 5
5h	16	8	16	32	32	16	6.992 8
5i	32	16	16	16	64	32	6.232 1
5j	64	32	32	128	128	64	5.695 6
5k	32	128	64	64	128	128	5.400 7
5l	64	128	32	128	64	128	5.199 1
5m	128	-	128	128	-	128	5.072 8
5n	64	64	128	128	-	128	5.352 0
5o	32	16	16	64	64	64	6.210 5
5p	64	32	32	16	64	32	6.118 7
5q	64	128	32	64	128	64	5.277 5
5r	64	64	128	128	64	32	5.171 8
5s	64	128	64	128	-	128	5.028 7
5t	128	128	64	128	-	128	5.932 6
5u	128	128	64	64	128	128	5.277 5
Fluconazole	32	64	32	128	-	32	7.623 1
Amphotericin B	< 2	< 2	< 2	< 2	< 2	< 2	-

Compd.

C.n.

C.a.

A.f.

M.r.

T.m.

E.f.

C-Score

6.090 0

128

5.712 4

128

5.221 5

128

5.484 9

128

5.271 2

128

5.170 0

128

5.642 5

6.992 8

6.232 1

128

5.695 6

128

5.400 7

128

5.199 1

128

5.072 8

128

5.352 0

6.210 5

6.118 7

128

5.277 5

128

5.171 8

128

5.028 7

128

5.932 6

128

5.277 5

Fluconazole

128

7.623 1

Amphotericin B

< 2