药学学报

Compd.	Time/h	Physical property	mp/℃	Yield/%
3a	0.5	Light yellow solid	253-255	80
3b	1	Light purple solid	320-323	85
3c	0.5	White solid	276-278	85
3d	1	White solid	320-322	90
3e	1	Light purple solid	318-321	85
3f	0.5	Light yellow solid	250-252	85
3g	0.5	White solid	284-286	80
3h	1	Light purple solid	331-334	80
3i	0.5	Light purple solid	290-293	90
3j	1	Light purple solid	296-299	90
3k	0.5	Light purple solid	273-275	80
3l	1	Light purple solid	270-272	85
3m	0.5	Light purple solid	254-256	85
3n	1	Light purple solid	282-285	80

Compd.

Time/h

Physical property

mp/℃

Yield/%

0.5

Light yellow solid

253-255

Light purple solid

320-323

0.5

White solid

276-278

White solid

320-322

Light purple solid

318-321

0.5

Light yellow solid

250-252

0.5

White solid

284-286

Light purple solid

331-334

0.5

Light purple solid

290-293

Light purple solid

296-299

0.5

Light purple solid

273-275

Light purple solid

270-272

0.5

Light purple solid

254-256

Light purple solid

282-285

Compd.	Time/h	Physical property	mp/℃	Yield/%
3a	0.5	Light yellow solid	253-255	80
3b	1	Light purple solid	320-323	85
3c	0.5	White solid	276-278	85
3d	1	White solid	320-322	90
3e	1	Light purple solid	318-321	85
3f	0.5	Light yellow solid	250-252	85
3g	0.5	White solid	284-286	80
3h	1	Light purple solid	331-334	80
3i	0.5	Light purple solid	290-293	90
3j	1	Light purple solid	296-299	90
3k	0.5	Light purple solid	273-275	80
3l	1	Light purple solid	270-272	85
3m	0.5	Light purple solid	254-256	85
3n	1	Light purple solid	282-285	80

Compd.

Time/h

Physical property

mp/℃

Yield/%

0.5

Light yellow solid

253-255

Light purple solid

320-323

0.5

White solid

276-278

White solid

320-322

Light purple solid

318-321

0.5

Light yellow solid

250-252

0.5

White solid

284-286

Light purple solid

331-334

0.5

Light purple solid

290-293

Light purple solid

296-299

0.5

Light purple solid

273-275

Light purple solid

270-272

0.5

Light purple solid

254-256

Light purple solid

282-285

Compd.	¹H NMR (600 MHz,DMSO-d₆),¹³C NMR (150 MHz,DMSO-d₆) and HR-MS (ESI⁺,m/z)
3a	¹H NMR δ 12.77 (s,1H,NH),7.90 (d,J = 2.1 Hz,1H,ArH),7.54 (dd,J = 8.5,2.2 Hz,1H,ArH),7.39 (d,J = 8.5 Hz,1H,ArH),4.46 (t,J = 3.9 Hz,1H,CH),3.27 (dd,J = 17.0,4.3 Hz,1H,COCH₂),3.17 (dd,J = 17.0,3.8 Hz,1H,COCH₂),2.95 (q,J = 7.5 Hz,2H,CH₂),1.24 (t,J = 7.5 Hz,3H,CH₃). ¹³C NMR δ 190.73,168.91,166.00,157.88,136.10,133.25,131.32,130.35,129.39,126.69,40.74,40.02,22.65,13.71. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₄H₁₂ClN₃NaO₂S₂: 375.995 7; Found: 375.994 9.
3b	¹H NMR δ 13.13 (s,1H,NH),8.11 (d,J = 7.6 Hz,1H,ArH),7.92 (d,J = 2.1 Hz,1H,ArH),7.66 (d,J = 7.9 Hz,1H,ArH),7.58-7.49 (m,3H,ArH),7.41 (d,J = 8.5 Hz,1H,ArH),4.52 (t,J = 4.0 Hz,1H,CH),3.32 (dd,J = 17.1,4.4 Hz,1H,COCH₂),3.21 (dd,J = 17.0,3.6 Hz,1H,COCH₂). ¹³C NMR δ 190.68,169.27,159.70,158.20,136.05,133.34,131.89,131.28,131.05,130.71,130.57,130.41,129.43,128.68,127.84,126.75,40.65,40.04. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₈H₁₁Cl₂N₃NaO₂S₂: 457.956 7; Found: 457.955 7.
3c	¹H NMR δ 12.76 (s,1H,NH),7.90 (d,J = 2.2 Hz,1H,ArH),7.54 (dd,J = 8.5,2.2 Hz,1H,ArH),7.39 (d,J = 8.5 Hz,1H,ArH),4.46 (t,J = 4.1 Hz,1H,CH),3.27 (dd,J = 17.0,4.3 Hz,1H,COCH₂),3.18 (dd,J = 17.0,3.9 Hz,1H,COCH₂),2.57 (s,3H,CH₃). ¹³C NMR δ 190.75,168.41,159.77,153.12,136.15,133.27,131.31,130.35,129.39,126.71,40.76,40.05,14.77. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₃H₁₀ClN₃NaO₂S₂: 361.979 5; Found: 361.979 3.
3d	¹H NMR δ 13.02 (s,1H,NH),7.97-7.83 (m,3H,ArH),7.59-7.48 (m,4H,ArH),7.41 (d,J = 8.5 Hz,1H,ArH),4.50 (s,1H,CH),3.31 (dd,J = 17.0,4.0 Hz,1H,COCH₂),3.21 (dd,J = 16.9,3.5 Hz,1H,COCH₂). ¹³C NMR δ 190.76,169.29,162.20,158.53,136.18,133.27,131.37,130.61,130.35,130.05,129.44,129.30,129.08,126.84,126.72,126.27,40.93,40.05. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₈H₁₂ClN₃NaO₂S₂: 423.996 4; Found: 423.996 3.
3e	¹H NMR δ 12.86 (s,1H,NH),7.93-7.84 (m,3H,ArH),7.58-7.51 (m,3H,ArH),7.40 (d,J = 8.5 Hz,1H,ArH),4.47 (t,J = 4.5 Hz,1H,CH),3.29 (dd,J = 16.9,4.1 Hz,1H,COCH₂),3.16 (dd,J = 16.9,5.0 Hz,1H,COCH₂). ¹³C NMR δ 191.15,170.12,160.88,160.12,137.02,134.73,133.16,131.45,130.80,130.10,129.51,129.43,129.27,128.32,127.51,126.72,42.07,40.05. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₈H₁₁Cl₂N₃NaO₂S₂: 457.956 2; Found: 457.955 4.
3f	¹H NMR δ 12.75 (s,1H,NH),7.79 (s,1H,ArH),7.29 (d,J = 7.9 Hz,1H,ArH),7.20 (d,J = 8.0 Hz,1H,ArH),4.41 (t,J = 4.2 Hz,1H,CH),3.21 (dd,J = 17.0,4.4 Hz,1H,COCH₂),3.13 (dd,J = 16.9,4.0 Hz,1H,COCH₂),2.94 (q,J = 7.5 Hz,2H,CH₂),2.29 (s,3H,ArCH₃),1.24 (t,J = 7.5 Hz,3H,CH₃). ¹³C NMR δ 191.73,169.06,165.88,157.92,135.06,134.49,133.70,129.88,127.77,127.16,40.84,40.04,22.64,20.32,13.73. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₅H₁₅N₃NaO₂S₂: 356.049 8; Found: 356.049 5.
3g	¹H NMR δ 12.72 (s,1H,NH),7.79 (s,1H,ArH),7.29 (d,J = 7.9 Hz,1H,ArH),7.20 (d,J = 8.0 Hz,1H,ArH),4.41 (t,J = 4.2 Hz,1H,CH),3.21 (dd,J = 17.0,4.4 Hz,1H,COCH₂),3.13 (dd,J = 16.9,4.0 Hz,1H,COCH₂),2.57 (s,3H,CH₃),2.29 (s,3H,ArCH₃). ¹³C NMR δ 191.75,169.03,159.67,158.26,135.06,134.51,133.73,129.86,127.79,127.16,40.85,40.04,20.32,14.77. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₄H₁₃N₃NaO₂S₂: 342.034 1; Found: 342.034 0.
3h	¹H NMR δ 13.09 (s,1H,NH),8.11 (dd,J = 7.7,1.4 Hz,1H,ArH),7.81 (s,1H,ArH),7.66 (d,J = 7.9 Hz,1H,ArH),7.55 (td,J = 7.8,1.5 Hz,1H,ArH),7.51 (td,J = 7.5,0.7 Hz,1H,ArH),7.31 (dd,J = 8.0,0.8 Hz,1H,ArH),7.22 (d,J = 8.0 Hz,1H,ArH),4.47 (t,J = 4.1 Hz,1H,CH),3.25 (dd,J = 17.0,4.5 Hz,1H,COCH₂),3.16 (dd,J = 16.9,3.9 Hz,1H,COCH₂),2.30 (s,3H,ArCH₃). ¹³C NMR δ 191.69,169.46,159.83,158.08,135.13,134.57,133.64,131.85,131.04,130.70,130.56,129.85,128.74,127.83,127.81,127.20,40.76,40.05,20.33. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₉H₁₄ClN₃NaO₂S₂: 438.010 8; Found: 438.010 2.
3i	¹H NMR δ 12.74 (s,1H,NH),7.69 (s,1H,ArH),7.23 (s,1H,ArH),4.46 (t,J = 4.3 Hz,1H,CH),3.19 (dd,J = 16.8,4.4 Hz,1H,COCH₂),3.11 (dd,J = 16.8,4.3 Hz,1H,COCH₂),2.57 (s,3H,CH₃),2.26 (s,3H,ArCH₃),2.19 (s,3H,ArCH₃). ¹³C NMR δ 191.95,168.88,159.70,158.23,135.64,134.52,133.82,133.36,130.05,125.60,40.16,40.04,20.20,19.21,14.76. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₅H₁₅N₃NaO₂S₂: 356.049 8; Found: 356.049 7.
3j	¹H NMR δ 13.10 (s,1H,NH),8.10 (dd,J = 7.7,1.3 Hz,1H,ArH),7.70 (s,1H,ArH),7.66 (d,J = 7.9 Hz,1H,ArH),7.55 (td,J = 7.6,1.4 Hz,1H,ArH),7.51 (t,J = 7.5 Hz,1H,ArH),7.25 (s,1H,ArH),4.51 (t,J = 4.2 Hz,1H,CH),3.22 (dd,J = 16.8,4.5 Hz,1H,COCH₂),3.14 (dd,J = 16.8,4.1 Hz,1H,COCH₂),2.27 (s,3H,ArCH₃),2.20 (s,3H,ArCH₃). ¹³C NMR δ 191.89,170.08,169.34,158.10,135.70,134.57,133.88,133.26,131.86,131.05,130.72,130.57,130.06,128.75,127.84,125.62,40.18,40.05,20.21,19.23. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₂₀H₁₆ClN₃NaO₂S₂: 452.027 0; Found: 452.024 6.
3k	¹H NMR δ 12.75 (s,1H,NH),7.25 (d,J = 7.7 Hz,1H,ArH),6.98 (d,J = 7.5 Hz,1H,ArH),4.47 (t,J = 4.9 Hz,1H,CH),3.23 (dd,J = 16.3,4.7 Hz,1H,COCH₂),3.11 (dd,J = 16.3,5.2 Hz,1H,COCH₂),2.59 (s,3H,CH₃),2.52 (s,3H,ArCH₃),2.20 (s,3H,ArCH₃). ¹³C NMR δ 194.24,168.42,159.71,153.13,138.76,137.85,133.54,132.40,129.18,128.71,40.35,40.04,23.53,19.49,14.77. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₅H₁₅N₃NaO₂S₂: 356.049 8; Found: 356.049 8.
3l	¹H NMR δ 13.12 (s,1H,NH),8.12 (dd,J = 7.7,1.6 Hz,1H,ArH),7.66 (d,J = 7.9 Hz,1H,ArH),7.55 (td,J = 7.6,1.6 Hz,1H,ArH),7.52 (t,J = 7.5 Hz,1H,ArH),7.26 (d,J = 7.7 Hz,1H,ArH),6.98 (d,J = 7.7 Hz,1H,ArH),4.53 (t,J = 4.7 Hz,1H,CH),3.28 (dd,J = 16.2,4.7 Hz,1H,COCH₂),3.15 (dd,J = 16.3,4.8 Hz,1H,COCH₂),2.54 (s,3H,ArCH₃),2.22 (s,3H,ArCH₃). ¹³C NMR δ 194.08,169.15,159.79,158.12,138.85,137.78,133.62,132.40,131.85,131.04,130.73,130.56,129.07,128.76,128.73,127.83,40.13,40.04,23.65,19.51. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₂₀H₁₆ClN₃NaO₂S₂: 452.026 5; Found: 452.026 0.
3m	¹H NMR δ 12.77 (s,1H,NH),7.69 (s,1H,ArH),7.24 (s,1H,ArH),4.47 (t,J = 4.3 Hz,1H,CH),3.19 (dd,J = 16.8,4.4 Hz,1H,COCH₂),3.11 (dd,J = 16.8,4.3 Hz,1H,COCH₂),2.95 (q,J = 7.5 Hz,2H,CH₂),2.26 (s,3H,ArCH₃),2.19 (s,3H,ArCH₃),1.24 (t,J = 7.5 Hz,3H,CH₃). ¹³C NMR δ 191.92,168.94,165.89,157.91,135.61,134.52,133.81,133.33,130.07,125.58,40.14,40.04,22.64,20.19,19.21,13.74. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₆H₁₇N₃NaO₂S₂: 370.065 4; Found: 370.065 4.
3n	¹H NMR δ 13.02 (s,1H,NH),7.91 (dd,J = 6.4,2.7 Hz,2H,ArH),7.57-7.41 (m,3H,ArH),7.25 (d,J = 7.7 Hz,1H,ArH),6.98 (d,J = 7.7 Hz,1H,ArH),4.50 (t,J = 4.8 Hz,1H,CH),3.26 (dd,J = 16.3,4.7 Hz,1H,COCH₂),3.14 (dd,J = 16.3,5.0 Hz,1H,COCH₂),2.53 (s,3H,ArCH₃),2.21 (s,3H,ArCH₃). ¹³C NMR δ 194.18,169.09,162.18,158.45,138.82,137.83,133.57,132.42,130.61,130.04,129.31,129.15,129.08,128.73,126.86,126.27,40.32,40.03,23.63,19.51. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₂₀H₁₇N₃NaO₂S₂: 418.065 4; Found: 418.064 9.

Compd.

¹H NMR (600 MHz,DMSO-d₆),¹³C NMR (150 MHz,DMSO-d₆) and HR-MS (ESI⁺,m/z)

¹H NMR δ 12.77 (s,1H,NH),7.90 (d,J = 2.1 Hz,1H,ArH),7.54 (dd,J = 8.5,2.2 Hz,1H,ArH),7.39 (d,J = 8.5 Hz,1H,ArH),4.46 (t,J = 3.9 Hz,1H,CH),3.27 (dd,J = 17.0,4.3 Hz,1H,COCH₂),3.17 (dd,J = 17.0,3.8 Hz,1H,COCH₂),2.95 (q,J = 7.5 Hz,2H,CH₂),1.24 (t,J = 7.5 Hz,3H,CH₃). ¹³C NMR δ 190.73,168.91,166.00,157.88,136.10,133.25,131.32,130.35,129.39,126.69,40.74,40.02,22.65,13.71. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₄H₁₂ClN₃NaO₂S₂: 375.995 7; Found: 375.994 9.

¹H NMR δ 13.13 (s,1H,NH),8.11 (d,J = 7.6 Hz,1H,ArH),7.92 (d,J = 2.1 Hz,1H,ArH),7.66 (d,J = 7.9 Hz,1H,ArH),7.58-7.49 (m,3H,ArH),7.41 (d,J = 8.5 Hz,1H,ArH),4.52 (t,J = 4.0 Hz,1H,CH),3.32 (dd,J = 17.1,4.4 Hz,1H,COCH₂),3.21 (dd,J = 17.0,3.6 Hz,1H,COCH₂). ¹³C NMR δ 190.68,169.27,159.70,158.20,136.05,133.34,131.89,131.28,131.05,130.71,130.57,130.41,129.43,128.68,127.84,126.75,40.65,40.04. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₈H₁₁Cl₂N₃NaO₂S₂: 457.956 7; Found: 457.955 7.

¹H NMR δ 12.76 (s,1H,NH),7.90 (d,J = 2.2 Hz,1H,ArH),7.54 (dd,J = 8.5,2.2 Hz,1H,ArH),7.39 (d,J = 8.5 Hz,1H,ArH),4.46 (t,J = 4.1 Hz,1H,CH),3.27 (dd,J = 17.0,4.3 Hz,1H,COCH₂),3.18 (dd,J = 17.0,3.9 Hz,1H,COCH₂),2.57 (s,3H,CH₃). ¹³C NMR δ 190.75,168.41,159.77,153.12,136.15,133.27,131.31,130.35,129.39,126.71,40.76,40.05,14.77. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for
C₁₃H₁₀ClN₃NaO₂S₂: 361.979 5; Found: 361.979 3.

¹H NMR δ 13.02 (s,1H,NH),7.97-7.83 (m,3H,ArH),7.59-7.48 (m,4H,ArH),7.41 (d,J = 8.5 Hz,1H,ArH),4.50 (s,1H,CH),3.31 (dd,J = 17.0,4.0 Hz,1H,COCH₂),3.21 (dd,J = 16.9,3.5 Hz,1H,COCH₂). ¹³C NMR δ 190.76,169.29,162.20,158.53,136.18,133.27,131.37,130.61,130.35,130.05,129.44,129.30,129.08,126.84,126.72,126.27,40.93,40.05. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for
C₁₈H₁₂ClN₃NaO₂S₂: 423.996 4; Found: 423.996 3.

¹H NMR δ 12.86 (s,1H,NH),7.93-7.84 (m,3H,ArH),7.58-7.51 (m,3H,ArH),7.40 (d,J = 8.5 Hz,1H,ArH),4.47 (t,J = 4.5 Hz,1H,CH),3.29 (dd,J = 16.9,4.1 Hz,1H,COCH₂),3.16 (dd,J = 16.9,5.0 Hz,1H,COCH₂). ¹³C NMR δ 191.15,170.12,160.88,160.12,137.02,134.73,133.16,131.45,130.80,130.10,129.51,129.43,129.27,128.32,127.51,126.72,42.07,40.05. HR-MS (ESI⁺) [M+Na]⁺: Calcd.
for C₁₈H₁₁Cl₂N₃NaO₂S₂: 457.956 2; Found: 457.955 4.

¹H NMR δ 12.75 (s,1H,NH),7.79 (s,1H,ArH),7.29 (d,J = 7.9 Hz,1H,ArH),7.20 (d,J = 8.0 Hz,1H,ArH),4.41 (t,J = 4.2 Hz,1H,CH),3.21 (dd,J = 17.0,4.4 Hz,1H,COCH₂),3.13 (dd,J = 16.9,4.0 Hz,1H,COCH₂),2.94 (q,J = 7.5 Hz,2H,CH₂),2.29 (s,3H,ArCH₃),1.24 (t,J = 7.5 Hz,3H,CH₃). ¹³C NMR δ 191.73,169.06,165.88,157.92,135.06,134.49,133.70,129.88,127.77,127.16,40.84,40.04,22.64,20.32,13.73. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₅H₁₅N₃NaO₂S₂: 356.049 8; Found: 356.049 5.

¹H NMR δ 12.72 (s,1H,NH),7.79 (s,1H,ArH),7.29 (d,J = 7.9 Hz,1H,ArH),7.20 (d,J = 8.0 Hz,1H,ArH),4.41 (t,J = 4.2 Hz,1H,CH),3.21 (dd,J = 17.0,4.4 Hz,1H,COCH₂),3.13 (dd,J = 16.9,4.0 Hz,1H,COCH₂),2.57 (s,3H,CH₃),2.29 (s,3H,ArCH₃). ¹³C NMR δ 191.75,169.03,159.67,158.26,135.06,134.51,133.73,129.86,127.79,127.16,40.85,40.04,20.32,14.77. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for
C₁₄H₁₃N₃NaO₂S₂: 342.034 1; Found: 342.034 0.

¹H NMR δ 13.09 (s,1H,NH),8.11 (dd,J = 7.7,1.4 Hz,1H,ArH),7.81 (s,1H,ArH),7.66 (d,J = 7.9 Hz,1H,ArH),7.55 (td,J = 7.8,1.5 Hz,1H,ArH),7.51 (td,J = 7.5,0.7 Hz,1H,ArH),7.31 (dd,J = 8.0,0.8 Hz,1H,ArH),7.22 (d,J = 8.0 Hz,1H,ArH),4.47 (t,J = 4.1 Hz,1H,CH),3.25 (dd,J = 17.0,4.5 Hz,1H,COCH₂),3.16 (dd,J = 16.9,3.9 Hz,1H,COCH₂),2.30 (s,3H,ArCH₃). ¹³C NMR δ 191.69,169.46,159.83,158.08,135.13,134.57,133.64,131.85,131.04,130.70,130.56,129.85,128.74,127.83,127.81,127.20,40.76,40.05,20.33. HR-MS (ESI⁺)
[M+Na]⁺: Calcd. for C₁₉H₁₄ClN₃NaO₂S₂: 438.010 8; Found: 438.010 2.

¹H NMR δ 12.74 (s,1H,NH),7.69 (s,1H,ArH),7.23 (s,1H,ArH),4.46 (t,J = 4.3 Hz,1H,CH),3.19 (dd,J = 16.8,4.4 Hz,1H,COCH₂),3.11 (dd,J = 16.8,4.3 Hz,1H,COCH₂),2.57 (s,3H,CH₃),2.26 (s,3H,ArCH₃),2.19 (s,3H,ArCH₃). ¹³C NMR δ 191.95,168.88,159.70,158.23,135.64,134.52,133.82,133.36,130.05,125.60,40.16,40.04,20.20,19.21,14.76. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₅H₁₅N₃NaO₂S₂: 356.049 8; Found: 356.049 7.

¹H NMR δ 13.10 (s,1H,NH),8.10 (dd,J = 7.7,1.3 Hz,1H,ArH),7.70 (s,1H,ArH),7.66 (d,J = 7.9 Hz,1H,ArH),7.55 (td,J = 7.6,1.4 Hz,1H,ArH),7.51 (t,J = 7.5 Hz,1H,ArH),7.25 (s,1H,ArH),4.51 (t,J = 4.2 Hz,1H,CH),3.22 (dd,J = 16.8,4.5 Hz,1H,COCH₂),3.14 (dd,J = 16.8,4.1 Hz,1H,COCH₂),2.27 (s,3H,ArCH₃),2.20 (s,3H,ArCH₃). ¹³C NMR δ 191.89,170.08,169.34,158.10,135.70,134.57,133.88,133.26,131.86,131.05,130.72,130.57,130.06,128.75,127.84,125.62,40.18,40.05,20.21,19.23. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for
C₂₀H₁₆ClN₃NaO₂S₂: 452.027 0; Found: 452.024 6.

¹H NMR δ 12.75 (s,1H,NH),7.25 (d,J = 7.7 Hz,1H,ArH),6.98 (d,J = 7.5 Hz,1H,ArH),4.47 (t,J = 4.9 Hz,1H,CH),3.23 (dd,J = 16.3,4.7 Hz,1H,COCH₂),3.11 (dd,J = 16.3,5.2 Hz,1H,COCH₂),2.59 (s,3H,CH₃),2.52 (s,3H,ArCH₃),2.20 (s,3H,ArCH₃). ¹³C NMR δ 194.24,168.42,159.71,153.13,138.76,137.85,133.54,132.40,129.18,128.71,40.35,40.04,23.53,19.49,14.77. HR-MS (ESI⁺) [M+Na]⁺: Calcd.
for C₁₅H₁₅N₃NaO₂S₂: 356.049 8; Found: 356.049 8.

¹H NMR δ 13.12 (s,1H,NH),8.12 (dd,J = 7.7,1.6 Hz,1H,ArH),7.66 (d,J = 7.9 Hz,1H,ArH),7.55 (td,J = 7.6,1.6 Hz,1H,ArH),7.52 (t,J = 7.5 Hz,1H,ArH),7.26 (d,J = 7.7 Hz,1H,ArH),6.98 (d,J = 7.7 Hz,1H,ArH),4.53 (t,J = 4.7 Hz,1H,CH),3.28 (dd,J = 16.2,4.7 Hz,1H,COCH₂),3.15 (dd,J = 16.3,4.8 Hz,1H,COCH₂),2.54 (s,3H,ArCH₃),2.22 (s,3H,ArCH₃). ¹³C NMR δ 194.08,169.15,159.79,158.12,138.85,137.78,133.62,132.40,131.85,131.04,130.73,130.56,129.07,128.76,128.73,127.83,40.13,40.04,23.65,19.51. HR-MS (ESI⁺)
[M+Na]⁺: Calcd. for C₂₀H₁₆ClN₃NaO₂S₂: 452.026 5; Found: 452.026 0.

¹H NMR δ 12.77 (s,1H,NH),7.69 (s,1H,ArH),7.24 (s,1H,ArH),4.47 (t,J = 4.3 Hz,1H,CH),3.19 (dd,J = 16.8,4.4 Hz,1H,COCH₂),3.11 (dd,J = 16.8,4.3 Hz,1H,COCH₂),2.95 (q,J = 7.5 Hz,2H,CH₂),2.26 (s,3H,ArCH₃),2.19 (s,3H,ArCH₃),1.24 (t,J = 7.5 Hz,3H,CH₃). ¹³C NMR δ 191.92,168.94,165.89,157.91,135.61,134.52,133.81,133.33,130.07,125.58,40.14,40.04,22.64,20.19,19.21,13.74. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₆H₁₇N₃NaO₂S₂: 370.065 4; Found: 370.065 4.

¹H NMR δ 13.02 (s,1H,NH),7.91 (dd,J = 6.4,2.7 Hz,2H,ArH),7.57-7.41 (m,3H,ArH),7.25 (d,J = 7.7 Hz,1H,ArH),6.98 (d,J = 7.7 Hz,1H,ArH),4.50 (t,J = 4.8 Hz,1H,CH),3.26 (dd,J = 16.3,4.7 Hz,1H,COCH₂),3.14 (dd,J = 16.3,5.0 Hz,1H,COCH₂),2.53 (s,3H,ArCH₃),2.21 (s,3H,ArCH₃). ¹³C NMR δ 194.18,169.09,162.18,158.45,138.82,137.83,133.57,132.42,130.61,130.04,129.31,129.15,129.08,128.73,126.86,126.27,40.32,40.03,23.63,19.51. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₂₀H₁₇N₃NaO₂S₂: 418.065 4; Found: 418.064 9.

Compd.	¹H NMR (600 MHz,DMSO-d₆),¹³C NMR (150 MHz,DMSO-d₆) and HR-MS (ESI⁺,m/z)
3a	¹H NMR δ 12.77 (s,1H,NH),7.90 (d,J = 2.1 Hz,1H,ArH),7.54 (dd,J = 8.5,2.2 Hz,1H,ArH),7.39 (d,J = 8.5 Hz,1H,ArH),4.46 (t,J = 3.9 Hz,1H,CH),3.27 (dd,J = 17.0,4.3 Hz,1H,COCH₂),3.17 (dd,J = 17.0,3.8 Hz,1H,COCH₂),2.95 (q,J = 7.5 Hz,2H,CH₂),1.24 (t,J = 7.5 Hz,3H,CH₃). ¹³C NMR δ 190.73,168.91,166.00,157.88,136.10,133.25,131.32,130.35,129.39,126.69,40.74,40.02,22.65,13.71. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₄H₁₂ClN₃NaO₂S₂: 375.995 7; Found: 375.994 9.
3b	¹H NMR δ 13.13 (s,1H,NH),8.11 (d,J = 7.6 Hz,1H,ArH),7.92 (d,J = 2.1 Hz,1H,ArH),7.66 (d,J = 7.9 Hz,1H,ArH),7.58-7.49 (m,3H,ArH),7.41 (d,J = 8.5 Hz,1H,ArH),4.52 (t,J = 4.0 Hz,1H,CH),3.32 (dd,J = 17.1,4.4 Hz,1H,COCH₂),3.21 (dd,J = 17.0,3.6 Hz,1H,COCH₂). ¹³C NMR δ 190.68,169.27,159.70,158.20,136.05,133.34,131.89,131.28,131.05,130.71,130.57,130.41,129.43,128.68,127.84,126.75,40.65,40.04. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₈H₁₁Cl₂N₃NaO₂S₂: 457.956 7; Found: 457.955 7.
3c	¹H NMR δ 12.76 (s,1H,NH),7.90 (d,J = 2.2 Hz,1H,ArH),7.54 (dd,J = 8.5,2.2 Hz,1H,ArH),7.39 (d,J = 8.5 Hz,1H,ArH),4.46 (t,J = 4.1 Hz,1H,CH),3.27 (dd,J = 17.0,4.3 Hz,1H,COCH₂),3.18 (dd,J = 17.0,3.9 Hz,1H,COCH₂),2.57 (s,3H,CH₃). ¹³C NMR δ 190.75,168.41,159.77,153.12,136.15,133.27,131.31,130.35,129.39,126.71,40.76,40.05,14.77. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₃H₁₀ClN₃NaO₂S₂: 361.979 5; Found: 361.979 3.
3d	¹H NMR δ 13.02 (s,1H,NH),7.97-7.83 (m,3H,ArH),7.59-7.48 (m,4H,ArH),7.41 (d,J = 8.5 Hz,1H,ArH),4.50 (s,1H,CH),3.31 (dd,J = 17.0,4.0 Hz,1H,COCH₂),3.21 (dd,J = 16.9,3.5 Hz,1H,COCH₂). ¹³C NMR δ 190.76,169.29,162.20,158.53,136.18,133.27,131.37,130.61,130.35,130.05,129.44,129.30,129.08,126.84,126.72,126.27,40.93,40.05. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₈H₁₂ClN₃NaO₂S₂: 423.996 4; Found: 423.996 3.
3e	¹H NMR δ 12.86 (s,1H,NH),7.93-7.84 (m,3H,ArH),7.58-7.51 (m,3H,ArH),7.40 (d,J = 8.5 Hz,1H,ArH),4.47 (t,J = 4.5 Hz,1H,CH),3.29 (dd,J = 16.9,4.1 Hz,1H,COCH₂),3.16 (dd,J = 16.9,5.0 Hz,1H,COCH₂). ¹³C NMR δ 191.15,170.12,160.88,160.12,137.02,134.73,133.16,131.45,130.80,130.10,129.51,129.43,129.27,128.32,127.51,126.72,42.07,40.05. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₈H₁₁Cl₂N₃NaO₂S₂: 457.956 2; Found: 457.955 4.
3f	¹H NMR δ 12.75 (s,1H,NH),7.79 (s,1H,ArH),7.29 (d,J = 7.9 Hz,1H,ArH),7.20 (d,J = 8.0 Hz,1H,ArH),4.41 (t,J = 4.2 Hz,1H,CH),3.21 (dd,J = 17.0,4.4 Hz,1H,COCH₂),3.13 (dd,J = 16.9,4.0 Hz,1H,COCH₂),2.94 (q,J = 7.5 Hz,2H,CH₂),2.29 (s,3H,ArCH₃),1.24 (t,J = 7.5 Hz,3H,CH₃). ¹³C NMR δ 191.73,169.06,165.88,157.92,135.06,134.49,133.70,129.88,127.77,127.16,40.84,40.04,22.64,20.32,13.73. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₅H₁₅N₃NaO₂S₂: 356.049 8; Found: 356.049 5.
3g	¹H NMR δ 12.72 (s,1H,NH),7.79 (s,1H,ArH),7.29 (d,J = 7.9 Hz,1H,ArH),7.20 (d,J = 8.0 Hz,1H,ArH),4.41 (t,J = 4.2 Hz,1H,CH),3.21 (dd,J = 17.0,4.4 Hz,1H,COCH₂),3.13 (dd,J = 16.9,4.0 Hz,1H,COCH₂),2.57 (s,3H,CH₃),2.29 (s,3H,ArCH₃). ¹³C NMR δ 191.75,169.03,159.67,158.26,135.06,134.51,133.73,129.86,127.79,127.16,40.85,40.04,20.32,14.77. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₄H₁₃N₃NaO₂S₂: 342.034 1; Found: 342.034 0.
3h	¹H NMR δ 13.09 (s,1H,NH),8.11 (dd,J = 7.7,1.4 Hz,1H,ArH),7.81 (s,1H,ArH),7.66 (d,J = 7.9 Hz,1H,ArH),7.55 (td,J = 7.8,1.5 Hz,1H,ArH),7.51 (td,J = 7.5,0.7 Hz,1H,ArH),7.31 (dd,J = 8.0,0.8 Hz,1H,ArH),7.22 (d,J = 8.0 Hz,1H,ArH),4.47 (t,J = 4.1 Hz,1H,CH),3.25 (dd,J = 17.0,4.5 Hz,1H,COCH₂),3.16 (dd,J = 16.9,3.9 Hz,1H,COCH₂),2.30 (s,3H,ArCH₃). ¹³C NMR δ 191.69,169.46,159.83,158.08,135.13,134.57,133.64,131.85,131.04,130.70,130.56,129.85,128.74,127.83,127.81,127.20,40.76,40.05,20.33. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₉H₁₄ClN₃NaO₂S₂: 438.010 8; Found: 438.010 2.
3i	¹H NMR δ 12.74 (s,1H,NH),7.69 (s,1H,ArH),7.23 (s,1H,ArH),4.46 (t,J = 4.3 Hz,1H,CH),3.19 (dd,J = 16.8,4.4 Hz,1H,COCH₂),3.11 (dd,J = 16.8,4.3 Hz,1H,COCH₂),2.57 (s,3H,CH₃),2.26 (s,3H,ArCH₃),2.19 (s,3H,ArCH₃). ¹³C NMR δ 191.95,168.88,159.70,158.23,135.64,134.52,133.82,133.36,130.05,125.60,40.16,40.04,20.20,19.21,14.76. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₅H₁₅N₃NaO₂S₂: 356.049 8; Found: 356.049 7.
3j	¹H NMR δ 13.10 (s,1H,NH),8.10 (dd,J = 7.7,1.3 Hz,1H,ArH),7.70 (s,1H,ArH),7.66 (d,J = 7.9 Hz,1H,ArH),7.55 (td,J = 7.6,1.4 Hz,1H,ArH),7.51 (t,J = 7.5 Hz,1H,ArH),7.25 (s,1H,ArH),4.51 (t,J = 4.2 Hz,1H,CH),3.22 (dd,J = 16.8,4.5 Hz,1H,COCH₂),3.14 (dd,J = 16.8,4.1 Hz,1H,COCH₂),2.27 (s,3H,ArCH₃),2.20 (s,3H,ArCH₃). ¹³C NMR δ 191.89,170.08,169.34,158.10,135.70,134.57,133.88,133.26,131.86,131.05,130.72,130.57,130.06,128.75,127.84,125.62,40.18,40.05,20.21,19.23. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₂₀H₁₆ClN₃NaO₂S₂: 452.027 0; Found: 452.024 6.
3k	¹H NMR δ 12.75 (s,1H,NH),7.25 (d,J = 7.7 Hz,1H,ArH),6.98 (d,J = 7.5 Hz,1H,ArH),4.47 (t,J = 4.9 Hz,1H,CH),3.23 (dd,J = 16.3,4.7 Hz,1H,COCH₂),3.11 (dd,J = 16.3,5.2 Hz,1H,COCH₂),2.59 (s,3H,CH₃),2.52 (s,3H,ArCH₃),2.20 (s,3H,ArCH₃). ¹³C NMR δ 194.24,168.42,159.71,153.13,138.76,137.85,133.54,132.40,129.18,128.71,40.35,40.04,23.53,19.49,14.77. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₅H₁₅N₃NaO₂S₂: 356.049 8; Found: 356.049 8.
3l	¹H NMR δ 13.12 (s,1H,NH),8.12 (dd,J = 7.7,1.6 Hz,1H,ArH),7.66 (d,J = 7.9 Hz,1H,ArH),7.55 (td,J = 7.6,1.6 Hz,1H,ArH),7.52 (t,J = 7.5 Hz,1H,ArH),7.26 (d,J = 7.7 Hz,1H,ArH),6.98 (d,J = 7.7 Hz,1H,ArH),4.53 (t,J = 4.7 Hz,1H,CH),3.28 (dd,J = 16.2,4.7 Hz,1H,COCH₂),3.15 (dd,J = 16.3,4.8 Hz,1H,COCH₂),2.54 (s,3H,ArCH₃),2.22 (s,3H,ArCH₃). ¹³C NMR δ 194.08,169.15,159.79,158.12,138.85,137.78,133.62,132.40,131.85,131.04,130.73,130.56,129.07,128.76,128.73,127.83,40.13,40.04,23.65,19.51. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₂₀H₁₆ClN₃NaO₂S₂: 452.026 5; Found: 452.026 0.
3m	¹H NMR δ 12.77 (s,1H,NH),7.69 (s,1H,ArH),7.24 (s,1H,ArH),4.47 (t,J = 4.3 Hz,1H,CH),3.19 (dd,J = 16.8,4.4 Hz,1H,COCH₂),3.11 (dd,J = 16.8,4.3 Hz,1H,COCH₂),2.95 (q,J = 7.5 Hz,2H,CH₂),2.26 (s,3H,ArCH₃),2.19 (s,3H,ArCH₃),1.24 (t,J = 7.5 Hz,3H,CH₃). ¹³C NMR δ 191.92,168.94,165.89,157.91,135.61,134.52,133.81,133.33,130.07,125.58,40.14,40.04,22.64,20.19,19.21,13.74. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₆H₁₇N₃NaO₂S₂: 370.065 4; Found: 370.065 4.
3n	¹H NMR δ 13.02 (s,1H,NH),7.91 (dd,J = 6.4,2.7 Hz,2H,ArH),7.57-7.41 (m,3H,ArH),7.25 (d,J = 7.7 Hz,1H,ArH),6.98 (d,J = 7.7 Hz,1H,ArH),4.50 (t,J = 4.8 Hz,1H,CH),3.26 (dd,J = 16.3,4.7 Hz,1H,COCH₂),3.14 (dd,J = 16.3,5.0 Hz,1H,COCH₂),2.53 (s,3H,ArCH₃),2.21 (s,3H,ArCH₃). ¹³C NMR δ 194.18,169.09,162.18,158.45,138.82,137.83,133.57,132.42,130.61,130.04,129.31,129.15,129.08,128.73,126.86,126.27,40.32,40.03,23.63,19.51. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₂₀H₁₇N₃NaO₂S₂: 418.065 4; Found: 418.064 9.

Compd.

¹H NMR (600 MHz,DMSO-d₆),¹³C NMR (150 MHz,DMSO-d₆) and HR-MS (ESI⁺,m/z)

Compd.	MIC/μg·mL^-1
3a	32	32	8	16	32
3b	128	128	128	32	64
3c	32	32	8	16	128
3d	64	32	32	64	32
3e	128	64	64	32	16
3f	＞128	＞128	32	64	64
3g	64	32	16	64	64
3h	64	64	32	32	32
3i	32	32	16	128	32
3j	64	64	64	32	64
3k	32	32	16	128	＞128
3l	128	32	128	32	32
3m	32	32	16	16	32
3n	64	＞128	64	32	128
Fluconazole	32	16	32	32	16
Amphotericin B	4	2	4	4	2

Compd.

MIC/μg·mL^-1

C.n.

C.a.

E.f.

M.r.

C.k.

128

＞128

128

＞128

128

＞128

128

Fluconazole

Amphotericin B

Compd.	MIC/μg·mL^-1
3a	32	32	8	16	32
3b	128	128	128	32	64
3c	32	32	8	16	128
3d	64	32	32	64	32
3e	128	64	64	32	16
3f	＞128	＞128	32	64	64
3g	64	32	16	64	64
3h	64	64	32	32	32
3i	32	32	16	128	32
3j	64	64	64	32	64
3k	32	32	16	128	＞128
3l	128	32	128	32	32
3m	32	32	16	16	32
3n	64	＞128	64	32	128
Fluconazole	32	16	32	32	16
Amphotericin B	4	2	4	4	2

Compd.

MIC/μg·mL^-1

C.n.

C.a.

E.f.

M.r.

C.k.

128

＞128

128

＞128

128

＞128

128

Fluconazole

Amphotericin B

Compd.	MIC/μg·mL^-1
3a	64	128	64	64	32	128	128
3b	16	16	128	64	64	128	64
3c	64	128	＞128	64	128	＞128	64
3d	64	32	32	128	64	64	32
3e	16	8	64	16	32	64	32
3f	64	32	128	＞128	64	64	64
3g	64	32	32	32	32	32	＞128
3h	32	64	64	32	64	32	64
3i	64	32	64	64	128	＞128	128
3j	128	64	128	32	64	64	64
3k	64	32	＞128	64	32	32	64
3l	32	64	64	128	＞128	128	128
3m	64	64	128	64	64	＞128	32
3n	128	＞128	64	64	128	64	64
Carbendazim	32	16	32	32	16	32	32

Compd.

MIC/μg·mL^-1

H.m.

S.s.

A.t.

B.c.

F.o.

V.m.

C.g.

128

＞128

128

＞128

128

＞128

128

＞128

128

＞128

128

＞128

128

＞128

128

＞128

128

Carbendazim

Compd.	MIC/μg·mL^-1
3a	64	128	64	64	32	128	128
3b	16	16	128	64	64	128	64
3c	64	128	＞128	64	128	＞128	64
3d	64	32	32	128	64	64	32
3e	16	8	64	16	32	64	32
3f	64	32	128	＞128	64	64	64
3g	64	32	32	32	32	32	＞128
3h	32	64	64	32	64	32	64
3i	64	32	64	64	128	＞128	128
3j	128	64	128	32	64	64	64
3k	64	32	＞128	64	32	32	64
3l	32	64	64	128	＞128	128	128
3m	64	64	128	64	64	＞128	32
3n	128	＞128	64	64	128	64	64
Carbendazim	32	16	32	32	16	32	32

Compd.

MIC/μg·mL^-1

H.m.

S.s.

A.t.

B.c.

F.o.

V.m.

C.g.

128

＞128

128

＞128

128

＞128

128

＞128

128

＞128

128

＞128

128

＞128

128

＞128

128

Carbendazim

N-1,3,4-噻二唑-2-基硫色满-4-酮-2-甲酰胺衍生物的合成及抗真菌活性测定

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韩晓燕 ¹ , 李生彬 ¹ , 梁国超 ¹ , 周冠 ¹ , 钟一凡 ¹ , 齐慧 ¹ , 宋亚丽 ¹^,²^,^* , 乔晓强 ¹^,²^,^*

药学学报 | 研究论文 2017,52(1): 113-119

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药学学报 | 研究论文 2017, 52(1): 113-119

N-1,3,4-噻二唑-2-基硫色满-4-酮-2-甲酰胺衍生物的合成及抗真菌活性测定

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韩晓燕¹, 李生彬¹, 梁国超¹, 周冠¹, 钟一凡¹, 齐慧¹, 宋亚丽¹^,²^,^*, 乔晓强¹^,²^,^*

作者信息

1.河北大学药学院, 河北省药品质量控制重点实验室, 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

通讯作者:

* Tel:13483283338,E-mail:yalisong@hbu.edu.cn;

Tel:15903120430,E-mail:xiaoqiao@hbu.edu.cn

Synthesis and antifungal activities of N-1,3,4-thiadiazol-2-yl-4-oxo-thiochroman-2-yl-formamide derivatives

Xiao-yan HAN¹, Sheng-bin LI¹, Guo-chao LIANG¹, Guan ZHOU¹, Yi-fan ZHONG¹, Hui QI¹, Ya-li SONG¹^,²^,^*, Xiao-qiang QIAO¹^,²^,^*

Affiliations

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

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

出版时间: 2017-01-12 doi: 10.16438/j.0513-4870.2016-1023

文章导航

摘要

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鉴于1，3，4-噻二唑和硫色满酮类化合物均是具有广泛生物活性的杂环化合物，为寻找具有抗真菌生物活性的新颖化合物，本文以取代苯硫酚和顺丁烯二酸酐为原料，合成中间产物2-羧基-硫色满酮，再与2-氨基-1，3，4-噻二唑反应，最终合成了14个含有1，3，4-噻二唑片段的硫色满酮类衍生物。目标化合物的结构均由核磁共振氢谱（¹H NMR）、核磁共振碳谱（¹³C NMR）和高分辨质谱（HR-MS）确证。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3a和3c对絮状表皮癣菌和总状毛霉菌的最小抑菌浓度分别达到8 μg·mL^-1和16 μg·mL^-1，均优于阳性对照药物氟康唑。化合物3e对玉米小斑病菌、油菜菌核病菌、番茄灰霉病菌的抑制活性均优于阳性对照药物多菌灵。化合物3b对玉米小斑病菌的抑制活性优于阳性对照药物多菌灵。

关键词

硫色满酮 / 1,3,4-噻二唑 / 微量稀释法 / 抗真菌活性

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 bioactivity, substituted thiophenol and maleic anhydride were used to synthesize the intermediate 4-oxothiochromane-2-carboxylic acid. It was reacted with 2-amino-1,3,4-thiadiazol to get fourteen target compounds containing 1,3,4-thiadazole moiety. The structures of the obtained compounds were confirmed by ¹H NMR, ¹³C NMR and HR-MS. All compounds were investigated for antifungal activity via microdilution broth method. The results showed that the target compounds 3a and 3c to Epidermophyton floccosum and Mucor racemosus exhibited better antifungal activity than the positive control fluconazole, in which the minimum inhibition concentration can reach 8 μg·mL^-1 and 16 μg·mL^-1. Compound 3e showed significant inhibitory activity to Helminthosporium maydis, Sclerotinia sclerotiorum and Botrytis cinerea compared with that of the positive control carbendazim. Compound 3b exhibited inhibitory activity to Helminthosporium maydis better than the positive control carbendazim.

Key words

thiochromanone / 1,3,4-thiadazole / microdilution broth method / antifungal activity

引用本文

韩晓燕, 李生彬, 梁国超, 周冠, 钟一凡, 齐慧, 宋亚丽, 乔晓强. N-1,3,4-噻二唑-2-基硫色满-4-酮-2-甲酰胺衍生物的合成及抗真菌活性测定. 药学学报, 2017 , 52 (1) : 113 -119 . DOI: 10.16438/j.0513-4870.2016-1023

Xiao-yan HAN, Sheng-bin LI, Guo-chao LIANG, Guan ZHOU, Yi-fan ZHONG, Hui QI, Ya-li SONG, Xiao-qiang QIAO. Synthesis and antifungal activities of N-1,3,4-thiadiazol-2-yl-4-oxo-thiochroman-2-yl-formamide derivatives[J]. Acta Pharmaceutica Sinica, 2017 , 52 (1) : 113 -119 . DOI: 10.16438/j.0513-4870.2016-1023

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。在过去20年中,由于大量病人进行器官移植和癌症化疗时造成潜在的宿主免疫功能不全,所以侵袭性真菌感染的发病率和死亡率已急剧增加^[1]。在临床上,烟曲霉 (死亡率50%～90%)、新型隐球菌 (死亡率20%～70%) 和白色念珠菌 (死亡率20%～40%) 被认为是引发真菌感染的最重要的三大致病真菌^[2-4]。目前高效和低毒的抗真菌药物是有限的,所以人们不断地对新型抗真菌药物进行探索研究,试图寻找具有高效性、专一性以及低毒性等特点的新型抗真菌药物。同时植物病原真菌在植物生长的不同时期侵染植物的根、叶柄、卷须、花穗和果实等器官,对植物的生长造成非常不利的影响。每年都有大量农作物因病原菌侵染而导致严重损伤、减产^[5]。因此寻找能够有效抑制植物病原真菌活性的药物也非常重要。

1,3,4-噻二唑是一类含有两个N原子和一个S原子的五元杂环化合物,由于“氮碳硫”结构能作为活性中心螯合生物体中的某些金属离子,从而具有广谱的生物活性^[6],如抗菌和抗真菌^[7-9]、抗炎^[10]、抗肿瘤^[11]、抗病毒^[12]等生物活性,一些含有1,3,4-噻二唑的化合物已开发成除草剂、杀菌剂、驱虫剂、植物生长调节剂等农药^[13]。噻二唑类化合物因具有广泛的生物活性而倍受关注^[14]。Matysiak等^[7]合成了一系列5-取代的2-(2,4-二羟基苯基)-1,3,4-噻二唑衍生物 (图 1, 化合物1),并测定了其抗念珠菌活性,结果显示,当噻二唑C-2位取代基为甲基、苯基、4-乙氧基苯基和卤代苯基时,化合物显示出较高的抗真菌活性。Dogan等^[15]的研究结果表明,含1,3,4-噻二唑环的化合物 (图 1,化合物2),不仅对金色葡萄球菌、大肠杆菌、绿脓杆菌有较好的抑制活性,同时它们对真菌白色念球菌也有很好的抑制活性。Tan等^[16]报道1-(4-氯苯甲酰基)-3-[5-(4-吡啶基)-1,3,4-噻二唑-2-基]脲化合物 (图 1,化合物3),对棉花枯萎病菌、水稻纹枯病菌、黄瓜灰霉病菌、小麦赤霉病菌、苹果轮纹病菌均具有一定的抑制活性,尤其是对黄瓜灰霉病菌和苹果轮纹病菌的抑制效果较好,抑制率可达到80%以上,对水稻纹枯病菌的抑制率也接近80%。Che等^[17]通过将吡啶、1,3,4-噻二唑和酰胺拼连到同一分子中,得到了2-氨基-5-(2-氯吡啶-4-基)-1,3,4-噻二唑衍生物,实验表明,该衍生物对葡萄白腐病菌有一定的抑制作用。

硫色满酮是一类重要的含硫杂环化合物^[18],具有抗炎、抗菌^{[19, 20]}、抗癌^[21]等多种生物活性。目前,人们对此类化合物的合成和生物活性已经做了大量研究,2003年,Yang等^[22]合成了一系列硫色满酮季铵盐化合物,该类化合物水溶性较好,对浅部和深部真菌均表现出良好的抑制作用,尤其对白色念珠菌表现出较强的抑制活性 (MIC为6.25 μg·mL^-1)。2004年,Qi等^[23]合成了一系列3位Mannich碱化合物,其体外抗白色念珠菌活性与对照克霉唑相当。2007年,Das等^[24]合成了一系列3-苄基-硫色满酮化合物,表现出了较好的体外抗白色念珠菌活性 (MIC为6 μg·mL^-1)。2009年,Li等^[25]合成了一系列2位烃硫基的硫色满酮衍生物,该类化合物具有较好的体外抗白色念珠菌活性,MIC可达2 μg·mL^-1。Song等^[26]设计在硫色满酮的2位引入吲哚环,体外抗真菌实验显示该类化合物对新生隐球菌和絮状表皮癣菌抑制的MIC值均达到4 μg·mL^-1,并且这些化合物抑制浅部真菌的能力强于深部真菌; 当硫色满酮的苯环上具有吸电子基团如氟或氯时,抑制活性优于给电子基团的甲基。

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,以此为基础,根据药物设计的生物活性基团拼接原理^[27],本文以2-羧基-硫色满酮与2-氨基-1,3,4-噻二唑反应生成N-1,3,4-噻二唑-2-基硫色满-4-酮-2-甲酰胺衍生物,通过在硫色满酮的苯环上及1,3,4-噻二唑的2位引入电性不同的基团,采用微量稀释法评价其对活性的影响,得出初步构效关系,为新结构化合物的设计提供新思路。化合物的合成见合成路线1。

结果与讨论

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1 化合物的合成及鉴定

合成化合物的结构经¹H NMR、¹³C NMR、HR-MS确证,理化数据见表 1、2。

2 抗真菌活性

以新生隐球菌 (Cryptococcus neoformans,C.n.)、白色念珠菌 (Canidia albicans,C.a.)、絮状表皮癣菌 (Epidermophyton floccosum,E.f.)、总状毛霉菌 (Mucor racemosus,M.r.) 和克柔念珠菌 (Candida krusei,C.k.) 为供试对象,对合成的目标化合物3a～3n的抑菌活性进行初步筛选,结果见表 3。从测试结果可以看出,目标化合物3a～3n对C.n.、C.a.和C.k.有较差的抗真菌活性,对E.f.和M.r.有较好的抗真菌活性。首先, 化合物3a和3c对E.f.的最小抑菌浓度均可达到8 μg·mL^-1,优于阳性对照药物氟康唑; 化合物3g、3i、3k和3m对E.f.的抑菌活性仅次于3a和3c (MIC = 16 μg·mL^-1)。其次,化合物3a、3c和3m对M.r.的抑制活性优于阳性对照药物氟康唑,最小抑菌浓度均为16 μg·mL^-1; 3b、3e、3h、3j、3l和3n对M.r.的抑制活性与阳性对照药物氟康唑相当 (MIC = 32 μg·mL^-1)。从初步构效关系分析发现,当硫色满酮的苯环上带有吸电子取代基时 (如氯),1,3,4-噻二唑的2位为供电子取代基时 (如甲基或乙基),化合物对E.f.和M.r. 表现出较好的抑制活性,这对进一步设计工作具有指导意义。

以玉米小斑病菌 (Helminthosporium maydis,H.m.)、油菜菌核病菌 (Sclerotinia sclerotiorum,S.s.)、花生冠腐病菌 (Aspergillusnigervan tiegh,A.t.)、番茄灰霉病菌 (Botrytis cinerea,B.c.)、尖孢镰刀病菌 (Fusarium oxysporum,F.o.)、苹果树腐烂病菌 (Valsa mali,V.m.)、辣椒炭疽病菌 (Colletotrichum gloeosporioides,C.g.)为供试对象,对合成的目标化合物3a～3n进行植物病原菌的抗真菌活性测试,结果见表 4。从测试结果可看出,化合物3b对H.m.的最小抑菌浓度达到16 μg·mL^-1,优于阳性对照药物多菌灵; 化合物3h、3l对H.m.的抗菌活性和阳性对照药物多菌灵相当 (MIC = 32 μg·mL^-1)。化合物3e对S.s.、H.m.和B.c.的抑制活性均优于阳性对照药物多菌灵。化合物3g、3h、3j对B.c.的抗菌活性和阳性对照药物多菌灵相当。此外,从构效关系看,当硫色满酮的苯环上取代基为氯时,1,3,4-噻二唑的2位为2-Cl苯基或4-Cl苯基时化合物对H.m.、S.s.和B.c.有良好的抑制活性。化合物3e对植物病原菌H.m.、S.s.和B.c.具有广谱的抗菌效果,所以可作为潜在的抗菌化合物开发利用。

3 结论

本文以取代苯硫酚为原料,经3步反应,设计合成了14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,首先化合物3a、3c对E.f.和M.r.的抗真菌活性效果明显,抑制活性优于阳性对照药物氟康唑。其次,化合物3e对H.m.、S.s.和B.c.的抑制活性均优于阳性对照药物多菌灵; 化合物3b对H.m.的抑制活性优于阳性对照药物多菌灵。因此,含1,3,4-噻二唑片段的硫色满酮衍生物对真菌的抑制作用具有进一步研究意义。

实验部分

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Bruker AVШ-600MHz型核磁共振波谱仪(Bruker公司),内标物TMS,溶剂为DMSO-d₆; SGWX-4型显微熔点仪 (北京泰克公司); Bruker apex ultra 7.0 T傅里叶变换离子回旋质谱仪 (美国Bruker Daltonik); 旋转蒸发器 (RE 2000A) (上海亚荣仪器有限公司); 集热式恒温加热磁力搅拌器 (DF-101S) (巩义市予华科技有限公司)。所有试剂均为分析纯。

1 化合物合成

1.1 中间体1的合成

按照文献^{[28, 29]}合成中间体1。

1.2 中间体2的合成

方法一: 在100 mL烧瓶中加入10 mmol氨基硫脲、10 mmol芳基羧酸和15 mL三氯氧磷,80 ℃反应30 min后冷却至室温,在冰水浴条件下于30 min内缓缓滴加45 mL水,滴毕,80 ℃反应3 h后,经过TLC (石油醚/乙酸乙酯) 监测显示反应完全。反应液冷却至室温,倒入冰水中,搅拌下渐渐析出沉淀。冰水浴冷却下用1 mol·L^-1氢氧化钠溶液调pH值到8～9,析出大量白色沉淀,抽滤得粗品,用混合溶剂 (DMF/H₂O) 重结晶得中间体2,产率约为70%～85%。

方法二: 在100 mL烧瓶中加入10 mmol氨基硫脲和10 mmol烷基羧酸,搅拌下加入20 mL浓HCl,80 ℃反应4 h后,经过TLC (石油醚/乙酸乙酯) 监测显示反应完全。反应液冷却后倒入冰水中,搅拌出现沉淀。冰水浴冷却下用1 mol·L^-1氢氧化钠溶液调pH值到8～9,析出大量白色沉淀,抽滤得粗品,用混合溶剂 (DMF/H₂O) 重结晶得中间体2,产率约为75%～90%。

1.3 目标化合物3a～3n的合成

在100 mL圆底烧瓶中,将10 mmol中间体1和10 mmol中间体2加入到溶有10 mmol TBTU和1 mL三乙胺的二氯甲烷溶剂中,反应0.5～1 h后有沉淀析出,经过TLC (石油醚/乙酸乙酯) 监测显示反应完全。抽滤得粗品,用混合溶剂 (乙酸乙酯/DMF) 重结晶得目标产物,产率约为80%～90%。

2 抗真菌活性测试

2.1 体外抗真菌活性

本实验受试真菌均来自于中国医学科学院菌种保藏中心。阳性对照品氟康唑来自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。

本实验采用微量稀释法对5种受试真菌进行活性测试,14个目标化合物先用适量二甲基亚砜溶解,再用无菌蒸馏水稀释,然后加入到已灭过菌的1% 的葡萄糖蛋白胨琼脂培养基中,样品浓度分别为128、64、32、16、8、4、2 μg·mL^-1。对照品氟康唑和两性霉素B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。之后接种供试菌 (每种菌同时作一空白对照),置恒温烘箱中培养2～7天。以无菌生长的最低浓度为最小抑菌浓度 (MIC值)。

2.2 植物病原菌的抗真菌活性

本实验受试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。阳性对照品多菌灵来自江苏泰仓农化有限公司。

本实验采用微量稀释法对7种受试植物病原真菌进行活性测试,将14个目标化合物分别用二甲基亚砜溶解,配置成样品储备液。采用倍比稀释法稀释样品,得到一系列浓度样品溶液分别是128、64、32、16、8、4、2 μg·mL^-1。对照品多菌灵的稀释方法同上。用血球计数法将受试菌的菌悬液浓度配成1×10⁶ CFU·mL^-1。将100 μL样品溶液及100 μL菌悬液加到96孔板中 (每种菌同时作一空白对照),混匀后恒温28 ℃培养3～6天,以无菌生长的最低浓度为最小抑菌浓度 (MIC值)。

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(B2015201016)
河北大学杰出青年科学基金资助项目(2015JQ06)
河北大学实验室开放项目(sy201617)

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2017年第52卷第1期

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doi: 10.16438/j.0513-4870.2016-1023

接收时间：2016-10-20
首发时间：2026-01-14
出版时间：2017-01-12

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收稿日期：2016-10-20
修回日期：2016-12-01

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(B2015201016)

河北大学杰出青年科学基金资助项目(2015JQ06)

河北大学实验室开放项目(sy201617)

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1.河北大学药学院, 河北省药品质量控制重点实验室, 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

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* Tel:13483283338,E-mail:yalisong@hbu.edu.cn;

Tel: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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Compd.	Time/h	Physical property	mp/℃	Yield/%
3a	0.5	Light yellow solid	253-255	80
3b	1	Light purple solid	320-323	85
3c	0.5	White solid	276-278	85
3d	1	White solid	320-322	90
3e	1	Light purple solid	318-321	85
3f	0.5	Light yellow solid	250-252	85
3g	0.5	White solid	284-286	80
3h	1	Light purple solid	331-334	80
3i	0.5	Light purple solid	290-293	90
3j	1	Light purple solid	296-299	90
3k	0.5	Light purple solid	273-275	80
3l	1	Light purple solid	270-272	85
3m	0.5	Light purple solid	254-256	85
3n	1	Light purple solid	282-285	80

Compd.

Time/h

Physical property

mp/℃

Yield/%

0.5

Light yellow solid

253-255

Light purple solid

320-323

0.5

White solid

276-278

White solid

320-322

Light purple solid

318-321

0.5

Light yellow solid

250-252

0.5

White solid

284-286

Light purple solid

331-334

0.5

Light purple solid

290-293

Light purple solid

296-299

0.5

Light purple solid

273-275

Light purple solid

270-272

0.5

Light purple solid

254-256

Light purple solid

282-285

Compd.	¹H NMR (600 MHz,DMSO-d₆),¹³C NMR (150 MHz,DMSO-d₆) and HR-MS (ESI⁺,m/z)
3a	¹H NMR δ 12.77 (s,1H,NH),7.90 (d,J = 2.1 Hz,1H,ArH),7.54 (dd,J = 8.5,2.2 Hz,1H,ArH),7.39 (d,J = 8.5 Hz,1H,ArH),4.46 (t,J = 3.9 Hz,1H,CH),3.27 (dd,J = 17.0,4.3 Hz,1H,COCH₂),3.17 (dd,J = 17.0,3.8 Hz,1H,COCH₂),2.95 (q,J = 7.5 Hz,2H,CH₂),1.24 (t,J = 7.5 Hz,3H,CH₃). ¹³C NMR δ 190.73,168.91,166.00,157.88,136.10,133.25,131.32,130.35,129.39,126.69,40.74,40.02,22.65,13.71. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₄H₁₂ClN₃NaO₂S₂: 375.995 7; Found: 375.994 9.
3b	¹H NMR δ 13.13 (s,1H,NH),8.11 (d,J = 7.6 Hz,1H,ArH),7.92 (d,J = 2.1 Hz,1H,ArH),7.66 (d,J = 7.9 Hz,1H,ArH),7.58-7.49 (m,3H,ArH),7.41 (d,J = 8.5 Hz,1H,ArH),4.52 (t,J = 4.0 Hz,1H,CH),3.32 (dd,J = 17.1,4.4 Hz,1H,COCH₂),3.21 (dd,J = 17.0,3.6 Hz,1H,COCH₂). ¹³C NMR δ 190.68,169.27,159.70,158.20,136.05,133.34,131.89,131.28,131.05,130.71,130.57,130.41,129.43,128.68,127.84,126.75,40.65,40.04. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₈H₁₁Cl₂N₃NaO₂S₂: 457.956 7; Found: 457.955 7.
3c	¹H NMR δ 12.76 (s,1H,NH),7.90 (d,J = 2.2 Hz,1H,ArH),7.54 (dd,J = 8.5,2.2 Hz,1H,ArH),7.39 (d,J = 8.5 Hz,1H,ArH),4.46 (t,J = 4.1 Hz,1H,CH),3.27 (dd,J = 17.0,4.3 Hz,1H,COCH₂),3.18 (dd,J = 17.0,3.9 Hz,1H,COCH₂),2.57 (s,3H,CH₃). ¹³C NMR δ 190.75,168.41,159.77,153.12,136.15,133.27,131.31,130.35,129.39,126.71,40.76,40.05,14.77. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₃H₁₀ClN₃NaO₂S₂: 361.979 5; Found: 361.979 3.
3d	¹H NMR δ 13.02 (s,1H,NH),7.97-7.83 (m,3H,ArH),7.59-7.48 (m,4H,ArH),7.41 (d,J = 8.5 Hz,1H,ArH),4.50 (s,1H,CH),3.31 (dd,J = 17.0,4.0 Hz,1H,COCH₂),3.21 (dd,J = 16.9,3.5 Hz,1H,COCH₂). ¹³C NMR δ 190.76,169.29,162.20,158.53,136.18,133.27,131.37,130.61,130.35,130.05,129.44,129.30,129.08,126.84,126.72,126.27,40.93,40.05. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₈H₁₂ClN₃NaO₂S₂: 423.996 4; Found: 423.996 3.
3e	¹H NMR δ 12.86 (s,1H,NH),7.93-7.84 (m,3H,ArH),7.58-7.51 (m,3H,ArH),7.40 (d,J = 8.5 Hz,1H,ArH),4.47 (t,J = 4.5 Hz,1H,CH),3.29 (dd,J = 16.9,4.1 Hz,1H,COCH₂),3.16 (dd,J = 16.9,5.0 Hz,1H,COCH₂). ¹³C NMR δ 191.15,170.12,160.88,160.12,137.02,134.73,133.16,131.45,130.80,130.10,129.51,129.43,129.27,128.32,127.51,126.72,42.07,40.05. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₈H₁₁Cl₂N₃NaO₂S₂: 457.956 2; Found: 457.955 4.
3f	¹H NMR δ 12.75 (s,1H,NH),7.79 (s,1H,ArH),7.29 (d,J = 7.9 Hz,1H,ArH),7.20 (d,J = 8.0 Hz,1H,ArH),4.41 (t,J = 4.2 Hz,1H,CH),3.21 (dd,J = 17.0,4.4 Hz,1H,COCH₂),3.13 (dd,J = 16.9,4.0 Hz,1H,COCH₂),2.94 (q,J = 7.5 Hz,2H,CH₂),2.29 (s,3H,ArCH₃),1.24 (t,J = 7.5 Hz,3H,CH₃). ¹³C NMR δ 191.73,169.06,165.88,157.92,135.06,134.49,133.70,129.88,127.77,127.16,40.84,40.04,22.64,20.32,13.73. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₅H₁₅N₃NaO₂S₂: 356.049 8; Found: 356.049 5.
3g	¹H NMR δ 12.72 (s,1H,NH),7.79 (s,1H,ArH),7.29 (d,J = 7.9 Hz,1H,ArH),7.20 (d,J = 8.0 Hz,1H,ArH),4.41 (t,J = 4.2 Hz,1H,CH),3.21 (dd,J = 17.0,4.4 Hz,1H,COCH₂),3.13 (dd,J = 16.9,4.0 Hz,1H,COCH₂),2.57 (s,3H,CH₃),2.29 (s,3H,ArCH₃). ¹³C NMR δ 191.75,169.03,159.67,158.26,135.06,134.51,133.73,129.86,127.79,127.16,40.85,40.04,20.32,14.77. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₄H₁₃N₃NaO₂S₂: 342.034 1; Found: 342.034 0.
3h	¹H NMR δ 13.09 (s,1H,NH),8.11 (dd,J = 7.7,1.4 Hz,1H,ArH),7.81 (s,1H,ArH),7.66 (d,J = 7.9 Hz,1H,ArH),7.55 (td,J = 7.8,1.5 Hz,1H,ArH),7.51 (td,J = 7.5,0.7 Hz,1H,ArH),7.31 (dd,J = 8.0,0.8 Hz,1H,ArH),7.22 (d,J = 8.0 Hz,1H,ArH),4.47 (t,J = 4.1 Hz,1H,CH),3.25 (dd,J = 17.0,4.5 Hz,1H,COCH₂),3.16 (dd,J = 16.9,3.9 Hz,1H,COCH₂),2.30 (s,3H,ArCH₃). ¹³C NMR δ 191.69,169.46,159.83,158.08,135.13,134.57,133.64,131.85,131.04,130.70,130.56,129.85,128.74,127.83,127.81,127.20,40.76,40.05,20.33. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₉H₁₄ClN₃NaO₂S₂: 438.010 8; Found: 438.010 2.
3i	¹H NMR δ 12.74 (s,1H,NH),7.69 (s,1H,ArH),7.23 (s,1H,ArH),4.46 (t,J = 4.3 Hz,1H,CH),3.19 (dd,J = 16.8,4.4 Hz,1H,COCH₂),3.11 (dd,J = 16.8,4.3 Hz,1H,COCH₂),2.57 (s,3H,CH₃),2.26 (s,3H,ArCH₃),2.19 (s,3H,ArCH₃). ¹³C NMR δ 191.95,168.88,159.70,158.23,135.64,134.52,133.82,133.36,130.05,125.60,40.16,40.04,20.20,19.21,14.76. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₅H₁₅N₃NaO₂S₂: 356.049 8; Found: 356.049 7.
3j	¹H NMR δ 13.10 (s,1H,NH),8.10 (dd,J = 7.7,1.3 Hz,1H,ArH),7.70 (s,1H,ArH),7.66 (d,J = 7.9 Hz,1H,ArH),7.55 (td,J = 7.6,1.4 Hz,1H,ArH),7.51 (t,J = 7.5 Hz,1H,ArH),7.25 (s,1H,ArH),4.51 (t,J = 4.2 Hz,1H,CH),3.22 (dd,J = 16.8,4.5 Hz,1H,COCH₂),3.14 (dd,J = 16.8,4.1 Hz,1H,COCH₂),2.27 (s,3H,ArCH₃),2.20 (s,3H,ArCH₃). ¹³C NMR δ 191.89,170.08,169.34,158.10,135.70,134.57,133.88,133.26,131.86,131.05,130.72,130.57,130.06,128.75,127.84,125.62,40.18,40.05,20.21,19.23. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₂₀H₁₆ClN₃NaO₂S₂: 452.027 0; Found: 452.024 6.
3k	¹H NMR δ 12.75 (s,1H,NH),7.25 (d,J = 7.7 Hz,1H,ArH),6.98 (d,J = 7.5 Hz,1H,ArH),4.47 (t,J = 4.9 Hz,1H,CH),3.23 (dd,J = 16.3,4.7 Hz,1H,COCH₂),3.11 (dd,J = 16.3,5.2 Hz,1H,COCH₂),2.59 (s,3H,CH₃),2.52 (s,3H,ArCH₃),2.20 (s,3H,ArCH₃). ¹³C NMR δ 194.24,168.42,159.71,153.13,138.76,137.85,133.54,132.40,129.18,128.71,40.35,40.04,23.53,19.49,14.77. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₅H₁₅N₃NaO₂S₂: 356.049 8; Found: 356.049 8.
3l	¹H NMR δ 13.12 (s,1H,NH),8.12 (dd,J = 7.7,1.6 Hz,1H,ArH),7.66 (d,J = 7.9 Hz,1H,ArH),7.55 (td,J = 7.6,1.6 Hz,1H,ArH),7.52 (t,J = 7.5 Hz,1H,ArH),7.26 (d,J = 7.7 Hz,1H,ArH),6.98 (d,J = 7.7 Hz,1H,ArH),4.53 (t,J = 4.7 Hz,1H,CH),3.28 (dd,J = 16.2,4.7 Hz,1H,COCH₂),3.15 (dd,J = 16.3,4.8 Hz,1H,COCH₂),2.54 (s,3H,ArCH₃),2.22 (s,3H,ArCH₃). ¹³C NMR δ 194.08,169.15,159.79,158.12,138.85,137.78,133.62,132.40,131.85,131.04,130.73,130.56,129.07,128.76,128.73,127.83,40.13,40.04,23.65,19.51. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₂₀H₁₆ClN₃NaO₂S₂: 452.026 5; Found: 452.026 0.
3m	¹H NMR δ 12.77 (s,1H,NH),7.69 (s,1H,ArH),7.24 (s,1H,ArH),4.47 (t,J = 4.3 Hz,1H,CH),3.19 (dd,J = 16.8,4.4 Hz,1H,COCH₂),3.11 (dd,J = 16.8,4.3 Hz,1H,COCH₂),2.95 (q,J = 7.5 Hz,2H,CH₂),2.26 (s,3H,ArCH₃),2.19 (s,3H,ArCH₃),1.24 (t,J = 7.5 Hz,3H,CH₃). ¹³C NMR δ 191.92,168.94,165.89,157.91,135.61,134.52,133.81,133.33,130.07,125.58,40.14,40.04,22.64,20.19,19.21,13.74. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₁₆H₁₇N₃NaO₂S₂: 370.065 4; Found: 370.065 4.
3n	¹H NMR δ 13.02 (s,1H,NH),7.91 (dd,J = 6.4,2.7 Hz,2H,ArH),7.57-7.41 (m,3H,ArH),7.25 (d,J = 7.7 Hz,1H,ArH),6.98 (d,J = 7.7 Hz,1H,ArH),4.50 (t,J = 4.8 Hz,1H,CH),3.26 (dd,J = 16.3,4.7 Hz,1H,COCH₂),3.14 (dd,J = 16.3,5.0 Hz,1H,COCH₂),2.53 (s,3H,ArCH₃),2.21 (s,3H,ArCH₃). ¹³C NMR δ 194.18,169.09,162.18,158.45,138.82,137.83,133.57,132.42,130.61,130.04,129.31,129.15,129.08,128.73,126.86,126.27,40.32,40.03,23.63,19.51. HR-MS (ESI⁺) [M+Na]⁺: Calcd. for C₂₀H₁₇N₃NaO₂S₂: 418.065 4; Found: 418.064 9.

Compd.

¹H NMR (600 MHz,DMSO-d₆),¹³C NMR (150 MHz,DMSO-d₆) and HR-MS (ESI⁺,m/z)

Compd.	MIC/μg·mL^-1
3a	32	32	8	16	32
3b	128	128	128	32	64
3c	32	32	8	16	128
3d	64	32	32	64	32
3e	128	64	64	32	16
3f	＞128	＞128	32	64	64
3g	64	32	16	64	64
3h	64	64	32	32	32
3i	32	32	16	128	32
3j	64	64	64	32	64
3k	32	32	16	128	＞128
3l	128	32	128	32	32
3m	32	32	16	16	32
3n	64	＞128	64	32	128
Fluconazole	32	16	32	32	16
Amphotericin B	4	2	4	4	2

Compd.

MIC/μg·mL^-1

C.n.

C.a.

E.f.

M.r.

C.k.

128

＞128

128

＞128

128

＞128

128

Fluconazole

Amphotericin B

Compd.	MIC/μg·mL^-1
3a	64	128	64	64	32	128	128
3b	16	16	128	64	64	128	64
3c	64	128	＞128	64	128	＞128	64
3d	64	32	32	128	64	64	32
3e	16	8	64	16	32	64	32
3f	64	32	128	＞128	64	64	64
3g	64	32	32	32	32	32	＞128
3h	32	64	64	32	64	32	64
3i	64	32	64	64	128	＞128	128
3j	128	64	128	32	64	64	64
3k	64	32	＞128	64	32	32	64
3l	32	64	64	128	＞128	128	128
3m	64	64	128	64	64	＞128	32
3n	128	＞128	64	64	128	64	64
Carbendazim	32	16	32	32	16	32	32

Compd.

MIC/μg·mL^-1

H.m.

S.s.

A.t.

B.c.

F.o.

V.m.

C.g.

128

＞128

128

＞128

128

＞128

128

＞128

128

＞128

128

＞128

128

＞128

128

＞128

128

Carbendazim