药学学报

Compd.	Formula	Yield/%	mp/℃	Elemental analysis/% Calcd. (Found)
10a	C₂₀H₁₄FN₃O₃	40.3	248-250	66.11 (66.37)	3.88 (3.65)	11.56 (11.74)
10b	C₂₁H₁₆FN₃O₃	37.2	236-238	66.84 (67.12)	4.27 (4.04)	11.13 (11.34)
10c	C₂₁H₁₆FN₃O₄	36.7	> 250	64.12 (64.34)	4.10 (4.26)	10.68 (16.92)
10d	C₂₀H₁₃F₂N₃O₃	46.5	> 250	62.99 (63.24)	3.44 (3.18)	11.02 (11.26)
10e	C₂₀H₁₃F₂N₃O₃	30.5	242-244	62.99 (63.17)	3.44 (3.20)	11.02 (11.27)
10f	C₂₀H₁₃F₂N₃O₃	18.6	235-237	62.99 (63.26)	3.44 (3.16)	11.02 (11.22)
10g	C₂₀H₁₃ClFN₃O₃	36.5	> 250	60.39 (60.64)	3.29 (3.17)	10.56 (10.77)
10h	C₂₀H₁₃ClFN₃O₃	28.4	> 250	60.39 (60.61)	3.29 (3.11)	10.56 (10.84)
10i	C₂₀H₁₃ClFN₃O₃	16.4	242-244	60.39 (60.63)	3.29 (3.42)	10.56 (10.75)
10j	C₁₉H₁₃FN₄O₃	47.5	> 250	62.64 (62.87)	3.60 (3.38)	15.38 (15.63)
10k	C₁₆H₁₄FN₃O₃	25.0	> 250	60.95 (61.14)	4.48 (4.25)	13.33 (13.57)
10l	C₁₇H₁₄FN₃O₃	36.7	> 250	62.38 (62.62)	4.31 (4.08)	12.84 (13.06)
10m	C₁₇H₁₆FN₃O₃	25.4	236-238	62.00 (62.23)	4.90 (4.74)	12.76 (13.02)
10n	C₁₇H₁₆FN₃O₃	18.5	231-233	62.00 (62.26)	4.90 (4.75)	12.76 (12.93)
10o	C₁₈H₁₈FN₃O₃	17.8	227-230	62.97 (63.22)	5.28 (5.04)	12.24 (12.46)
10p	C₁₈H₁₈FN₃O₃	15.3	235-237	62.97 (63.20)	5.28 (5.06)	12.24 (12.42)

Compd.	Formula	Yield/%	mp/℃	Elemental analysis/% Calcd. (Found)
10a	C₂₀H₁₄FN₃O₃	40.3	248-250	66.11 (66.37)	3.88 (3.65)	11.56 (11.74)
10b	C₂₁H₁₆FN₃O₃	37.2	236-238	66.84 (67.12)	4.27 (4.04)	11.13 (11.34)
10c	C₂₁H₁₆FN₃O₄	36.7	> 250	64.12 (64.34)	4.10 (4.26)	10.68 (16.92)
10d	C₂₀H₁₃F₂N₃O₃	46.5	> 250	62.99 (63.24)	3.44 (3.18)	11.02 (11.26)
10e	C₂₀H₁₃F₂N₃O₃	30.5	242-244	62.99 (63.17)	3.44 (3.20)	11.02 (11.27)
10f	C₂₀H₁₃F₂N₃O₃	18.6	235-237	62.99 (63.26)	3.44 (3.16)	11.02 (11.22)
10g	C₂₀H₁₃ClFN₃O₃	36.5	> 250	60.39 (60.64)	3.29 (3.17)	10.56 (10.77)
10h	C₂₀H₁₃ClFN₃O₃	28.4	> 250	60.39 (60.61)	3.29 (3.11)	10.56 (10.84)
10i	C₂₀H₁₃ClFN₃O₃	16.4	242-244	60.39 (60.63)	3.29 (3.42)	10.56 (10.75)
10j	C₁₉H₁₃FN₄O₃	47.5	> 250	62.64 (62.87)	3.60 (3.38)	15.38 (15.63)
10k	C₁₆H₁₄FN₃O₃	25.0	> 250	60.95 (61.14)	4.48 (4.25)	13.33 (13.57)
10l	C₁₇H₁₄FN₃O₃	36.7	> 250	62.38 (62.62)	4.31 (4.08)	12.84 (13.06)
10m	C₁₇H₁₆FN₃O₃	25.4	236-238	62.00 (62.23)	4.90 (4.74)	12.76 (13.02)
10n	C₁₇H₁₆FN₃O₃	18.5	231-233	62.00 (62.26)	4.90 (4.75)	12.76 (12.93)
10o	C₁₈H₁₈FN₃O₃	17.8	227-230	62.97 (63.22)	5.28 (5.04)	12.24 (12.46)
10p	C₁₈H₁₈FN₃O₃	15.3	235-237	62.97 (63.20)	5.28 (5.06)	12.24 (12.42)

Compd.	¹H NMR (DMSO-d₆, 400 MHz) δ	ESI-MS (m/z)
10a	15.23 (s, 1H, COOH), 8.38 (s, 1H, 6-H), 7.06-7.42 (m, 9H, Ph-H), 2.62 (s, 3H, CH₃)	364 [M+H]⁺
10b	15.25 (s, 1H, COOH), 8.42 (s, 1H, 6-H), 7.10-7.43 (m, 8H, Ph-H), 2.61 (s, 3H, CH₃), 2.18 (s, 3H, Ph-CH₃)	378 [M+H]⁺
10c	15.24 (s, 1H, COOH), 8.44 (s, 1H, 6-H), 7.07-7.45 (m, 8H, Ph-H), 3.87 (s, 3H, OCH₃), 2.63 (s, 3H, CH₃)	394 [M+H]⁺
10d	15.25 (s, 1H, COOH), 8.46 (s, 1H, 6-H), 7.15-7.46 (m, 8H, Ph-H), 2.64 (s, 3H, CH₃)	382 [M+H]⁺
10e	15.25 (s, 1H, COOH), 8.44 (s, 1H, 6-H), 7.17-7.46 (m, 8H, Ph-H), 2.64 (s, 3H, CH₃)	382 [M+H]⁺
10f	15.25 (s, 1H, COOH), 8.46 (s, 1H, 6-H), 7.17-7.46 (m, 8H, Ph-H), 2.65 (s, 3H, CH₃)	382 [M+H]⁺
10g	15.26 (s, 1H, COOH), 8.45 (s, 1H, 6-H), 7.15-7.44 (m, 8H, Ph-H), 2.65 (s, 3H, CH₃)	398 [M+H]⁺ (³⁵Cl), 400 [M+H]⁺ (³⁷Cl)
10h	15.25 (s, 1H, COOH), 8.46 (s, 1H, 6-H), 7.16-7.43 (m, 8H, Ph-H), 2.64 (s, 3H, CH₃)	398 [M+H]⁺ (³⁵Cl), 400 [M+H]⁺ (³⁷Cl)
10i	11.55 (s, 1H, COOH), 8.44 (s, 1H, 6-H), 7.16-7.45 (m, 8H, Ph-H), 2.63 (s, 3H, CH₃)	398 [M+H]⁺ (³⁵Cl), 400 [M+H]⁺ (³⁷Cl)
10j	15.27 (brs, 1H, COOH), 8.64 (s, 1H, Py-H), 8.53 (s, 1H, 6-H), 7.37-7.34 (m, 1H, Py-H), 7.24-7.13 (m, 6H, Py-H and Ph-H), 2.65 (s, 3H, CH₃)	365 [M+H]⁺
10k	15.28 (s, 1H, COOH), 8.43 (s, 1H, 6-H), 7.26-7.62 (m, 4H, Ph-H), 4.12 (q, J = 6.4 Hz, 2H, CH₂), 2.62 (s, 3H, CH₃), 1.00 (t, J = 6.4 Hz, 3H, 3-CH₃)	316 [M+H]⁺
10l	15.30 (s, 1H, COOH), 8.63 (s, 1H, 6-H), 7.32-7.67 (m, 4H, Ph-H), 3.42-3.30 (m, 1H, CH), 2.58 (s, 3H, CH₃), 1.23-0.92 (m, 4H, CH₂CH₂)	328 [M+H]⁺
10m	15.27 (s, 1H, COOH), 8.62 (s, 1H, 6-H), 7.33-7.65 (m, 4H, Ph-H), 3.38 (t, J = 5.8 Hz, 2H, CH₂), 2.60 (s, 3H, CH₃), 1.42-0.87 (m, 5H, CH₂CH₃)	330 (M⁺)
10n	15.25 (s, 1H, COOH), 8.63 (s, 1H, 6-H), 7.32-7.64 (m, 4H, Ph-H), 3.34-3.16 (m, 1H, CH), 2.61 (s, 3H, CH₃), 0.86 (d, J = 7.2 Hz, 6H, 2×CH₃)	330 [M+H]⁺
10o	15.32 (s, 1H, COOH), 8.65 (s, 1H, 6-H), 7.35-7.66 (m, 4H, Ph-H), 3.82-3.91 (m, 2H, CH₂), 2.58 (s, 3H, CH₃), 1.36-0.72 (m, 7H, CH₂CH₂CH₃)	344 [M+H]⁺
10p	15.31 (s, 1H, COOH), 8.66 (s, 1H, 6-H), 7.38-7.67 (m, 4H, Ph-H), 2.57 (s, 3H, CH₃), 1.17 (s, 9H, C(CH₃)₃)	344 [M+H]⁺

Compd.	¹H NMR (DMSO-d₆, 400 MHz) δ	ESI-MS (m/z)
10a	15.23 (s, 1H, COOH), 8.38 (s, 1H, 6-H), 7.06-7.42 (m, 9H, Ph-H), 2.62 (s, 3H, CH₃)	364 [M+H]⁺
10b	15.25 (s, 1H, COOH), 8.42 (s, 1H, 6-H), 7.10-7.43 (m, 8H, Ph-H), 2.61 (s, 3H, CH₃), 2.18 (s, 3H, Ph-CH₃)	378 [M+H]⁺
10c	15.24 (s, 1H, COOH), 8.44 (s, 1H, 6-H), 7.07-7.45 (m, 8H, Ph-H), 3.87 (s, 3H, OCH₃), 2.63 (s, 3H, CH₃)	394 [M+H]⁺
10d	15.25 (s, 1H, COOH), 8.46 (s, 1H, 6-H), 7.15-7.46 (m, 8H, Ph-H), 2.64 (s, 3H, CH₃)	382 [M+H]⁺
10e	15.25 (s, 1H, COOH), 8.44 (s, 1H, 6-H), 7.17-7.46 (m, 8H, Ph-H), 2.64 (s, 3H, CH₃)	382 [M+H]⁺
10f	15.25 (s, 1H, COOH), 8.46 (s, 1H, 6-H), 7.17-7.46 (m, 8H, Ph-H), 2.65 (s, 3H, CH₃)	382 [M+H]⁺
10g	15.26 (s, 1H, COOH), 8.45 (s, 1H, 6-H), 7.15-7.44 (m, 8H, Ph-H), 2.65 (s, 3H, CH₃)	398 [M+H]⁺ (³⁵Cl), 400 [M+H]⁺ (³⁷Cl)
10h	15.25 (s, 1H, COOH), 8.46 (s, 1H, 6-H), 7.16-7.43 (m, 8H, Ph-H), 2.64 (s, 3H, CH₃)	398 [M+H]⁺ (³⁵Cl), 400 [M+H]⁺ (³⁷Cl)
10i	11.55 (s, 1H, COOH), 8.44 (s, 1H, 6-H), 7.16-7.45 (m, 8H, Ph-H), 2.63 (s, 3H, CH₃)	398 [M+H]⁺ (³⁵Cl), 400 [M+H]⁺ (³⁷Cl)
10j	15.27 (brs, 1H, COOH), 8.64 (s, 1H, Py-H), 8.53 (s, 1H, 6-H), 7.37-7.34 (m, 1H, Py-H), 7.24-7.13 (m, 6H, Py-H and Ph-H), 2.65 (s, 3H, CH₃)	365 [M+H]⁺
10k	15.28 (s, 1H, COOH), 8.43 (s, 1H, 6-H), 7.26-7.62 (m, 4H, Ph-H), 4.12 (q, J = 6.4 Hz, 2H, CH₂), 2.62 (s, 3H, CH₃), 1.00 (t, J = 6.4 Hz, 3H, 3-CH₃)	316 [M+H]⁺
10l	15.30 (s, 1H, COOH), 8.63 (s, 1H, 6-H), 7.32-7.67 (m, 4H, Ph-H), 3.42-3.30 (m, 1H, CH), 2.58 (s, 3H, CH₃), 1.23-0.92 (m, 4H, CH₂CH₂)	328 [M+H]⁺
10m	15.27 (s, 1H, COOH), 8.62 (s, 1H, 6-H), 7.33-7.65 (m, 4H, Ph-H), 3.38 (t, J = 5.8 Hz, 2H, CH₂), 2.60 (s, 3H, CH₃), 1.42-0.87 (m, 5H, CH₂CH₃)	330 (M⁺)
10n	15.25 (s, 1H, COOH), 8.63 (s, 1H, 6-H), 7.32-7.64 (m, 4H, Ph-H), 3.34-3.16 (m, 1H, CH), 2.61 (s, 3H, CH₃), 0.86 (d, J = 7.2 Hz, 6H, 2×CH₃)	330 [M+H]⁺
10o	15.32 (s, 1H, COOH), 8.65 (s, 1H, 6-H), 7.35-7.66 (m, 4H, Ph-H), 3.82-3.91 (m, 2H, CH₂), 2.58 (s, 3H, CH₃), 1.36-0.72 (m, 7H, CH₂CH₂CH₃)	344 [M+H]⁺
10p	15.31 (s, 1H, COOH), 8.66 (s, 1H, 6-H), 7.38-7.67 (m, 4H, Ph-H), 2.57 (s, 3H, CH₃), 1.17 (s, 9H, C(CH₃)₃)	344 [M+H]⁺

Compd.	MIC/μg·mL^-1
10a	64	> 128	32	> 128
10b	64	> 128	32	> 128
10c	32	> 128	64	> 128
10d	16	> 128	32	> 128
10e	32	> 128	32	> 128
10f	8	> 128	16	> 128
10g	64	> 128	> 128	> 128
10h	> 128	> 128	> 128	> 128
10i	32	> 128	32	> 128
10j	16	> 128	64	> 128
10k	8	64	4	32
10l	2	32	2	16
10m	32	> 128	64	64
10n	> 128	> 128	> 128	> 128
10o	64	> 128	> 128	> 128
10p	> 128	> 128	> 128	> 128
Norfloxacin	1	2	4	1
Ciprofloxacin	0.5	1	1	0.5

Compd.	MIC/μg·mL^-1
10a	64	> 128	32	> 128
10b	64	> 128	32	> 128
10c	32	> 128	64	> 128
10d	16	> 128	32	> 128
10e	32	> 128	32	> 128
10f	8	> 128	16	> 128
10g	64	> 128	> 128	> 128
10h	> 128	> 128	> 128	> 128
10i	32	> 128	32	> 128
10j	16	> 128	64	> 128
10k	8	64	4	32
10l	2	32	2	16
10m	32	> 128	64	64
10n	> 128	> 128	> 128	> 128
10o	64	> 128	> 128	> 128
10p	> 128	> 128	> 128	> 128
Norfloxacin	1	2	4	1
Ciprofloxacin	0.5	1	1	0.5

Compd.	IC₅₀/μmol·L^-1
10a	34.2 ± 2.6	25.7 ± 2.1	16.8 ± 2.0	12.5 ± 1.3
10b	38.7 ± 2.5	32.6 ± 2.8	28.7 ± 2.6	18.6 ± 2.0
10c	26.7 ± 2.0	16.6 ± 1.4	21.6 ± 1.8	14.0 ± 1.3
10d	17.5 ± 1.0	8.2 ± 1.1	6.4 ± 1.0	3.6 ± 0.5
10e	12.8 ± 1.6	6.2 ± 0.7	5.3 ± 0.6	2.8 ± 0.4
10f	10.6 ± 1.2	5.5 ± 0.6	4.7 ± 0.8	3.6 ± 0.5
10g	27.8 ± 2.4	21.6 ± 2.3	17.2 ± 2.1	15.7 ± 1.8
10h	26.3 ± 2.5	23.6 ± 2.2	20.6 ± 1.6	12.3 ± 1.1
10i	15.8 ± 1.6	17.5 ± 1.3	14.5 ± 1.3	14.5 ± 1.3
10j	12.7 ± 1.3	8.5 ± 1.3	6.2 ± 0.6	5.0 ± 0.7
10k	8.6 ± 1.1	4.8 ± 1.0	4.7 ± 0.4	3.8 ± 0.6
10l	6.7 ± 0.6	3.6 ± 0.5	3.2 ± 0.4	3.0 ± 0.5
10m	15.3 ± 1.4	12.7 ± 1.2	14.6 ± 1.3	11.5 ± 1.2
10n	17.2 ± 1.5	16.4 ± 1.8	13.5 ± 1.2	16.2 ± 1.4
10o	22.5 ± 2.1	18.7 ± 2.0	15.6 ± 1.4	12.8 ± 1.2
10p	30.8 ± 2.6	26.3 ± 2.2	24.7 ± 2.5	23.6 ± 2.2
DOX	4.6 ± 0.7	3.6 ± 0.5	3.2 ± 0.5	4.8 ± 0.6
Ciprofloxacin	> 100	> 50	> 50	> 50
Norfloxacin	> 100	> 100	> 100	> 100

Compd.	IC₅₀/μmol·L^-1
10a	34.2 ± 2.6	25.7 ± 2.1	16.8 ± 2.0	12.5 ± 1.3
10b	38.7 ± 2.5	32.6 ± 2.8	28.7 ± 2.6	18.6 ± 2.0
10c	26.7 ± 2.0	16.6 ± 1.4	21.6 ± 1.8	14.0 ± 1.3
10d	17.5 ± 1.0	8.2 ± 1.1	6.4 ± 1.0	3.6 ± 0.5
10e	12.8 ± 1.6	6.2 ± 0.7	5.3 ± 0.6	2.8 ± 0.4
10f	10.6 ± 1.2	5.5 ± 0.6	4.7 ± 0.8	3.6 ± 0.5
10g	27.8 ± 2.4	21.6 ± 2.3	17.2 ± 2.1	15.7 ± 1.8
10h	26.3 ± 2.5	23.6 ± 2.2	20.6 ± 1.6	12.3 ± 1.1
10i	15.8 ± 1.6	17.5 ± 1.3	14.5 ± 1.3	14.5 ± 1.3
10j	12.7 ± 1.3	8.5 ± 1.3	6.2 ± 0.6	5.0 ± 0.7
10k	8.6 ± 1.1	4.8 ± 1.0	4.7 ± 0.4	3.8 ± 0.6
10l	6.7 ± 0.6	3.6 ± 0.5	3.2 ± 0.4	3.0 ± 0.5
10m	15.3 ± 1.4	12.7 ± 1.2	14.6 ± 1.3	11.5 ± 1.2
10n	17.2 ± 1.5	16.4 ± 1.8	13.5 ± 1.2	16.2 ± 1.4
10o	22.5 ± 2.1	18.7 ± 2.0	15.6 ± 1.4	12.8 ± 1.2
10p	30.8 ± 2.6	26.3 ± 2.2	24.7 ± 2.5	23.6 ± 2.2
DOX	4.6 ± 0.7	3.6 ± 0.5	3.2 ± 0.5	4.8 ± 0.6
Ciprofloxacin	> 100	> 50	> 50	> 50
Norfloxacin	> 100	> 100	> 100	> 100

新型吡唑并[3,4-b]吡啶-4-酮-5-羧酸类化合物的合成及抗菌抗肿瘤活性

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李阳杰 ¹ , 李珂 ¹ , 胡国强 ²^,^* , 黄文龙 ³

药学学报 | 研究论文 2023,58(10): 3070-3075

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药学学报 |研究论文 2023 , 58 (10) : 3070 -3075

新型吡唑并[3,4-b]吡啶-4-酮-5-羧酸类化合物的合成及抗菌抗肿瘤活性

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李阳杰¹, 李珂¹, 胡国强²^,^*, 黄文龙³

作者信息

1.郑州工业应用技术学院, 河南省水环境与健康河南省工程技术研究中心, 河南郑州 451150

2.河南大学临床医学院, 河南开封 475004

3.中国药科大学新药中心, 江苏南京 210009

通讯作者:

*胡国强, Tel/Fax: 86-378-23880680, E-mail: hgqxy@sina.com.cn

Design, synthesis, antibacterial and antitumor activities of novel pyrazolo[3,4-b]pyridine-4-one-5-carboxylic acid derivatives

Yang-jie LI¹, Ke LI¹, Guo-qiang HU²^,^*, Wen-long HUANG³

Affiliations

1. Henan Engineering Technology Research Center of Water Environment and Health, Zhengzhou University of Industrial Technology, Zhengzhou 451150, China

2. School of Clinical Medicine, Henan University, Kaifeng 475004, China

3. Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China

出版时间: 2023-10-12 doi: 10.16438/j.0513-4870.2023-0157

文章导航

摘要

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为发现新结构苗头化合物, 基于吡唑与吡啶酮酸片段在药物分子中的重要性, 设计合成了一系列吡唑并[3,4-b]吡啶-4-酮-5-羧酸类新结构目标化合物(10a~10p), 其结构经光谱数据和元素分析确证。目标化合物体外对4种实验菌株显示出较弱的抗菌活性或抗菌活性消失, 而对4种癌细胞株的抗肿瘤活性强于对照氟喹诺酮药, 尤其是双-氟苯基(10d、10e、10f)、吡啶基(10j)、乙基(10k) 和环丙(10l) 等取代化合物对Capan-1和A549细胞株的IC₅₀值达到微摩尔浓度。为此, 吡唑并吡啶-4-酮-5-羧酸类化合物虽然抗菌活性不及氟喹诺酮类, 而其抗肿瘤活性显著强于对照氟喹诺酮药, 其中部分化合物抗肿瘤活性与多柔比星活性相当, 预示可作为新结构抗肿瘤苗头化合物值得进一步发展。

关键词

吡唑 / 吡啶酮羧 / 吡唑并吡啶酮羧 / 抗菌活性 / 抗肿瘤活性

Abstract

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To discover new structural hits, based on the important role of pyrazole ring and fragment of pyridinone carboxylic acid in drug design, novel title pyrazolo[3,4-b]pyridine-4-one-5-carboxylic acid derivatives (10a-10p) were designed and synthesized, the structures were confirmed by spectral data and elemental analyses. The antibacterial and antitumor activities were evaluated by the measured minimum inhibitory concentration (MIC) values against the tested four strains and half inhibitory concentration (IC₅₀) values against the tested four cancer cells, respectively. The results displayed markedly poor antibacterial activity and observably potent antitumor activity. In particularly, the title difluorophenyl (10d, 10e, 10f), pyridyl (10j), ethyl (10k) and cycloproyl (10l) compounds exhibited comparable activity against Capan-1 and A549 cells to that of the comparison doxorubicin. Thus, pyrazolo[3,4-b]pyridine-4-one-5-carboxylic acid derivatives as promising antitumor hits need to be developed.

Key words

pyrazole / pyridinone carboxylic acid / pyrazolopyridinone carboxylic acid / antibacterial activity / antitumor activity

引用本文

李阳杰, 李珂, 胡国强, 黄文龙. 新型吡唑并[3,4-b]吡啶-4-酮-5-羧酸类化合物的合成及抗菌抗肿瘤活性. 药学学报, 2023 , 58 (10) : 3070 -3075 . DOI: 10.16438/j.0513-4870.2023-0157

Yang-jie LI, Ke LI, Guo-qiang HU, Wen-long HUANG. Design, synthesis, antibacterial and antitumor activities of novel pyrazolo[3,4-b]pyridine-4-one-5-carboxylic acid derivatives[J]. Acta Pharmaceutica Sinica, 2023 , 58 (10) : 3070 -3075 . DOI: 10.16438/j.0513-4870.2023-0157

正文

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吡唑及其衍生物因具有抗炎^[1]、抗菌^[2]、抗肿瘤^[3]、抗病毒^[4]及抗真菌^[5]等广泛的生物活性, 在新(农) 药创制中备受关注。如何选择新优势骨架与吡唑环相杂合产生新颖结构的化合物, 进一步通过活性筛选发现具有药理活性的苗头物是促进吡唑衍生物研究向前发展的关键。考虑到喹诺酮药物抗菌作用靶点—拓扑异构酶也是抗肿瘤药物的重要作用靶标^{[6, 7]}, 且其结构共有吡啶-4-酮羧酸优势骨架片段^[8]。基于结构药物设计策略^[9], 用吡唑环与吡啶-4-酮羧酸优势骨架相稠合而构建的吡唑并吡啶酮羧酸化合物有可能保留或改善喹诺酮药物的药效功能, 实现双方优势结构互补、扩展研究领域。为此, 为彰显氟原子的引入在喹诺酮药物向氟喹诺酮药物发展中所发挥的重要性^[10], 本文以对氟苯肼(1) 为原料, 经多步反应构建了结构新颖的吡唑并吡啶酮酸类目标化合物, 1-(4-氟苯基)-3-甲基-7-取代-1H-吡唑并[3,4-b]吡啶-4(7-H)-酮-5-羧酸(10a~10p), 以期发现有潜在发展价值的苗头化合物, 为进一步的新药研发探索提供依据。

结果与讨论

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1 化学合成

目标化合物10a~10p的合成如合成路线1所示。对氟苯肼(1) 与乙酰乙酸乙酯发生缩-环合反应可得吡唑啉酮(2), 接着经Vilsmeier-Haack反应到氯吡唑醛(3), 用高锰酸钾氧化3可生成相应的氯吡唑酸(4)。羰基二咪唑(CDI) 与4发生酰化反应生成活性中间体吡唑咪唑酰胺(5), 不经分离与丙二酸单乙酯钾盐在无水氯化镁的催化下发生缩合反应到氯吡唑甲酰乙酸乙酯(6)。N, N-二甲基甲酰胺二甲基缩醛(DMF-DMA) 与中间体6在甲苯中进行缩合反应得到氯吡唑烯胺酮乙酯(7), 不经分离与伯胺类在甲醇-二氯甲烷中发生取代反应得到氨甲叉基氯吡唑甲酰乙酸乙酯(8), 接着用无水碳酸钾作束酸剂在DMF中发生分子内环合反应到吡唑并吡啶酮羧酸酯(9), 粗品酯9用稀氢氧化钠水溶液水解到目标化合物吡唑并吡啶酮羧酸(10)。目标化合物10a~10p的理化性质及光谱数据见表 1、2。目标物的¹H NMR在低场δ 15.30处出现的单质子化学位移单峰可归属为吡唑并吡啶-4-酮骨架5-COOH、δ 8.4~8.7处出现的单质子化学位移单峰可归属6-H, 其他低场处出现的化学位移峰质子数与1-位和7-位的取代基芳香环的质子相对应; 高场δ 2.60处出现的三质子化学位移单峰可归属为稠核骨架3-CH₃, 其他高场处出现的化学位移峰质子数与1-位烃基和7-位芳香环取代基的质子相对应。另外, 元素分析和MS测定值与目标物10的结构相吻合, 表明通过合成路线1可成功构建预期的吡唑并吡啶-4-酮-5-羧酸目标物。

2 活性评价

目标化合物10a~10p及对照药诺氟沙星(NF) 和环丙沙星(CF) 预配成1 280 μg·mL^-1的DMSO溶液作为供试贮存液, 参考美国国家临床实验室标准化委员会(NCCLS) 推荐使用试管二倍稀释方法^[11]测定供试贮存液对金葡菌(S. aureus) ATCC25923、枯草芽孢杆菌(B. substilis) 63501、大肠埃希氏菌(E. coli) ATCC25922和铜绿假单孢菌(P. aeruginosa) ATCC 27853的体外最低抑制菌浓度(MICs)。同时, 另外将目标化合物10a~10p、对照抗菌药氟喹诺酮环丙沙星(CF) 和诺氟沙星(NF) 及抗肿瘤药多柔比星(DOX) 用DMSO配成为1.0×10^-2 mol·L^-1的溶液作为供试样品, 用MTT实验方法^[12]测定其对人白血病细胞株(HL60)、人肝癌细胞株(SMMC-7721)、人胰腺癌细胞株(Capan-1) 和人非小细胞肺癌细胞(A549) 的半数抑制浓度(IC₅₀)。所用实验在相同的条件下重复3次, 抗菌和抗肿瘤测试结果分别见表 3和表 4。

表 3的抑菌活性测定结果显示, 仅有乙基(10k) 和环丙基(10l) 2个目标化合物对枯草芽孢杆菌和铜绿假单孢菌显示出一定的抑制作用(MIC ≤ 64 μg·mL^-1), 而其余目标化合物均无明显的抑制活性(MIC > 128 μg·mL^-1); 同时多数目标化合物对金葡菌和大肠埃希氏菌显示不同程度的抑菌活性(MIC ≤ 64 μg·mL^-1), 尤其是化合物(10k、10l) 的MIC值均低于10 μg·mL^-1, 但仍弱于对照诺氟沙星和环丙沙星, 说明用吡唑并吡啶酮羧酸结构环替代氟喹诺酮药物分子中的喹啉酮羧酸部分导致抗菌活性显著下降或消失。然而目标物的体外抗肿瘤活性结果(表 4) 表明, 目标化合物对4种实验肿瘤细胞株的IC₅₀ < 40.0 μmol·L^-1, 而对照诺氟沙星和环丙沙星的IC₅₀ > 50.0 μmol·L^-1, 表明用吡唑环替代喹诺酮骨架中的苯环而构建的吡唑并吡啶酮羧酸类化合物的体外抗肿瘤活性强于氟喹诺酮药, 尤其是双氟苯基化合物(4d、4e、4l) 及乙基(10k) 和环丙基(10l) 化合物对SMMC-7721、Capan-1和A549 3种实验肿瘤细胞株的IC₅₀ < 10.0 μmol·L^-1, 其活性与对照多柔比星在同一数量级, 具有潜在的研究价值。

小结

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本文基于结构药物设计策略, 把具有广泛药理活性的药效团吡唑环与喹诺酮药物的共有优势骨架吡啶酮酸片段相稠合构建了系列吡唑并吡啶酮羧酸衍生物, 其结构经元素分析和光谱数据确证。目标化合物的体外抗菌活性弱于对照药氟喹诺酮或消失, 表明吡唑并吡啶酮羧酸部分并非是抗菌活性所需的结构, 然而, 目标物的体外肿瘤活性强于对照药氟喹诺酮, 其中部分化合物的IC₅₀值与对照抗肿瘤药物多柔比星相当。为此, 通过吡唑环与吡啶酮羧酸片段相拼合构建的吡唑并吡啶酮羧酸衍生物有可能成为新结构的抗肿瘤苗头化合物, 值得进一步研究。

实验部分

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WK-1B型数字熔点仪(上海申光仪器有限公司), 温度未校正; Bruker AM-400型核磁共振仪、质谱仪MS HP1100型(德国Bruker公司); 元素分析仪为Carlo Erba 1106 (美国Perkin-Elmer公司); RAD-680型酶标仪(美国Bio-Rad公司)。试剂为分析纯, 未经处理, 直接使用。

1 化合物合成

1.1 3-甲基-5-氯-1-(4-氟苯基)-1H-吡唑-4-羧酸(4)^[13]

按文献方法, 由4-氟苯肼与乙酰乙酸乙酯经缩合、Vilsmeier-Haack氯甲酰化、高锰酸钾氧化等反应制备。

1.2 3-甲基-5-氯-1-(4-氟苯基)-1H-吡唑-4-甲酰乙酸乙酯(6)

吡唑羧酸4 (15.0 g, 59.0 mmol) 溶于无水四氢呋喃(150 mL), 常温搅拌下慢慢加入羰基二咪唑(CDI) (15.0 g, 93.0 mmol), 混合物搅拌反应6 h, 放置备用。

在冰浴搅拌下, 将丙二酸单乙酯钾盐(12.0 g, 71.05 mmol) 加入到含有无水氯化镁(8.5 g, 90.0mmol)和三乙胺(12.0 g, 118.0 mmol) 的乙腈混合物中, 搅拌反应3 h。将上述制备的吡唑咪唑酰胺液转移到该反应瓶中, 搅拌混合均匀。在50~55 ℃水浴下搅拌反应12 h。减压蒸除溶剂, 向残留物中加入冰水(500 mL), 用醋酸酸化, 放置固化, 过滤, 水洗中性。粗品悬浮于饱和碳酸氢钠溶液(500 mL) 中, 充分搅拌至无气体逸出, 过滤, 水洗中性。自然干燥, 用乙酸乙酯-正己烷(V∶V = 1∶3) 溶解, 冷冻析出结晶, 自然干燥, 得中间体(6), 收率60.7%, mp 86~88 ℃; ¹H NMR (CDCl₃, 400 MHz) δ: 1.13 (t, J = 7.2 Hz, 3H, ethyl CH₃), 2.48 (s, 3H, CH₃), 4.12 (q, J = 7.2 Hz, 2H, ethyl CH₂), 4.02 (s, 2H, CH₂), 7.25~7.46 (m, 4H, Ph-H) (keto-isomer); 1.21 (t, J = 7.2 Hz, 3H, ethyl CH₃), 2.54 (s, 3H, CH₃), 4.18 (q, J = 7.2 Hz, 2H, ethyl CH₂), 5.46 (s, 1H, =CH), 7.35~7.52 (m, 4H, Ph-H), 12.25 (s, 1H, OH) (enol-isomer); ESI-MS (m/z): 325[M+H] ⁺。

1.3 3-甲基-1-(4-氟苯基)-7-取代-1H-吡唑并[3,4-b]吡啶-4(7H)-酮-5-羧酸(10a~10p) 合成通法

化合物6 (2.0 g, 6.2 mmol) 溶于DMF-DMA (1.5 g, 12.4 mmol) 和甲苯(10 mL) 混合溶剂中, 混合物加热回流反应6 h。常压慢慢蒸出低沸点溶剂至反应温度高于100 ℃, 补加DMF-DMA (1.5 g, 12.4 mmol), 继续回流反应6 h。减压蒸除溶剂, 加入二氯甲烷(15 mL) 和甲醇(5 mL) 溶解黏稠物, 冰浴搅拌下加入伯胺类化合物(10.0 mmol), 常温反应至原料消失(TLC检测)。减压蒸除溶剂, 加入DMF (30 mL) 和无水碳酸钾溶液(1.3 g, 9.5 mmol), 混合物在120~125 ℃搅拌反应12 h。冷却至室温, 加入冰水(50 mL), 充分搅拌分散产生的固体, 放置过夜。过滤, 水洗中性。固体环合酯用氢氧化钠(2.5 g, 63.0 mmol) 溶液(50 mL) 回流水解至固体溶解完全, 加入适量的活性炭脱色1 h, 热过滤。滤液用盐酸酸化至pH 2.0, 滤集产生的固体, 水洗呈中性。粗品用无水乙醇重结晶, 真空干燥, 得目标物10a~10p。

2 目标化合物的活性测定

2.1 抗菌活性测定

目标化合物10a~10p及对照药诺氟沙星(NF) 和环丙沙星(CF) 用DMSO溶解后用培养基稀释配成1 280 μg·mL^-1供试待测药液。取无菌试管13支排成一排, 除第1管加入肉汤培养基1.6 mL外, 其余各管加入肉汤培养基1 mL, 在第1管加待测药液0.4 mL, 混匀, 然后吸取1 mL至第2管, 混匀后吸取1 mL至第3管, 如此连续倍比稀释至第11管, 并从第11管吸取1 mL弃去, 第12管为不含待测药物的生长对照。此时各管待测药物的浓度依次为256、128、64、32、16、8、4、2、1、0.5、0.25 μg·mL^-1。然后在每管内加入制备好的菌悬液1 mL, 使每管最终菌液浓度约为5×10⁵ CFU·mL^-1。第1管至第11管待测药物的浓度分别为128、64、32、16、8、4、2、1、0.5、0.25、0.125 μg·mL^-1。将接种好的稀释试管塞好塞子, 置37 ℃摇床培养16~20 h, 肉眼观察各试管细菌的生长情况, 无菌生长者即为待测药物的最低抑菌浓度(MIC)。

2.2 抗肿瘤活性测定

将目标化合物10a~10p及对照分别用二甲基亚砜(DMSO) 溶解, 配制成1.0×10^-2 mol·L^-1浓度的储备药液, 用RPMI-1640培养液将储备药液稀释成具有5个浓度梯度(0.1、1.0、5.0、10.0、50.0 μmol·L^-1) 的待测药液。取对数生长期的人白血病细胞株(HL60)、人肝癌细胞株(SMMC-7721)、人胰腺癌细胞株(Capan-1) 和人非小细胞肺癌细胞(A549), 以每孔6 000个细胞接种于96孔板, 随后分别加入具有5个浓度梯度的待测药液, 培养48 h后每孔加入5 g·L^-1 MTT (噻唑蓝) 溶液10 μL, 继续再培养4 h之后加入100 μL质量百分比浓度为10%的十二烷基硫酸钠(SDS) 溶液。培养24 h, 然后用酶标仪在570 nm波长处测定吸光度(OD) 值。按公式计算不同浓度的待测药液对癌细胞的抑制率: 癌细胞抑制率= [(1-实验组OD值) / 对照组OD值] × 100%; 然后以待测药液各浓度的负对数值对各浓度对应的癌细胞抑制率作线性回归, 得到剂量-效应方程, 以此计算出待测药物对实验癌细胞的半数抑制浓度(IC₅₀); 每个数据平行测定3次, 求其平均值。

致谢: 光谱和元素分析由河南大学化学化工学院完成, 抗菌活性由河南大学淮河医学院协助测定。

作者贡献: 李阳杰、李珂为实验的完成者及论文的写作者, 胡国强、黄文龙为课题的设计与论文校对。

利益冲突: 无利益冲突。

基金

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国家自然科学基金资助项目(20872028)
国家自然科学基金资助项目(21072045)

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2023年第58卷第10期

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doi: 10.16438/j.0513-4870.2023-0157

接收时间：2023-02-15
首发时间：2025-11-21
出版时间：2023-10-12

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收稿日期：2023-02-15
修回日期：2023-03-24

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国家自然科学基金资助项目(20872028)

国家自然科学基金资助项目(21072045)

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1.郑州工业应用技术学院, 河南省水环境与健康河南省工程技术研究中心, 河南郑州 451150

2.河南大学临床医学院, 河南开封 475004

3.中国药科大学新药中心, 江苏南京 210009

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*胡国强, Tel/Fax: 86-378-23880680, E-mail: hgqxy@sina.com.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.	Formula	Yield/%	mp/℃	Elemental analysis/% Calcd. (Found)
10a	C₂₀H₁₄FN₃O₃	40.3	248-250	66.11 (66.37)	3.88 (3.65)	11.56 (11.74)
10b	C₂₁H₁₆FN₃O₃	37.2	236-238	66.84 (67.12)	4.27 (4.04)	11.13 (11.34)
10c	C₂₁H₁₆FN₃O₄	36.7	> 250	64.12 (64.34)	4.10 (4.26)	10.68 (16.92)
10d	C₂₀H₁₃F₂N₃O₃	46.5	> 250	62.99 (63.24)	3.44 (3.18)	11.02 (11.26)
10e	C₂₀H₁₃F₂N₃O₃	30.5	242-244	62.99 (63.17)	3.44 (3.20)	11.02 (11.27)
10f	C₂₀H₁₃F₂N₃O₃	18.6	235-237	62.99 (63.26)	3.44 (3.16)	11.02 (11.22)
10g	C₂₀H₁₃ClFN₃O₃	36.5	> 250	60.39 (60.64)	3.29 (3.17)	10.56 (10.77)
10h	C₂₀H₁₃ClFN₃O₃	28.4	> 250	60.39 (60.61)	3.29 (3.11)	10.56 (10.84)
10i	C₂₀H₁₃ClFN₃O₃	16.4	242-244	60.39 (60.63)	3.29 (3.42)	10.56 (10.75)
10j	C₁₉H₁₃FN₄O₃	47.5	> 250	62.64 (62.87)	3.60 (3.38)	15.38 (15.63)
10k	C₁₆H₁₄FN₃O₃	25.0	> 250	60.95 (61.14)	4.48 (4.25)	13.33 (13.57)
10l	C₁₇H₁₄FN₃O₃	36.7	> 250	62.38 (62.62)	4.31 (4.08)	12.84 (13.06)
10m	C₁₇H₁₆FN₃O₃	25.4	236-238	62.00 (62.23)	4.90 (4.74)	12.76 (13.02)
10n	C₁₇H₁₆FN₃O₃	18.5	231-233	62.00 (62.26)	4.90 (4.75)	12.76 (12.93)
10o	C₁₈H₁₈FN₃O₃	17.8	227-230	62.97 (63.22)	5.28 (5.04)	12.24 (12.46)
10p	C₁₈H₁₈FN₃O₃	15.3	235-237	62.97 (63.20)	5.28 (5.06)	12.24 (12.42)

Compd.

Formula

Yield/%

mp/℃

Elemental analysis/%
Calcd. (Found)

10a

C₂₀H₁₄FN₃O₃

40.3

248-250

66.11 (66.37)

3.88 (3.65)

11.56 (11.74)

10b

C₂₁H₁₆FN₃O₃

37.2

236-238

66.84 (67.12)

4.27 (4.04)

11.13 (11.34)

10c

C₂₁H₁₆FN₃O₄

36.7

> 250

64.12 (64.34)

4.10 (4.26)

10.68 (16.92)

10d

C₂₀H₁₃F₂N₃O₃

46.5

> 250

62.99 (63.24)

3.44 (3.18)

11.02 (11.26)

10e

C₂₀H₁₃F₂N₃O₃

30.5

242-244

62.99 (63.17)

3.44 (3.20)

11.02 (11.27)

10f

C₂₀H₁₃F₂N₃O₃

18.6

235-237

62.99 (63.26)

3.44 (3.16)

11.02 (11.22)

10g

C₂₀H₁₃ClFN₃O₃

36.5

> 250

60.39 (60.64)

3.29 (3.17)

10.56 (10.77)

10h

C₂₀H₁₃ClFN₃O₃

28.4

> 250

60.39 (60.61)

3.29 (3.11)

10.56 (10.84)

10i

C₂₀H₁₃ClFN₃O₃

16.4

242-244

60.39 (60.63)

3.29 (3.42)

10.56 (10.75)

10j

C₁₉H₁₃FN₄O₃

47.5

> 250

62.64 (62.87)

3.60 (3.38)

15.38 (15.63)

10k

C₁₆H₁₄FN₃O₃

25.0

> 250

60.95 (61.14)

4.48 (4.25)

13.33 (13.57)

10l

C₁₇H₁₄FN₃O₃

36.7

> 250

62.38 (62.62)

4.31 (4.08)

12.84 (13.06)

10m

C₁₇H₁₆FN₃O₃

25.4

236-238

62.00 (62.23)

4.90 (4.74)

12.76 (13.02)

10n

C₁₇H₁₆FN₃O₃

18.5

231-233

62.00 (62.26)

4.90 (4.75)

12.76 (12.93)

10o

C₁₈H₁₈FN₃O₃

17.8

227-230

62.97 (63.22)

5.28 (5.04)

12.24 (12.46)

10p

C₁₈H₁₈FN₃O₃

15.3

235-237

62.97 (63.20)

5.28 (5.06)

12.24 (12.42)

Compd.	¹H NMR (DMSO-d₆, 400 MHz) δ	ESI-MS (m/z)
10a	15.23 (s, 1H, COOH), 8.38 (s, 1H, 6-H), 7.06-7.42 (m, 9H, Ph-H), 2.62 (s, 3H, CH₃)	364 [M+H]⁺
10b	15.25 (s, 1H, COOH), 8.42 (s, 1H, 6-H), 7.10-7.43 (m, 8H, Ph-H), 2.61 (s, 3H, CH₃), 2.18 (s, 3H, Ph-CH₃)	378 [M+H]⁺
10c	15.24 (s, 1H, COOH), 8.44 (s, 1H, 6-H), 7.07-7.45 (m, 8H, Ph-H), 3.87 (s, 3H, OCH₃), 2.63 (s, 3H, CH₃)	394 [M+H]⁺
10d	15.25 (s, 1H, COOH), 8.46 (s, 1H, 6-H), 7.15-7.46 (m, 8H, Ph-H), 2.64 (s, 3H, CH₃)	382 [M+H]⁺
10e	15.25 (s, 1H, COOH), 8.44 (s, 1H, 6-H), 7.17-7.46 (m, 8H, Ph-H), 2.64 (s, 3H, CH₃)	382 [M+H]⁺
10f	15.25 (s, 1H, COOH), 8.46 (s, 1H, 6-H), 7.17-7.46 (m, 8H, Ph-H), 2.65 (s, 3H, CH₃)	382 [M+H]⁺
10g	15.26 (s, 1H, COOH), 8.45 (s, 1H, 6-H), 7.15-7.44 (m, 8H, Ph-H), 2.65 (s, 3H, CH₃)	398 [M+H]⁺ (³⁵Cl), 400 [M+H]⁺ (³⁷Cl)
10h	15.25 (s, 1H, COOH), 8.46 (s, 1H, 6-H), 7.16-7.43 (m, 8H, Ph-H), 2.64 (s, 3H, CH₃)	398 [M+H]⁺ (³⁵Cl), 400 [M+H]⁺ (³⁷Cl)
10i	11.55 (s, 1H, COOH), 8.44 (s, 1H, 6-H), 7.16-7.45 (m, 8H, Ph-H), 2.63 (s, 3H, CH₃)	398 [M+H]⁺ (³⁵Cl), 400 [M+H]⁺ (³⁷Cl)
10j	15.27 (brs, 1H, COOH), 8.64 (s, 1H, Py-H), 8.53 (s, 1H, 6-H), 7.37-7.34 (m, 1H, Py-H), 7.24-7.13 (m, 6H, Py-H and Ph-H), 2.65 (s, 3H, CH₃)	365 [M+H]⁺
10k	15.28 (s, 1H, COOH), 8.43 (s, 1H, 6-H), 7.26-7.62 (m, 4H, Ph-H), 4.12 (q, J = 6.4 Hz, 2H, CH₂), 2.62 (s, 3H, CH₃), 1.00 (t, J = 6.4 Hz, 3H, 3-CH₃)	316 [M+H]⁺
10l	15.30 (s, 1H, COOH), 8.63 (s, 1H, 6-H), 7.32-7.67 (m, 4H, Ph-H), 3.42-3.30 (m, 1H, CH), 2.58 (s, 3H, CH₃), 1.23-0.92 (m, 4H, CH₂CH₂)	328 [M+H]⁺
10m	15.27 (s, 1H, COOH), 8.62 (s, 1H, 6-H), 7.33-7.65 (m, 4H, Ph-H), 3.38 (t, J = 5.8 Hz, 2H, CH₂), 2.60 (s, 3H, CH₃), 1.42-0.87 (m, 5H, CH₂CH₃)	330 (M⁺)
10n	15.25 (s, 1H, COOH), 8.63 (s, 1H, 6-H), 7.32-7.64 (m, 4H, Ph-H), 3.34-3.16 (m, 1H, CH), 2.61 (s, 3H, CH₃), 0.86 (d, J = 7.2 Hz, 6H, 2×CH₃)	330 [M+H]⁺
10o	15.32 (s, 1H, COOH), 8.65 (s, 1H, 6-H), 7.35-7.66 (m, 4H, Ph-H), 3.82-3.91 (m, 2H, CH₂), 2.58 (s, 3H, CH₃), 1.36-0.72 (m, 7H, CH₂CH₂CH₃)	344 [M+H]⁺
10p	15.31 (s, 1H, COOH), 8.66 (s, 1H, 6-H), 7.38-7.67 (m, 4H, Ph-H), 2.57 (s, 3H, CH₃), 1.17 (s, 9H, C(CH₃)₃)	344 [M+H]⁺

Compd.

¹H NMR (DMSO-d₆, 400 MHz) δ

ESI-MS (m/z)

10a

15.23 (s, 1H, COOH), 8.38 (s, 1H, 6-H), 7.06-7.42 (m, 9H, Ph-H), 2.62 (s, 3H, CH₃)

364 [M+H]⁺

10b

15.25 (s, 1H, COOH), 8.42 (s, 1H, 6-H), 7.10-7.43 (m, 8H, Ph-H), 2.61 (s, 3H, CH₃), 2.18 (s, 3H, Ph-CH₃)

378 [M+H]⁺

10c

15.24 (s, 1H, COOH), 8.44 (s, 1H, 6-H), 7.07-7.45 (m, 8H, Ph-H), 3.87 (s, 3H, OCH₃), 2.63 (s, 3H, CH₃)

394 [M+H]⁺

10d

15.25 (s, 1H, COOH), 8.46 (s, 1H, 6-H), 7.15-7.46 (m, 8H, Ph-H), 2.64 (s, 3H, CH₃)

382 [M+H]⁺

10e

15.25 (s, 1H, COOH), 8.44 (s, 1H, 6-H), 7.17-7.46 (m, 8H, Ph-H), 2.64 (s, 3H, CH₃)

382 [M+H]⁺

10f

15.25 (s, 1H, COOH), 8.46 (s, 1H, 6-H), 7.17-7.46 (m, 8H, Ph-H), 2.65 (s, 3H, CH₃)

382 [M+H]⁺

10g

15.26 (s, 1H, COOH), 8.45 (s, 1H, 6-H), 7.15-7.44 (m, 8H, Ph-H), 2.65 (s, 3H, CH₃)

398 [M+H]⁺ (³⁵Cl),
400 [M+H]⁺ (³⁷Cl)

10h

15.25 (s, 1H, COOH), 8.46 (s, 1H, 6-H), 7.16-7.43 (m, 8H, Ph-H), 2.64 (s, 3H, CH₃)

398 [M+H]⁺ (³⁵Cl),
400 [M+H]⁺ (³⁷Cl)

10i

11.55 (s, 1H, COOH), 8.44 (s, 1H, 6-H), 7.16-7.45 (m, 8H, Ph-H), 2.63 (s, 3H, CH₃)

398 [M+H]⁺ (³⁵Cl),
400 [M+H]⁺ (³⁷Cl)

10j

15.27 (brs, 1H, COOH), 8.64 (s, 1H, Py-H), 8.53 (s, 1H, 6-H), 7.37-7.34 (m, 1H, Py-H), 7.24-7.13 (m, 6H, Py-H and Ph-H), 2.65 (s, 3H, CH₃)

365 [M+H]⁺

10k

15.28 (s, 1H, COOH), 8.43 (s, 1H, 6-H), 7.26-7.62 (m, 4H, Ph-H), 4.12 (q, J = 6.4 Hz, 2H, CH₂), 2.62 (s, 3H, CH₃), 1.00 (t, J = 6.4 Hz, 3H, 3-CH₃)

316 [M+H]⁺

10l

15.30 (s, 1H, COOH), 8.63 (s, 1H, 6-H), 7.32-7.67 (m, 4H, Ph-H), 3.42-3.30 (m, 1H, CH), 2.58 (s, 3H, CH₃), 1.23-0.92 (m, 4H, CH₂CH₂)

328 [M+H]⁺

10m

15.27 (s, 1H, COOH), 8.62 (s, 1H, 6-H), 7.33-7.65 (m, 4H, Ph-H), 3.38 (t, J = 5.8 Hz, 2H, CH₂), 2.60 (s, 3H, CH₃), 1.42-0.87 (m, 5H, CH₂CH₃)

330 (M⁺)

10n

15.25 (s, 1H, COOH), 8.63 (s, 1H, 6-H), 7.32-7.64 (m, 4H, Ph-H), 3.34-3.16 (m, 1H, CH), 2.61 (s, 3H, CH₃), 0.86 (d, J = 7.2 Hz, 6H, 2×CH₃)

330 [M+H]⁺

10o

15.32 (s, 1H, COOH), 8.65 (s, 1H, 6-H), 7.35-7.66 (m, 4H, Ph-H), 3.82-3.91 (m, 2H, CH₂), 2.58 (s, 3H, CH₃), 1.36-0.72 (m, 7H, CH₂CH₂CH₃)

344 [M+H]⁺

10p

15.31 (s, 1H, COOH), 8.66 (s, 1H, 6-H), 7.38-7.67 (m, 4H, Ph-H), 2.57 (s, 3H, CH₃), 1.17 (s, 9H, C(CH₃)₃)

344 [M+H]⁺

Compd.	MIC/μg·mL^-1
10a	64	> 128	32	> 128
10b	64	> 128	32	> 128
10c	32	> 128	64	> 128
10d	16	> 128	32	> 128
10e	32	> 128	32	> 128
10f	8	> 128	16	> 128
10g	64	> 128	> 128	> 128
10h	> 128	> 128	> 128	> 128
10i	32	> 128	32	> 128
10j	16	> 128	64	> 128
10k	8	64	4	32
10l	2	32	2	16
10m	32	> 128	64	64
10n	> 128	> 128	> 128	> 128
10o	64	> 128	> 128	> 128
10p	> 128	> 128	> 128	> 128
Norfloxacin	1	2	4	1
Ciprofloxacin	0.5	1	1	0.5

Compd.

MIC/μg·mL^-1

S. aureus ATCC25923

B. substilis
63501

E. coli
ATCC25922

P. aeruginosa ATCC 27853

10a

> 128

10b

> 128

10c

> 128

10d

> 128

10e

> 128

10f

> 128

10g

> 128

10h

> 128

10i

> 128

10j

> 128

10k

10l

10m

> 128

10n

> 128

10o

> 128

10p

> 128

Norfloxacin

Ciprofloxacin

0.5

Compd.	IC₅₀/μmol·L^-1
10a	34.2 ± 2.6	25.7 ± 2.1	16.8 ± 2.0	12.5 ± 1.3
10b	38.7 ± 2.5	32.6 ± 2.8	28.7 ± 2.6	18.6 ± 2.0
10c	26.7 ± 2.0	16.6 ± 1.4	21.6 ± 1.8	14.0 ± 1.3
10d	17.5 ± 1.0	8.2 ± 1.1	6.4 ± 1.0	3.6 ± 0.5
10e	12.8 ± 1.6	6.2 ± 0.7	5.3 ± 0.6	2.8 ± 0.4
10f	10.6 ± 1.2	5.5 ± 0.6	4.7 ± 0.8	3.6 ± 0.5
10g	27.8 ± 2.4	21.6 ± 2.3	17.2 ± 2.1	15.7 ± 1.8
10h	26.3 ± 2.5	23.6 ± 2.2	20.6 ± 1.6	12.3 ± 1.1
10i	15.8 ± 1.6	17.5 ± 1.3	14.5 ± 1.3	14.5 ± 1.3
10j	12.7 ± 1.3	8.5 ± 1.3	6.2 ± 0.6	5.0 ± 0.7
10k	8.6 ± 1.1	4.8 ± 1.0	4.7 ± 0.4	3.8 ± 0.6
10l	6.7 ± 0.6	3.6 ± 0.5	3.2 ± 0.4	3.0 ± 0.5
10m	15.3 ± 1.4	12.7 ± 1.2	14.6 ± 1.3	11.5 ± 1.2
10n	17.2 ± 1.5	16.4 ± 1.8	13.5 ± 1.2	16.2 ± 1.4
10o	22.5 ± 2.1	18.7 ± 2.0	15.6 ± 1.4	12.8 ± 1.2
10p	30.8 ± 2.6	26.3 ± 2.2	24.7 ± 2.5	23.6 ± 2.2
DOX	4.6 ± 0.7	3.6 ± 0.5	3.2 ± 0.5	4.8 ± 0.6
Ciprofloxacin	> 100	> 50	> 50	> 50
Norfloxacin	> 100	> 100	> 100	> 100

Compd.

IC₅₀/μmol·L^-1

HL60

SMMC-7721

Capan-1

A549

10a

34.2 ± 2.6

25.7 ± 2.1

16.8 ± 2.0

12.5 ± 1.3

10b

38.7 ± 2.5

32.6 ± 2.8

28.7 ± 2.6

18.6 ± 2.0

10c

26.7 ± 2.0

16.6 ± 1.4

21.6 ± 1.8

14.0 ± 1.3

10d

17.5 ± 1.0

8.2 ± 1.1

6.4 ± 1.0

3.6 ± 0.5

10e

12.8 ± 1.6

6.2 ± 0.7

5.3 ± 0.6

2.8 ± 0.4

10f

10.6 ± 1.2

5.5 ± 0.6

4.7 ± 0.8

3.6 ± 0.5

10g

27.8 ± 2.4

21.6 ± 2.3

17.2 ± 2.1

15.7 ± 1.8

10h

26.3 ± 2.5

23.6 ± 2.2

20.6 ± 1.6

12.3 ± 1.1

10i

15.8 ± 1.6

17.5 ± 1.3

14.5 ± 1.3

10j

12.7 ± 1.3

8.5 ± 1.3

6.2 ± 0.6

5.0 ± 0.7

10k

8.6 ± 1.1

4.8 ± 1.0

4.7 ± 0.4

3.8 ± 0.6

10l

6.7 ± 0.6

3.6 ± 0.5

3.2 ± 0.4

3.0 ± 0.5

10m

15.3 ± 1.4

12.7 ± 1.2

14.6 ± 1.3

11.5 ± 1.2

10n

17.2 ± 1.5

16.4 ± 1.8

13.5 ± 1.2

16.2 ± 1.4

10o

22.5 ± 2.1

18.7 ± 2.0

15.6 ± 1.4

12.8 ± 1.2

10p

30.8 ± 2.6

26.3 ± 2.2

24.7 ± 2.5

23.6 ± 2.2

DOX

4.6 ± 0.7

3.6 ± 0.5

3.2 ± 0.5

4.8 ± 0.6

Ciprofloxacin

> 100

> 50

Norfloxacin

> 100