3-乙酰基-7-羟基香豆素衍生物的设计、合成及抗血小板聚集活性

尚飞扬; 刘成波; 谭鸿舟; 何冰; 何黎琴

doi:10.11665/j.issn.1000-5048.2023072901

3-乙酰基-7-羟基香豆素衍生物的设计、合成及抗血小板聚集活性

安徽中医药大学药学院, 合肥230038

基金项目: 安徽省教育厅自然科学科研项目（No.KJ2020A0957, No.KJ2021B003）

详细信息

通讯作者:
何黎琴: Tel：13956022936　E-mail：hlq661125@126.com

^#尚飞扬与刘成波为共同第一作者

中图分类号: R914.5;R965
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出版历程
- 收稿日期: 2023-07-28
- 网络出版日期: 2024-06-24
- 刊出日期: 2024-06-24

Design, synthesis and antiplatelet aggregation activity of 3-acetyl-7-hydroxycoumarin derivatives

College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230038, China

Funds: This study was supported by the Natural Science Foundation of Department of Education of Anhui Province（No. KJ2020A0957, No.KJ2021B003）

摘要

摘要:
为寻找安全有效的抗血小板聚集药物，以间苯二酚为起始原料，经Vilsmeier-Haack反应、Knoevenagel反应制备先导化合物3-乙酰基-7-羟基-香豆素；再对其7-位羟基进行氨基烷基醚化，3-位酮羰基肟化，得到25个目标化合物(6a~6y)。所合成的目标化合物的结构经过高分辨质谱、核磁共振氢谱和红外光谱确证。采用Bron比浊法分别测试了目标化合物对二磷酸腺苷（ADP）、胶原、花生四烯酸（AA）和凝血酶诱导的血小板聚集的抑制作用。结果表明，合成的目标化合物对4种诱导剂诱导的血小板聚集均具有一定的抑制活性，部分化合物的活性远优于阳性对照药阿司匹林。其中，目标化合物6a、6b对4种诱导剂诱导的血小板聚集均有较强的抑制活性，且具有较好的水溶性和脂水分配系数（溶解度为3.46和3.85 mg/mL，脂水分配系数为2.56和2.85），有望成为具有多靶点抗血小板聚集作用的临床前候选化合物。
- 3-乙酰基-7-羟基-香豆素 /
- 肟 /
- 水溶性 /
- 抗血小板聚集
Abstract:
In order to search for coumarin-based anti-platelet aggregation compounds with high efficacy and good druggability, twenty-five 3-acetyl-7-hydroxy-coumarin oxime derivatives (6a-6y) were synthesized via Vilsmeier-Haack reaction, Knoevenagel reaction, Williamson reaction, electrophilic substitution reaction and oximation reaction from resorcinol. Their structures were confirmed by HRMS and ¹H NMR spectra. The anti-platelet aggregation activity of the target compounds was evaluated using Born’s turbidimetric method. The results revealed that most of them could significantly inhibit platelet aggregation induced by adenosine diphosphate (ADP), collagen, arachidonic acid (AA) and thrombin. Among them, the target compounds 6a and 6b not only had strong inhibitory activity on platelet aggregation induced by the four inducers, but also exhibited good water solubility (3.46 mg/mL and 3.85 mg/mL, respectively) and lipid-water partition coefficient (2.56 and 2.85, respectively) and were expected to become a preclinical candidate compound with multi-target action against platelet aggregation.
- 3-acetyl-7-hydroxy-coumarin /
- oxime /
- aqueous solubility /
- anti-platelet aggregation

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1. Synthetic routes of target compounds 6a-6y

Reagents and conditions: (i) (1) DMF, POCl₃, MeCN, ~0℃, 6 h; (2) H₂O, 80℃, 0.5 h; (ii) Ethyl acetoacetate, HAc, piperidine, EtOH, 30℃, 10 h; (iii) Br-(CH₂)_n-Br, DMF, K₂CO₃, 50℃, 4 h; (iv) Amines（morpholine, piperidine,N-methyl piperazine, N-ethyl piperazine, N- (2-hydroxyethyl) piperazine）, MeCN, 60℃, 2 h; (v) NH₂OH,HCI, EtOH, pyridine, 60℃

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Table 1 Yield, melting point, HRMS data and ¹HNMR data of compounds 6a–6y

Compd.	Yield/%	Melting/℃	HRMS m/z [M+H]⁺	¹H NMR(400 MHz)，δ
6a	76.6	210.0–211.5	333.1472	11.35 (1H, s, NOH), 8.04 (1H, s, Ar-H), 7.71 (1H, d, J=8.7 Hz, Ar-H), 7.04 (1H, s, Ar-H), 6.98(1H, d, J=2.3 Hz, Ar-H), 4.21(2H, t, J=5.7 Hz,OCH₂), 3.64–3.52(4H, m, OCH₂), 2.72 (2H, t, J=5.6 Hz, NCH₂), 2.48 (4H, d, J=4.1 Hz, NCH₂), 2.07 (3H,s, CH₃)
6b	69.7	197.2–200.4	347.1627	11.34 (1H, s,NOH), 8.04 (1H, s, Ar-H), 7.71 (1H, d, J=8.6 Hz, Ar-H), 7.00 (1H, s, Ar-H), 6.95 (1H, d, J = 8.8 Hz, Ar-H), 4.13 ( 2H, t, J = 6.2 Hz,OCH₂), 3.59–3.55 (4H, m, OCH₂), 2.43–2.38 (6H, m,NCH₂), 2.06 (3H, s,CH₃), 1.90–1.86 (2H, m,CH₂)
6c	72.5	181.3–182.5	361.1786	11.34 (1H, s, NOH), 8.04 (1H, s, Ar-H), 7.71 (1H, d, J = 8.6 Hz, Ar-H), 7.00 (1H, s, Ar-H), 6.95 (1H, d, J = 8.8 Hz, Ar-H), 4.13 (2H, t, J = 6.2 Hz, OCH₂), 3.59–3.55 (4H, m, OCH₂), 2.43–2.38 (6H, m,NCH₂), 2.06 ( 3H, s,CH₃), 1.90–1.86 (4H, m, CH₂)
6d	80.5	176.4–177.3	375.2172	11.35(1H, s, NOH), 8.04 (1H, s, Ar-H), 7.71 (1H, d, J = 8.6 Hz, Ar-H), 7.04 (1H, s, Ar-H), 6.98 (1H, d, J = 2.2 Hz, Ar-H), 4.21 (2H, t, J = 5.6 Hz, OCH₂), 3.64–3.52 (4H, m, OCH₂), 2.72 (2H, t, J = 5.6 Hz, NCH₂), 2.48 (4H, d, J = 4.0 Hz, NCH₂), 2.07 (3H, s, CH₃)，1.92–1.88 (6H, m, CH₂)
6e	76.0	161.8–162.7	389.2097	11.35 (1H, s, NOH), 8.04 (1H, s, Ar-H), 7.71 (1H, d, J = 8.6 Hz, Ar-H), 7.04 (s, 1H), 6.98 (1H, d, J=2.2Hz, Ar-H), 4.21 (2H, t, J=5.6 Hz, OCH₂), 3.64–3.52(4H, m, OCH₂), 2.72 (2H, t, J=5.6 Hz, NCH₂), 2.48 (4H, d, J=4.0 Hz, NCH₂), 2.07(3H, s, CH₃)，1.92–1.88 (8H, m, CH₂)
6f	80.6	193.0–194.5	331.1682	11.38 (1H, s, NOH), 8.01 (1H, s, Ar-H), 7.71 (1H, d, J = 8.6 Hz,Ar-H), 7.02 (1H, d, J = 2.2 Hz, Ar-H), 6.97 (1H, s, Ar-H), 4.09 (2H,t, J = 7.2 Hz, OCH₂), 2.86 (2H, t, J = 8.4 Hz, NCH₂), 2.32 (4H, t, J = 7.6 Hz, NCH₂), 2.06 (3H, s, CH₃), 1.30–1.22 (6H, m, CH₂)
6g	82.6	183.4–184.5	345.2186	11.34 (1H, s, NOH), 8.04 (1H, s, Ar-H), 7.71 (1H, d, J = 8.6 Hz,Ar-H), 6.51 (1H, d, J = 8.4 Hz, Ar-H), 6.44 (1H, s, Ar-H), 4.13 (2H,t, J = 6.2 Hz, OCH₂), 3.59–3.55 (4H, m, OCH₂), 2.43–2.38 (6H, m, NCH₂), 2.06 (3H, s, CH₃), 1.90–1.86 (2H,m, CH₂), 1.29– 1.21 (6H,m, CH₂)
6h	81.6	179.2–180.7	359.1994	11.36 (1H, s, NOH), 8.05 (1H, s, Ar-H), 7.72 (1H, d, J = 8.6 Hz,Ar-H), 7.03 (1H, d, J = 2.2 Hz, Ar-H), 6.95 (1H, s, Ar-H), 4.09 (2H,t, J = 7.2 Hz, OCH₂), 2.86 (2H, t, J = 8.4 Hz,NCH₂), 2.32 (4H, t, J = 7.6 Hz, NCH₂), 2.06 (3H, s, CH₃), 1.38–1.34 (2H,m, CH₂), 1.32–1.22 (8H, m, CH₂)
6i	73.1	171.8–172.8	373.2287	11.35 (1H, s, NOH), 8.05 (1H, s, Ar-H)), 7.72 (1H, d, J = 8.6 Hz,Ar-H), 7.02 (1H, d, J = 2.2 Hz, Ar-H), 6.97 (1H, s, Ar-H), 4.07 (2H,t, J = 7.2 Hz, OCH₂), 2.90 (2H, t, J = 8.4 Hz, NCH₂), 2.30 (4H, t, J = 7.6 Hz, NCH₂), 2.06 (3H, s, CH₃), 1.40–1.32 (2H,m, CH₂), 1.28–1.22 (10H,m, CH₂)
6j	73.5	162.3–163.9	387.2305	11.35 (1H, s, NOH), 8.05 (1H, s, Ar-H), 7.72 (1H, d, J = 8.6 Hz,Ar-H), 7.02 (1H, d, J = 2.2 Hz, Ar-H), 6.97 (1H, s, Ar-H), 4.09 (2H,t, J = 7.2 Hz, OCH₂), 2.86 (2H, t, J = 8.4 Hz, NCH₂), 2.32 (4H, t, J = 7.6 Hz, NCH₂), 2.06 (3H, s, CH₃), 1.37–1.31 (2H,m, CH₂), 1.30–1.22 (12H,m, CH₂)
6k	70.0	212.6–213.9	346.2051	11.37 (1H, s, NOH), 8.05 (1H, s, Ar-H), 7.72 (1H, d, J = 8.6 Hz,Ar-H), 7.04 (1H, d, J = 8.2 Hz, Ar-H), 6.98 (1H, s, Ar-H), 4.22 (2H,t, J = 6.8Hz, OCH₂), 3.07–3.02 (8H, m, NCH₂), 2.82 (2H, t, J = 8.4 Hz,NCH₂), 2.70 (3H, s, NCH₃), 2.06 (3H, s, CH₃)
6l	81.9	175.0–177.4	360.1952	11.37 (1H, s, NOH), 8.05 (1H, s, Ar-H), 7.71 (1H, d, J = 8.4 Hz,Ar-H), 7.03 (1H, d, J = 8.6 Hz, Ar-H), 6.98 (1H, s, Ar-H), 4.22 (2H,t, J = 6.8Hz, OCH₂), 3.07–3.02 (8H, m, NCH₂), 2.82 (2H, t, J = 8.4 Hz,NCH₂), 2.70 (3H, s, NCH₃), 2.06 (3H, s, NCH₃), 1.78–1.66 (2H,m, CH₂)
6m	68.1	164.2–165.5	374.2109	11.37 (1H, s, NOH), 8.05 (1H, s, Ar-H), 7.71 (1H, d, J = 8.4 Hz,Ar-H), 7.03 (1H, d, J = 8.6 Hz, Ar-H), 6.96 (1H, s, Ar-H), 4.24 (2H, t, J = 6.8Hz, OCH₂), 3.07–3.02 (8H, m, NCH₂), 2.82 (2H, t, J = 8.4 Hz,NCH₂), 2.72 (3H, s, NCH₃), 1.78–1.66 (2H,m, CH₂), 1.56–1.48 (2H, m, CH₂)
6n	73.2	151.3–152.0	388.2263	11.37 (1H, s, NOH), 8.04 (1H, s, Ar-H), 7.71 (1H, d, J = 8.4 Hz,Ar-H), 7.02 (1H, d, J = 8.6 Hz, Ar-H), 6.96 (1H, s, Ar-H), 4.09 (2H, t, J = 6.8Hz, OCH₂), 2.89–2.51 (8H, m, NCH₂), 2.46 (2H, t, J = 8.4 Hz,NCH₂), 2.40 (3H, s, NCH₃), 1.75–1.64 (2H,m, CH₂), 1.54–1.43 (4H, m, CH₂)
6o	71.8	142.0–143.5	402.2414	11.35(1H, s, NOH), 8.04 (1H, s, Ar-H), 7.71 (1H, d, J = 8.6 Hz, Ar-H), 7.00 (1H, d, J = 8.6 Hz, Ar-H), 6.96 (1H, s, Ar-H), 4.07 (2H, t, J = 6.8Hz, OCH₂), 2.50–2.16 (8H, m, NCH₂), 2.15(2H, t, J = 8.4 Hz, NCH₂), 2.07 (3H, s, NCH₃), 1.78–1.68 (2H,m,CH₂), 1.36–1.28(6H, m,CH₂)
6p	72.1	167.0–168.4	360.1952	11.34(1H, s, NOH), 8.05(1H, s, Ar-H), 7.71 (1H, d, J = 8.6 Hz,Ar-H), 7.02 (1H, d, J = 8.6 Hz, Ar-H), 6.97 (1H, s, Ar-H), 4.11 (2H, t, J = 6.4Hz, OCH₂), 2.64–2.48 (12H, m, NCH₂), 2.06(3H, s, NCH₃), 1.08 (3H, t, J = 7.2 Hz, CH₃)
6q	74.0	150.8–151.7	374.2109	111.34(1H, s, NOH), 8.05(1H, s, Ar-H), 7.71 (1H, d, J = 8.6 Hz,Ar-H), 7.02 (1H, d, J = 8.2 Hz, Ar-H), 6.97 (1H, s, Ar-H), 4.11 (2H, t, J = 6.4Hz, OCH₂), 2.64–2.48 (12H, m, NCH₂), 2.06(3H, s, NCH₃), 1.84–1.78 (m, 2H,CH₂), 1.08 (3H, t, J = 7.2 Hz, CH₃)
6r	75.6	135.8–136.9	388.2263	11.36(1H, s, NOH), 8.04(1H, s, Ar-H), 7.71 (1H, d, J = 8.6 Hz,Ar-H), 7.01 (1H, d, J = 8.2 Hz, Ar-H), 6.97 (1H, s, Ar-H), 4.11 (2H, t, J = 6.4Hz, OCH₂), 2.64–2.48 (10H, m,NCH₂), 2.06(3H, s, NCH₃), 1.79–1.70 (m, 2H,CH₂),1.62–1.54 (2H, m,CH₂), 1.25–1.10 (2H, m, CH₂), 1.08 (3H, t, J = 7.2 Hz, CH₃)
6s	75.1	130.4–131.8	402.2413	11.36(1H, s, NOH), 8.04(1H, s, Ar-H), 7.71 (1H, d, J = 8.6 Hz,Ar-H), 7.01 (1H, d, J = 8.2 Hz, Ar-H), 6.97 (1H, s, Ar-H), 4.11 (2H, t, J = 6.4Hz, OCH₂), 2.64–2.48 (10H, m, NCH₂), 2.06(3H, s, NCH₃), 1.80–1.70 (m, 2H,CH₂),1.68–1.59 (4H, m,CH₂), 1.25–1.10 (2H, m, CH₂), 1.08 (3H, t, J = 7.2 Hz, CH₃)
6t	75.9	127.3–128.4	416.2572	11.36(1H, s, NOH), 8.04(1H, s, Ar-H), 7.71 (1H, d, J = 8.6 Hz,Ar-H), 7.01 (1H, d, J = 8.2 Hz, Ar-H), 6.97 (1H, s, Ar-H), 4.11 (2H, t, J = 6.4Hz, OCH₂), 2.64–2.48 (10H, m, NCH₂), 2.06(3H, s, NCH₃), 1.79–1.70 (m, 2H,CH₂),1.62–1.54 (4H, m,CH₂), 1.24–1.14 (2H, m, CH₂), 1.08 (3H, t, J = 7.2 Hz, CH₃)
6u	76.3	192.9–193.9	376.1892	11.37(1H, s, NOH), 7.98(1H, s, Ar-H), 7.67 (1H, d, J = 8.6 Hz,Ar-H), 6.97(1H, d, J = 8.6 Hz, Ar-H), 6.94 (1H, s, Ar-H), 4.09 (2H, t, J = 6.4Hz, OCH₂),3.47 (2H, t, J = 8.2 Hz, OHCH₂) 2.51–2.49 (4H, m, NCH₂), 2.45–2.33 (8H, m, NCH₂),2.02(3H, s, NCH₃)
6v	74.3	183.4–184.5	390.2049	11.37(1H, s, NOH), 7.98(1H, s, Ar-H), 7.67 (1H, d, J = 8.6 Hz,Ar-H), 6.97(1H, d, J = 8.6 Hz, Ar-H), 6.94 (1H, s, Ar-H), 4.09 (2H, t, J = 6.4Hz, OCH₂),3.47 (2H, t, J = 8.2 Hz, OHCH₂) 2.51–2.49 (4H, m, NCH₂), 2.45–2.33 (8H, m, NCH₂),2.02(3H, s, NCH₃),1.87–1.76 (2H, m, CH₂)
6w	73.2	173.5–174.7	404.2221	11.37(1H, s, NOH), 7.98(1H, s, Ar-H), 7.67 (1H, d, J = 8.6 Hz,Ar-H), 6.97(1H, d, J = 8.6 Hz, Ar-H), 6.94 (1H, s, Ar-H), 4.09 (2H, t, J = 6.4Hz, OCH₂),3.47 (2H, t, J = 8.2 Hz, OHCH₂) 2.51–2.49 (4H, m, NCH₂), 2.45–2.33 (8H, m, NCH₂),2.02(3H, s, NCH₃), 1.87–1.76 (2H, m, CH₂) 1.48–1.42 (2H, m, CH₂)
6x	74.1	170.3–171.2	418.2369	11.36(1H, s, NOH), 8.04(1H, s, Ar-H), 7.72 (1H, d, J = 8.6 Hz,Ar-H), 7.04(1H, d, J = 8.6 Hz, Ar-H), 6.94 (1H, s, Ar-H), 4.09 (2H, t, J = 6.4Hz, OCH₂),3.47 (2H, t, J = 8.2 Hz, OHCH₂) 2.51–2.49 (4H, m, NCH₂), 2.45–2.33 (8H, m, NCH₂),2.06(3H, s, NCH₃), 1.88–1.54 (2H, m, CH₂) 1.48–1.42 (4H, m, CH₂)
6y	74.0	165.4–166.9	432.2369	11.36(1H, s, NOH), 8.04(1H, s, Ar-H), 7.72 (1H, d, J = 8.6 Hz,Ar-H), 7.01(1H, d, J = 8.6 Hz, Ar-H), 6.97 (1H, s, Ar-H), 4.10 (2H, t, J = 6.2Hz, OCH₂),3.47 (2H, t, J = 8.2 Hz, OHCH₂) 2.51–2.49 (4H, m, NCH₂), 2.45–2.33 (8H, m, NCH₂),2.06(3H, s, NCH₃),1.88–1.54 (2H, m, CH₂) 1.48–1.42 (6H, m, CH₂)

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Table 2 Inhibition of platelet aggregation induced by different inducers by target compound of 100 μg/mL　　　　　　　　　　　　　　　　　　　　　　　

Compd.	n	X	Inhibition/%
Compd.	n	X	Adenosine diphosphate	Collagen	Arachidonic acid	Thrombin
6a	2	O	76.10	71.86	73.85	61.67
6b	3	O	81.04	73.33	66.46	92.21
6c	4	O	50.71	75.88	45.23	70.90
6d	5	O	30.03	27.22	81.68	76.17
6e	6	O	76.17	48.33	82.72	80.40
6f	2	CH₂	85.91	41.21	61.67	64.26
6g	3	CH₂	82.91	76.95	35.69	28.15
6h	4	CH₂	84.58	83.08	77.38	55.93
6i	5	CH₂	66.29	81.09	40.62	74.91
6J	6	CH₂	94.39	69.15	54.46	23.70
6k	2	NCH₃	71.63	71.36	30.03	88.33
6l	3	NCH₃	47.53	64.68	62.68	89.70
6m	4	NCH₃	71.96	70.32	59.28	25.19
6n	5	NCH₃	62.55	85.24	73.30	55.93
6o	6	NCH₃	64.69	65.83	93.54	49.63
6p	2	NCH₂CH₃	70.29	85.07	83.77	70.23
6q	3	NCH₂CH₃	88.58	76.95	71.38	74.91
6r	4	NCH₂CH₃	68.96	70.65	76.00	44.26
6s	5	NCH₂CH₃	79.57	51.74	81.15	55.19
6t	6	NCH₂CH₃	78.77	72.14	62.77	34.32
6u	2	NCH₂CH₂OH	71.96	76.45	62.08	68.41
6v	3	NCH₂CH₂OH	72.50	77.89	88.70	67.02
6w	4	NCH₂CH₂OH	75.03	87.73	75.03	39.97
6x	5	NCH₂CH₂OH	80.17	89.22	94.83	31.48
6y	6	NCH₂CH₂OH	62.68	81.59	23.79	84.05
Aspirin	—	—	35.08	48.83	39.27	52.51

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Table 3 IC₅₀ values of some target compounds against platelet aggregation in vitro

Compd.	IC₅₀/(μmol/L)
Compd.	Adenosine diphosphate	Collagen	Arachidonic acid	Thrombin
6a	2.12	1.91	0.13	18.41
6b	0.35	0.73	0.82	0.41
6c	0.51	—	0.45	—
6d	NT	NT	0.98	—
6e	0.33	NT	0.54	22.16
6f	5.15×10^-2	NT	49.40	5.07
6g	21.93	1.33×10^-2	NT	NT
6h	2.14	2.40×10^-2	0.31	109.37
6i	22.85	0.11	—	2.19
6J	121.0	0.36	91.80	NT
6k	130.9	6.79	NT	1.97
6l	—	4.91	2.31×10^-3	—
6m	—	1.00×10^-2	52.79	NT
6n	16.64	1.26×10^-2	1.29	93.42
6o	1.04×10^-3	2.01	1.20×10^-4	NT
6p	1.25×10^-3	0.15	0.36	—
6q	2.09	1.90×10^-3	0.38	10.41
6r	3.02	0.53	0.14	NT
6s	2.22	NT	0.49	46.71
6t	2.15	0.84	97.89	—
6u	0.90	2.79	12.28	0.58
6v	2.42×10^-2	0.177	6.95	7.66
6w	4.58×10^-3	0.14	3.84×10^-2	—
6x	3.07×10^-3	0.28	NT	—
6y	1.92×10^-3	0.39	NT	9.97×10^-3
Aspirin	89.12	2.91	0.32	25.35
"NT" indicates that the compound was not tested, and "—" indicates that the curve of the measured compound has a poor fit and no IC₅₀ is obtained

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Table 4 Solubility and cLogP value of some compounds

Compd.	Solubility /（mg/mL）	cLogP	Compd.	Solubility /（mg/mL）	cLogP
6a	3.46	2.55	6u	7.18	2.83
6b	3.85	2.86	6v	8.67	3.13
6h	8.86	4.18	6w	13.31	3.24
6o	4.53	3.09	6x	5.87	3.76
6p	7.26	2.19	6y	9.42	4.19
6q	3.72	2.48	3	0.14	1.14

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