酸性神经鞘磷脂酶直接抑制剂的设计、 合成及生物活性

doi:10.7503/cjcu20140617

高等学校化学学报 ›› 2015, Vol. 36 ›› Issue (2): 279.doi: 10.7503/cjcu20140617

酸性神经鞘磷脂酶直接抑制剂的设计、合成及生物活性

杨侃¹, 张阔军¹, 胡松源¹, 顾勤兰², 董继斌³(), 王进欣¹

1. 中国药科大学药物分子设计与优化江苏省重点实验室, 南京 210009
2. 中国药科大学高等职业技术学院, 南京 211198
3. 复旦大学药学院生物化学教研室, 上海 201203

收稿日期:2014-07-03 出版日期:2015-02-10 发布日期:2015-01-22
作者简介:联系人简介: 董继斌, 女, 博士, 讲师, 主要从事磷脂代谢与心血管疾病相关的基础研究. E-mail: jbdong@shmu.edu.cn
基金资助:
南京市领军型创业人才计划(批准号: 2013B14007)和华海药业研究生培养创新基金(批准号: CX13S-001HH)资助

Design, Synthesis and Biological Activity of Acid Sphingomyelinase Inhibitors^†

YANG Kan¹, ZHANG Kuojun¹, HU Songyuan¹, GU Qinlan², DONG Jibin^3,^*(), WANG Jinxin^1,^*

1. Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
2. Altitude Vocational School, China Pharmaceutical University, Nanjing 211198, China
3. Department of Biochemistry, School of Pharmacy, Fudan University, Shanghai 201203, China

Received:2014-07-03 Online:2015-02-10 Published:2015-01-22
Contact: DONG Jibin,WANG Jinxin E-mail:jbdong@shmu.edu.cn
Supported by:
Supported by the Leading Entrepreneurship Talents Program of Nanjing, China(No.2013B14007) and the Huahai Pharmaceutical Co, Innovation Fund of Graduate Student Training, China(NoCX13S-001HH)

摘要/Abstract

摘要：

构建了基于配体的酸性神经鞘磷脂酶抑制剂药效团模型. 根据此模型, 以α-倒捻子素(α-Mangostin)为先导化合物进行结构优化, 完成了11个新型酸性神经鞘磷脂酶直接抑制剂的设计与合成, 其结构经过核磁共振波谱和质谱鉴定正确. 初步体外酶抑制活性筛选结果显示, 化合物Ⅰb, Ⅰd, Ⅰe和Ⅰf具有较好的酶抑制活性, 其中化合物Ⅰf的酶抑制率为88.9%.

关键词: 酸性鞘磷脂酶, 直接抑制剂, 药效团模型, α-倒捻子素

Abstract:

Acid sphingomyelinase(ASM) plays an important role in sphingolipid catabolism, which catalyzes the hydrolysis of sphingomyelin to ceramide and phosphorylcholine. Ceramide serves as one of the most important second messengers, and there is growing evidence shows that ASM activation and ceramide accumulation are involved in the development of various common human diseases. Nevertheless, only few inhibitors directly and selectively interacted with ASM. According to the reported inhibitors and their suppressive activity of ASM, 3D-pharmacophore model of ASM inhibitors based on ligands was built for the first time. Due to potent inhibitory ASM activity of α-Mangostin, a phytochemical content derived from garcinia mangostana linn, it was chosen as the lead compound for structure optimization. Then 11 new ASM direct inhibitors were designed and synthesized successfully. Their structures were confirmed by ¹H NMR, ¹³C NMR and mass spectrometry. Preliminary activity screening results in vitro showed that the compounds Ⅰb,Ⅰd,Ⅰe and Ⅰf had potent ASM inhibitory activity. The ASM inhibition rate of compoundⅠf was 88.9%. The structure-activity relationship indicated that the introduction of chain amino would influence the ASM activity obviously and removal of alkenyl had little impact on the ASM activity. This result will play a guiding role for designing better ASM inhibitors and proceeding basic research of ASM.

Key words: Acid sphingomyelinase(ASM), Direct inhibitor, Pharmacophore model, α-Mangostin

中图分类号:

O626

TrendMD:

杨侃, 张阔军, 胡松源, 顾勤兰, 董继斌, 王进欣. 酸性神经鞘磷脂酶直接抑制剂的设计、合成及生物活性. 高等学校化学学报, 2015, 36(2): 279.

YANG Kan, ZHANG Kuojun, HU Songyuan, GU Qinlan, DONG Jibin, WANG Jinxin. Design, Synthesis and Biological Activity of Acid Sphingomyelinase Inhibitors^†. Chem. J. Chinese Universities, 2015, 36(2): 279.

图/表 10

Fig.1 Molecular structure of α-Mangostin

Fig.2 Molecular structures of the researched ASM inhibitors 1—18

Fig.3 Pharmacophore model of the ASM inhibitors

Table 1 Superimposion of the training set compounds and pharmacophore model

Training set compound	Activity	Estimate	Training set compound	Activity	Estimate
1	0.04	0.07	10	9.5	13.2
2	0.16	0.18	11	21.5	14.5
3	0.4	0.47	12	15.3	15.1
4	2.3	1.3	13	4.1	23.9
5	3.1	1.9	14	101	30.7
6	4.2	2.3	15	24	21
7	5.1	4.8	16	10	31.2
8	16.5	5.3	17	39.6	33
9	5.3	5.8	18	6.8	32.5

Fig.4 Structures of the target compoundsⅠa—Ⅰi, Ⅱa and Ⅱb

Table 2 Appearance, yields, melting points, MS and IR data for compounds 4, Ⅰa—Ⅰi, 5—8, Ⅱa and Ⅱb

Compd.	Appearance	Yield(%)	m.p. /℃	IR(KBr), $ν ˙$ /cm^-1	MS, m/z
4	Yellow solid	70	240—248		365^a
Ⅰa	Yellow oil	45		3005, 1643, 1474, 1410, 1275, 1260, 1170, 1125, 756, 746	414.1918^a
Ⅰb	Yellow solid	45	235—241	3415, 3132, 1637, 1618, 1400, 1125, 1068,491	360.1447^a
Ⅰc	Yellow oil	33		3005, 2956, 2926, 2855, 1651, 1606, 1505, 1457, 1275, 1261, 1225, 1211, 759, 741	428.2069^a
Ⅰd	Yellow oil	67		1946, 1651, 1606, 1504, 1456, 1306, 1275, 1121, 1159, 1127, 764, 749	402.1913^a
Ⅰe	Yellow solid	29	223—231	2932, 1650, 1504, 1455, 1275, 1261, 1211, 1126, 764, 747	374.1602^a
Ⅰf	Yellow solid	59	>250	3440, 2962, 2359, 1650, 1606, 1505, 1456, 1275, 1210, 1162, 1126, 764	458.2547^a
Ⅰg	Yellow oil	57		2947, 1651, 1605, 1456, 1306, 1275, 211, 1159, 1157, 764, 749	429.2027^a
Ⅰh	Yellow oil	57		3116, 3010, 2922, 1649. 1595, 1450, 1275, 1259, 1062, 759, 738	397.1394^a
Ⅰi	Yellow solid	73	241—248	2925, 2854, 1737, 1654, 1462, 1377, 1275, 1260, 1122, 1074, 803, 747	416.1707^a
5	White solid	76	202—255		396^b
6	White solid	67	248—255		394^a
7	Yellow solid	35	219—221		350^c
8	Yellow solid	78	249—249		442^c
Ⅱa	Yellow oil	40		3005, 2923, 2852, 1606, 1462, 1278, 1264, 749, 737	474^a
Ⅱb	Yellow oil	38		3004, 2919, 1650, 1604, 1470, 1453, 1279, 1264, 1198, 1166, 746, 736	506.2296^a

Table 2 Appearance, yields, melting points, MS and IR data for compounds 4, Ⅰa—Ⅰi, 5—8, Ⅱa and Ⅱb

Compd.	Appearance	Yield(%)	m.p. /℃	IR(KBr), $ν ˙$ /cm^-1	MS, m/z
4	Yellow solid	70	240—248		365^a
Ⅰa	Yellow oil	45		3005, 1643, 1474, 1410, 1275, 1260, 1170, 1125, 756, 746	414.1918^a
Ⅰb	Yellow solid	45	235—241	3415, 3132, 1637, 1618, 1400, 1125, 1068,491	360.1447^a
Ⅰc	Yellow oil	33		3005, 2956, 2926, 2855, 1651, 1606, 1505, 1457, 1275, 1261, 1225, 1211, 759, 741	428.2069^a
Ⅰd	Yellow oil	67		1946, 1651, 1606, 1504, 1456, 1306, 1275, 1121, 1159, 1127, 764, 749	402.1913^a
Ⅰe	Yellow solid	29	223—231	2932, 1650, 1504, 1455, 1275, 1261, 1211, 1126, 764, 747	374.1602^a
Ⅰf	Yellow solid	59	>250	3440, 2962, 2359, 1650, 1606, 1505, 1456, 1275, 1210, 1162, 1126, 764	458.2547^a
Ⅰg	Yellow oil	57		2947, 1651, 1605, 1456, 1306, 1275, 211, 1159, 1157, 764, 749	429.2027^a
Ⅰh	Yellow oil	57		3116, 3010, 2922, 1649. 1595, 1450, 1275, 1259, 1062, 759, 738	397.1394^a
Ⅰi	Yellow solid	73	241—248	2925, 2854, 1737, 1654, 1462, 1377, 1275, 1260, 1122, 1074, 803, 747	416.1707^a
5	White solid	76	202—255		396^b
6	White solid	67	248—255		394^a
7	Yellow solid	35	219—221		350^c
8	Yellow solid	78	249—249		442^c
Ⅱa	Yellow oil	40		3005, 2923, 2852, 1606, 1462, 1278, 1264, 749, 737	474^a
Ⅱb	Yellow oil	38		3004, 2919, 1650, 1604, 1470, 1453, 1279, 1264, 1198, 1166, 746, 736	506.2296^a

Table 3 1 H NMR and 13C NMR data for compounds 4, Ⅰa—Ⅰi, 5—8, Ⅱa and Ⅱb

Compd.	¹H NMR(300 MHz), δ	¹³C NMR(300 MHz), δ
4^a	2.27—2.39(m, 2H, CH₂), 3.75—3.82(t, 2H, J=8.88 Hz, CH₂Cl), 3.89(s, 3H, OCH₃), 3.99(s, 3H, OCH₃), 4.21—4.29(t, 2H, J=7.59 Hz, OCH₂), 6.34—6.39(d, 2H, J=11.49 Hz, 2ArH), 6.85(s, 1H, ArH), 7.58(s, 1H, ArH), 12.99(s, 1H, ArOH)
Ⅰa^a	1.43—1.47(m, 2H, CH₂), 1.62—1.69(m, 4H, 2CH₂), 2.04—2.10(m, 2H, CH₂), 2.31—2.53(m, 6H, CH₂N), 3.81(s, 3H, OCH₃), 3.93(s, 3H, OCH₃), 4.16—4.18(t, 2H, J=3.00 Hz, CH₂OAr), 6.31—6.35(dd, 2H, J=9.00 Hz, ArH), 6.8(s, 1H, ArH), 7.51(s, 1H, ArH), 13.03(s, 1H, ArOH)	21.55, 24.23, 25.62, 26.22, 54.28, 55.29, 56.97, 67.52, 92.90, 97.25, 100.59, 103.01, 105.44, 112.64, 146.34, 152.32, 156.46, 157.55, 162.81, 166.22, 172.49, 179.43
Ⅰb^b	2.08—2.11(m, 2H, J=9.00 Hz, CH₂), 2.89—2.95(t, 2H, J=10.5 Hz, CH₂), 3.88—4.00(s, 6H, 2OCH₃), 4.14—4.16(t, 2H, J=6.00 Hz, CH₂), 6.35—6.36(d, 1H, J=1.95 Hz, ArH), 6.40—6.41(d, 1H, J=1.92 Hz, ArH), 7.29(s, 1H, ArH), 7.49(s, 1H, ArH)	22.59, 27.02, 46.88, 56.40, 56.90, 66.78, 92.74, 97.15, 100.39, 102.87, 105.26, 112.51, 146.05, 152.23, 156.20, 157.39, 162.72, 166.10, 179.26
Ⅰc^a	1.28—1.98(m, 10H, 5CH₂), 2.99—3.03(t, 2H, J=6.00 Hz, CH₂N), 3.77(s, 3H, OCH₃), 3.88(m, 1H, CHNH), 3.93(s, 3H, OCH₃), 4.16—4.18(t, 2H, J=3.00 Hz, CH₂OAr), 6.24—6.31(dd, 2H, J=1.5 Hz, 4.50 Hz, 2ArH), 6.77(s, 1H, ArH), 7.46(s, 1H , ArH), 12.91(s, 1H, ArOH)	24.37, 26.27, 26.10, 29.14, 41.53, 56.30, 56.53, 57.06, 66.55, 92.97, 97.31, 100.71, 103.01, 105.68, 112.65, 146.04, 152.49, 156.36, 157.56, 162.81, 166.29, 179.45
Ⅰd^a	1.28(s, 9H, 3CH₃), 2.26—2.30(m, 2H, CH₂), 2.99—3.04(t, 2H, J=7.50 Hz, CH₂N), 3.79(s, 3H, OCH₃), 3.86(s, 3H, OCH₃), 4.15—4.18(t, 2H, J=4.50 Hz, CH₂OAr), 6.22—6.26(dd, 2H, J=1.50 Hz, 4.50 Hz, 2ArH), 6.73(s, 1H, ArH), 7.40(s, 1H, ArH), 12.90(s, 1H, ArOH)	22.69, 26.27, 29.69, 38.14, 55.80, 56.62, 58.16, 59.51, 68.51, 92.51, 96.98, 99.93, 103.28, 106.14, 113.27, 144.75, 152.59, 155.09, 157.47, 163.06, 166.06, 179.36
Ⅰe^a	1.99—2.08(m, 2H, CH₂), 2.02[s, 6H, N(CH₃)₂], 2.44—2.48(t, 2H, J=7.35 Hz, CH₂N), 3.81(s, 3H, OCH₃), 3.93(s, 3H, OCH₃), 4.11—4.18(t, 2H, J=10.5 Hz, CH₂OAr), 6.29—6.34(m, 2H, 2ArH), 6.79(s, 1H, ArH), 7.53(s, 1H, ArH), 12.99(s, 1H, ArOH)	25.66, 43.99, 55.21, 56.43, 56.94, 66.95, 92.81, 97.19, 100.48, 102.91, 105.40, 112.55, 146.08, 152.30, 156.29, 157.45, 162.74, 166.15, 179.32
Ⅰf^a	1.34—1.47[m, 14H, N(CH₂CH₂CH₃)₂], 2.00—2.05(m, 2H, CH₂), 2.43—2.78(t, 4H, J=7.5 Hz, CH₂CH₂N), 2.63—2.66(t, 2H, J=4.5 Hz, CH₂N), 3.56—3.58(t, 4H, J=3 Hz, OCH₂), 3.88—3.96(s, 6H, 2OCH₃), 6.33—6.34(d, 1H, J=1.5 Hz, ArH), 6.38—6.39(d, 1H, J=1.5 Hz, ArH), 7.27(s, 1H, ArH), 7.56(s, 1H, ArH)	13.59, 20.18, 23.45, 25.26, 49.74, 52.55, 55.80, 56.38, 66.36, 92.62, 96.94, 98.52, 99.76, 106.96, 113.37, 145.55, 152.50, 155.33, 157.45, 165.94, 179.13
Ⅰg^c	2.03—2.08(m, 2H, CH₂), 2.40—2.41(s, 3H, NCH₃), 2.64—2.69[m, 8H, (CH₂)₄], 3.87—3.90(s, 6H, OCH₃), 4.05—4.09(t, 2H, J=6 Hz, OCH₂), 6.21—6.22(d, 1H, J=1.5 Hz, ArH), 6.33—6.34(d, 1H, J=1.5 Hz, ArH), 6.85(s, 1H, ArH), 7.33(s, 1H, ArH)	25.89, 30.31, 43.82, 49.79, 53.50, 53.87, 55.78, 56.48, 66.93, 92.60, 96.95, 99.66, 103.47, 106.80, 113.23, 145.95, 152.50, 155.99, 157.67, 163.19, 166.11, 179.83
Ⅰh^a	2.25—2.29(m, 2H, J=3 Hz, CH₂Ar), 3.88—4.00(s, 6H, 2OCH), 3.87—3.91(t, 2H, J=6 Hz, CH₂N), 4.16—4.18(d, 2H, CH₂Ar), 4.25—4.29(t, 2H, J=6 Hz, CH₂O), 4.93—5.02(m, 2H, CH₂), 6.02—6.18(m, 1H, CH), 6.30—6.33(d, 2H, J=4.5 Hz, CH CH), 6.78(s, 1H, ArH), 7.03(s, 1H, CH CHN), 7.11(s, 1H, CH CHN), 7.06(s, 1H, CH N)	30.23, 43.53, 55.73, 56.37, 63.35, 92.47, 96.87, 99.63, 103.33, 106.39, 113.10, 119.08, 128.58, 137.18, 145.44, 152.54, 155.88, 157.51, 163.07, 165.95, 174.46, 179.54
Ⅰi^b	1.90—1.94(m, 2H, CH₂), 2.41—2.46(t, 3H, J=7.5 Hz, CH₂N), 3.56—3.59(t, 4H, J=9 Hz, OCH₂), 3.87—3.94(s, 6H, OCH₃), 4.08—4.12(t, 2H, J=5.6 Hz, CH₂OAr), 6.37—6.38(d, 1H, J=1.5 Hz, ArH), 6.54—6.55(d, 1H, J=1.5 Hz, ArH), 7.15(s, 1H, ArH),7.41(s, 1H, ArH)	26.14, 53.59, 53.80, 55.21, 55.43, 56.40, 66.26, 66.64, 67.35, 92.73, 97.14, 100.44, 103.21, 105.11, 112.51, 146.57, 152.17, 157.44, 162.74, 166.11, 179.32
5^a	3.82—3.83(s, 3H, OCH₃), 3.87—3.89(s, 3H, OCH₃), 4.02—4.13(s, 6H, 2OCH₃), 6.44(s, 1H, ArH), 6.95(s, 1H, ArH), 8.02(s, 1H, ArH)
6^b	3.77—3.90(m, 9H, 2OCH₃), 4.00—4.03(s, 3H, CH₃), 6.63(s, 1H,ArH), 6.76(s, 1H, ArH), 7.40(s, 1H, ArH), 7.49—7.53(m, 1H, ArH), 7.82—7.83(m, 1H, ArH), 8.58(s, 1H, ArH)
7^b	3.79—3.85(s, 6H, 2OCH₃), 6.57(s, 1H, ArH), 6.73(s, 1H, ArH), 7.35—7.53(m, 5H, 2ArH), 13.45(s, 1H, ArOH)
8^a	2.18—2.28(m, 2H, CH₂), 3.75—3.79(m, 2H, CH₂Cl), 3.81—3.83(s, 1H, OCH₃), 3.86—3.88(s, 3H, OCH₃), 4.17—4.22(m, 2H, OCH₂), 6.68(s, 1H, ArH), 6.81—6.85(m, 1H, ArH), 7.45—7.47(m, 1H, ArH), 7.52—7.55(m, 1H, ArH), 7.85—7.87(m, 1H, ArH), 8.59—8.62(m, 2H, 2ArH), 13.47(s, 1H, ArOH)
Ⅱa^a	2.06—2.11(m, 2H, CH₂), 2.27—2.31(t, 2H, J=6 Hz, CH₂N), 3.85—3.69( s, 6H, 2OCH₃), 4.21—4.28(t, 2H, J=10.5 Hz, CH₂OAr), 6.47—6.48(d, 1H, J=1.5 Hz, ArH), 6.64—6.65(d, 1H, ArH), 7.35—7.36(m, 2H, ArH), 7.50—7.51(m, 1H, ArH), 7.76—7.78(m, 1H, CH N), 8.61—8.68(m, 3H, CH N), 13.35(s, 1H, ArOH)	30.479, 43.48, 57.06, 61.44, 66.20, 100.25, 104.97, 111.38, 112.14, 114.42, 119.85, 123.99, 128.26, 128.74, 137.73, 138.75, 146.39, 148.74, 149.09, 151.31, 152.42, 153.60, 156.87, 169.87, 162.05, 180.03
Ⅱb^c	1.88—1.98(m, 2H, CH₂), 2.27—2.31(m, 5H, NCH₂, NCH₃), 2.39—2.35(m, 8H, 4CH₂), 3.77—3.84(s, 6H, 2OCH₃), 4.01(m, 1H, ArH), 6.55(s, 1H, ArH), 7.32(s, 1H, ArH), 7.53(m, 1H, ArH), 7.95(m, 1H, ArH), 7.48—8.56(m, 2H, ArH)	26.15, 29.68, 44.80, 51.57, 54.26, 54.37, 56.66, 61.16, 67.34, 99.64, 105.50, 112.89, 114.44, 123.12, 123.39, 128.32, 138.29, 138.56, 146.58, 148.57, 151.47, 152.41, 156.61, 160.55, 162.08, 180.55

Table 3 1 H NMR and 13C NMR data for compounds 4, Ⅰa—Ⅰi, 5—8, Ⅱa and Ⅱb

Compd.	¹H NMR(300 MHz), δ	¹³C NMR(300 MHz), δ
4^a	2.27—2.39(m, 2H, CH₂), 3.75—3.82(t, 2H, J=8.88 Hz, CH₂Cl), 3.89(s, 3H, OCH₃), 3.99(s, 3H, OCH₃), 4.21—4.29(t, 2H, J=7.59 Hz, OCH₂), 6.34—6.39(d, 2H, J=11.49 Hz, 2ArH), 6.85(s, 1H, ArH), 7.58(s, 1H, ArH), 12.99(s, 1H, ArOH)
Ⅰa^a	1.43—1.47(m, 2H, CH₂), 1.62—1.69(m, 4H, 2CH₂), 2.04—2.10(m, 2H, CH₂), 2.31—2.53(m, 6H, CH₂N), 3.81(s, 3H, OCH₃), 3.93(s, 3H, OCH₃), 4.16—4.18(t, 2H, J=3.00 Hz, CH₂OAr), 6.31—6.35(dd, 2H, J=9.00 Hz, ArH), 6.8(s, 1H, ArH), 7.51(s, 1H, ArH), 13.03(s, 1H, ArOH)	21.55, 24.23, 25.62, 26.22, 54.28, 55.29, 56.97, 67.52, 92.90, 97.25, 100.59, 103.01, 105.44, 112.64, 146.34, 152.32, 156.46, 157.55, 162.81, 166.22, 172.49, 179.43
Ⅰb^b	2.08—2.11(m, 2H, J=9.00 Hz, CH₂), 2.89—2.95(t, 2H, J=10.5 Hz, CH₂), 3.88—4.00(s, 6H, 2OCH₃), 4.14—4.16(t, 2H, J=6.00 Hz, CH₂), 6.35—6.36(d, 1H, J=1.95 Hz, ArH), 6.40—6.41(d, 1H, J=1.92 Hz, ArH), 7.29(s, 1H, ArH), 7.49(s, 1H, ArH)	22.59, 27.02, 46.88, 56.40, 56.90, 66.78, 92.74, 97.15, 100.39, 102.87, 105.26, 112.51, 146.05, 152.23, 156.20, 157.39, 162.72, 166.10, 179.26
Ⅰc^a	1.28—1.98(m, 10H, 5CH₂), 2.99—3.03(t, 2H, J=6.00 Hz, CH₂N), 3.77(s, 3H, OCH₃), 3.88(m, 1H, CHNH), 3.93(s, 3H, OCH₃), 4.16—4.18(t, 2H, J=3.00 Hz, CH₂OAr), 6.24—6.31(dd, 2H, J=1.5 Hz, 4.50 Hz, 2ArH), 6.77(s, 1H, ArH), 7.46(s, 1H , ArH), 12.91(s, 1H, ArOH)	24.37, 26.27, 26.10, 29.14, 41.53, 56.30, 56.53, 57.06, 66.55, 92.97, 97.31, 100.71, 103.01, 105.68, 112.65, 146.04, 152.49, 156.36, 157.56, 162.81, 166.29, 179.45
Ⅰd^a	1.28(s, 9H, 3CH₃), 2.26—2.30(m, 2H, CH₂), 2.99—3.04(t, 2H, J=7.50 Hz, CH₂N), 3.79(s, 3H, OCH₃), 3.86(s, 3H, OCH₃), 4.15—4.18(t, 2H, J=4.50 Hz, CH₂OAr), 6.22—6.26(dd, 2H, J=1.50 Hz, 4.50 Hz, 2ArH), 6.73(s, 1H, ArH), 7.40(s, 1H, ArH), 12.90(s, 1H, ArOH)	22.69, 26.27, 29.69, 38.14, 55.80, 56.62, 58.16, 59.51, 68.51, 92.51, 96.98, 99.93, 103.28, 106.14, 113.27, 144.75, 152.59, 155.09, 157.47, 163.06, 166.06, 179.36
Ⅰe^a	1.99—2.08(m, 2H, CH₂), 2.02[s, 6H, N(CH₃)₂], 2.44—2.48(t, 2H, J=7.35 Hz, CH₂N), 3.81(s, 3H, OCH₃), 3.93(s, 3H, OCH₃), 4.11—4.18(t, 2H, J=10.5 Hz, CH₂OAr), 6.29—6.34(m, 2H, 2ArH), 6.79(s, 1H, ArH), 7.53(s, 1H, ArH), 12.99(s, 1H, ArOH)	25.66, 43.99, 55.21, 56.43, 56.94, 66.95, 92.81, 97.19, 100.48, 102.91, 105.40, 112.55, 146.08, 152.30, 156.29, 157.45, 162.74, 166.15, 179.32
Ⅰf^a	1.34—1.47[m, 14H, N(CH₂CH₂CH₃)₂], 2.00—2.05(m, 2H, CH₂), 2.43—2.78(t, 4H, J=7.5 Hz, CH₂CH₂N), 2.63—2.66(t, 2H, J=4.5 Hz, CH₂N), 3.56—3.58(t, 4H, J=3 Hz, OCH₂), 3.88—3.96(s, 6H, 2OCH₃), 6.33—6.34(d, 1H, J=1.5 Hz, ArH), 6.38—6.39(d, 1H, J=1.5 Hz, ArH), 7.27(s, 1H, ArH), 7.56(s, 1H, ArH)	13.59, 20.18, 23.45, 25.26, 49.74, 52.55, 55.80, 56.38, 66.36, 92.62, 96.94, 98.52, 99.76, 106.96, 113.37, 145.55, 152.50, 155.33, 157.45, 165.94, 179.13
Ⅰg^c	2.03—2.08(m, 2H, CH₂), 2.40—2.41(s, 3H, NCH₃), 2.64—2.69[m, 8H, (CH₂)₄], 3.87—3.90(s, 6H, OCH₃), 4.05—4.09(t, 2H, J=6 Hz, OCH₂), 6.21—6.22(d, 1H, J=1.5 Hz, ArH), 6.33—6.34(d, 1H, J=1.5 Hz, ArH), 6.85(s, 1H, ArH), 7.33(s, 1H, ArH)	25.89, 30.31, 43.82, 49.79, 53.50, 53.87, 55.78, 56.48, 66.93, 92.60, 96.95, 99.66, 103.47, 106.80, 113.23, 145.95, 152.50, 155.99, 157.67, 163.19, 166.11, 179.83
Ⅰh^a	2.25—2.29(m, 2H, J=3 Hz, CH₂Ar), 3.88—4.00(s, 6H, 2OCH), 3.87—3.91(t, 2H, J=6 Hz, CH₂N), 4.16—4.18(d, 2H, CH₂Ar), 4.25—4.29(t, 2H, J=6 Hz, CH₂O), 4.93—5.02(m, 2H, CH₂), 6.02—6.18(m, 1H, CH), 6.30—6.33(d, 2H, J=4.5 Hz, CH CH), 6.78(s, 1H, ArH), 7.03(s, 1H, CH CHN), 7.11(s, 1H, CH CHN), 7.06(s, 1H, CH N)	30.23, 43.53, 55.73, 56.37, 63.35, 92.47, 96.87, 99.63, 103.33, 106.39, 113.10, 119.08, 128.58, 137.18, 145.44, 152.54, 155.88, 157.51, 163.07, 165.95, 174.46, 179.54
Ⅰi^b	1.90—1.94(m, 2H, CH₂), 2.41—2.46(t, 3H, J=7.5 Hz, CH₂N), 3.56—3.59(t, 4H, J=9 Hz, OCH₂), 3.87—3.94(s, 6H, OCH₃), 4.08—4.12(t, 2H, J=5.6 Hz, CH₂OAr), 6.37—6.38(d, 1H, J=1.5 Hz, ArH), 6.54—6.55(d, 1H, J=1.5 Hz, ArH), 7.15(s, 1H, ArH),7.41(s, 1H, ArH)	26.14, 53.59, 53.80, 55.21, 55.43, 56.40, 66.26, 66.64, 67.35, 92.73, 97.14, 100.44, 103.21, 105.11, 112.51, 146.57, 152.17, 157.44, 162.74, 166.11, 179.32
5^a	3.82—3.83(s, 3H, OCH₃), 3.87—3.89(s, 3H, OCH₃), 4.02—4.13(s, 6H, 2OCH₃), 6.44(s, 1H, ArH), 6.95(s, 1H, ArH), 8.02(s, 1H, ArH)
6^b	3.77—3.90(m, 9H, 2OCH₃), 4.00—4.03(s, 3H, CH₃), 6.63(s, 1H,ArH), 6.76(s, 1H, ArH), 7.40(s, 1H, ArH), 7.49—7.53(m, 1H, ArH), 7.82—7.83(m, 1H, ArH), 8.58(s, 1H, ArH)
7^b	3.79—3.85(s, 6H, 2OCH₃), 6.57(s, 1H, ArH), 6.73(s, 1H, ArH), 7.35—7.53(m, 5H, 2ArH), 13.45(s, 1H, ArOH)
8^a	2.18—2.28(m, 2H, CH₂), 3.75—3.79(m, 2H, CH₂Cl), 3.81—3.83(s, 1H, OCH₃), 3.86—3.88(s, 3H, OCH₃), 4.17—4.22(m, 2H, OCH₂), 6.68(s, 1H, ArH), 6.81—6.85(m, 1H, ArH), 7.45—7.47(m, 1H, ArH), 7.52—7.55(m, 1H, ArH), 7.85—7.87(m, 1H, ArH), 8.59—8.62(m, 2H, 2ArH), 13.47(s, 1H, ArOH)
Ⅱa^a	2.06—2.11(m, 2H, CH₂), 2.27—2.31(t, 2H, J=6 Hz, CH₂N), 3.85—3.69( s, 6H, 2OCH₃), 4.21—4.28(t, 2H, J=10.5 Hz, CH₂OAr), 6.47—6.48(d, 1H, J=1.5 Hz, ArH), 6.64—6.65(d, 1H, ArH), 7.35—7.36(m, 2H, ArH), 7.50—7.51(m, 1H, ArH), 7.76—7.78(m, 1H, CH N), 8.61—8.68(m, 3H, CH N), 13.35(s, 1H, ArOH)	30.479, 43.48, 57.06, 61.44, 66.20, 100.25, 104.97, 111.38, 112.14, 114.42, 119.85, 123.99, 128.26, 128.74, 137.73, 138.75, 146.39, 148.74, 149.09, 151.31, 152.42, 153.60, 156.87, 169.87, 162.05, 180.03
Ⅱb^c	1.88—1.98(m, 2H, CH₂), 2.27—2.31(m, 5H, NCH₂, NCH₃), 2.39—2.35(m, 8H, 4CH₂), 3.77—3.84(s, 6H, 2OCH₃), 4.01(m, 1H, ArH), 6.55(s, 1H, ArH), 7.32(s, 1H, ArH), 7.53(m, 1H, ArH), 7.95(m, 1H, ArH), 7.48—8.56(m, 2H, ArH)	26.15, 29.68, 44.80, 51.57, 54.26, 54.37, 56.66, 61.16, 67.34, 99.64, 105.50, 112.89, 114.44, 123.12, 123.39, 128.32, 138.29, 138.56, 146.58, 148.57, 151.47, 152.41, 156.61, 160.55, 162.08, 180.55

Table 4 Inhibitory activity of the target compounds on ASM

Compd.	Ⅰa	Ⅰb	Ⅰc	Ⅰd	Ⅰe	Ⅰf	Ⅰg	Ⅰh	Ⅰi	Ⅱa	Ⅱb	α-Mangostin
Inhibition rate(%)		72.3		62.0	59.8	88.9						73.0

Scheme 1 Synthetic routes of target compounds Ⅰa—Ⅰi

Scheme 2 Synthetic routes of target compounds Ⅱa and Ⅱb

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酸性神经鞘磷脂酶直接抑制剂的设计、合成及生物活性

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酸性神经鞘磷脂酶直接抑制剂的设计、合成及生物活性

Design, Synthesis and Biological Activity of Acid Sphingomyelinase Inhibitors^†