Design, Synthesis and Biological Activity of Acid Sphingomyelinase Inhibitors†

doi:10.7503/cjcu20140617

Abstract

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

CLC Number:

O626

TrendMD:

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

Figures/Tables 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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