Synthesis of Novel Polyheterocyclic Molecules with 1,3,4-Oxadiazole Thioetheramide as Core Framework and Their Inhibitory Activity on Cdc25B and PTP1B†

doi:10.7503/cjcu20180525

Abstract

Abstract:

1,3,4-Oxadiazole derivatives(5) were constructed using aromatic hydrazide containing a triazines(3). Then, compound 5 was combined with the derivatives 6 containing 1,3,4-thiadiazole to synthesize eighteen target molecules. Their structures were characterized by infrared spectroscopy(IR), nuclear magnetic resonance(NMR) and high resolution mass spectrometry(HRMS). The inhibitory activities of the target molecules against cell division cycle 25B(Cdc25B) and protein tyrosine phosphatase 1B(PTP1B) were evaluated. The results showed that eight target molecules had better inhibitory activities than their positive reference and could be expected to be potential Cdc25B inhibitors; twelve target molecules had better inhibitory activities than their reference and could be expected to be potential PTP1B inhibitors.

Key words: 1, 3, 4-Oxadiazole, Triazine, 1, 3, 4-Thiadiazole, Cell division cycle 25B(Cdc25B), Protein tyrosine phosphatase 1B(PTP1B)

CLC Number:

O626

TrendMD:

ZHANG Chenglu,GONG Rongqing,YANG Jingyi,SUN Xiaona,LI Yilin,WANG Huayu,SONG Fulu,SUN Yuedong. Synthesis of Novel Polyheterocyclic Molecules with 1,3,4-Oxadiazole Thioetheramide as Core Framework and Their Inhibitory Activity on Cdc25B and PTP1B^†[J]. Chem. J. Chinese Universities, 2019, 40(2): 262.

Figures/Tables 9

Fig.1 Structures of DOMA, PTSA and target molecule

Scheme 1 Synthsis of the target molecules

Table 1 Melting points of compounds 1a—1c, 2a—2c, 3a, 3c and 6a—6f

Compd.	m. p./℃	Compd.	m. p./℃
1a	173.1—173.9(173—174^[29])	3c	241.5—243.1(242—243^[25,32])
1b	113.7—114.8(114—115^[29])	6a	227.7—228.8(228—229^[25,32])
1c	114.1—114.9(114—115^[29])	6b	239.9—240.6(240—241^[25,32])
2a	289.1—289.7(289—290^[30,31])	6c	231.1—231.7(230—232^[25,32])
2b	>300(>300^[30,31])	6d	243.6—244.2(243—244^[25,32])
2c	287.8—289.1(288—290^[30,31])	6e	162.5—163.1(162—163^[25,32])
3a	139.6—140.9(139—141^[25,32])	6f	169.6—170.9(170—171^[25,32])

Table 2 Appearance, yields, melting points and IR data of compounds 3b, 4a—4c and 5a—5c

Compd.	Appearance	Yield(%)	m. p./℃	IR(KBr), $ν ˙$ /cm^-1
3b	White solid	85.3	257.1—257.9	3419, 3033, 2960, 1694, 1630, 1578, 1519, 1453, 1276, 1172, 864
4a	White solid	82.3	229.5—230.3	3412, 3025, 2979, 1715, 1618, 1499, 1401, 1250, 1172, 857
4b	White solid	91.8	280.7—281.3	3416, 3036, 2971, 1702, 1616, 1566, 1513, 1428, 1172, 866
4c	White solid	89.2	164.9—165.7	3326, 3051, 2967, 1708, 1611, 1572, 1506, 1394, 1173, 858
5a	Light yellow solid	62.1	276.8—277.5	3418, 3025, 2934, 1611, 1493, 1401, 1362, 1238, 1165, 845
5b	Light yellow solid	69.5	>300	3431, 3051, 2966, 1604, 1499, 1388, 1335, 1244, 1159, 844
5c	Light yellow solid	56.2	281.7—282.6	3431, 3084, 2934, 1605, 1499, 1414, 1362, 1250, 1165, 845

Table 2 Appearance, yields, melting points and IR data of compounds 3b, 4a—4c and 5a—5c

Compd.	Appearance	Yield(%)	m. p./℃	IR(KBr), $ν ˙$ /cm^-1
3b	White solid	85.3	257.1—257.9	3419, 3033, 2960, 1694, 1630, 1578, 1519, 1453, 1276, 1172, 864
4a	White solid	82.3	229.5—230.3	3412, 3025, 2979, 1715, 1618, 1499, 1401, 1250, 1172, 857
4b	White solid	91.8	280.7—281.3	3416, 3036, 2971, 1702, 1616, 1566, 1513, 1428, 1172, 866
4c	White solid	89.2	164.9—165.7	3326, 3051, 2967, 1708, 1611, 1572, 1506, 1394, 1173, 858
5a	Light yellow solid	62.1	276.8—277.5	3418, 3025, 2934, 1611, 1493, 1401, 1362, 1238, 1165, 845
5b	Light yellow solid	69.5	>300	3431, 3051, 2966, 1604, 1499, 1388, 1335, 1244, 1159, 844
5c	Light yellow solid	56.2	281.7—282.6	3431, 3084, 2934, 1605, 1499, 1414, 1362, 1250, 1165, 845

Table 3 1H NMR data of compounds 3b, 4a—4c and 5a—5c

Compd.	¹H NMR(500 MHz, DMSO-d₆), δ
3b	9.46(s, 1H, NH), 7.98(d,J=8.4 Hz, 2H, PhH), 7.87(d, J=8.5 Hz, 2H, PhH), 3.82(s, 3H, OCH₃), 3.52—3.49(m, 8H, pyrrolidine), 1.91(s, 8H, pyrrolidine)
4a	9.53(s, 1H, NH), 9.34(s, 1H, NH), 7.74(s, 4H, PhH), 4.42(s, 2H, NH₂), 3.71(s, 8H, morpholine), 3.63(s, 8H, morpholine)
4b	9.52(s, 1H, NH), 9.19(s, 1H, NH), 7.91(d,J=8.3 Hz, 2H, PhH), 7.74(d, J=8.3 Hz, 2H, PhH), 4.36(s, 2H, NH₂), 3.50—3.45(m, 8H, pyrrolidine), 1.90(s, 8H, pyrrolidine)
4c	9.52(s, 1H, NH), 9.19(s, 1H, NH), 7.74(q,J=8.8 Hz, 4H, PhH), 4.42(s, 2H, NH₂), 3.71(d, J=4.35 Hz, 8H, piperidine), 1.62—1.50(m, 12H, piperidine)
5a	14.49(s, 1H, SH), 9.59(s, 1H, NH), 7.93(d,J=8.6 Hz, 2H, PhH), 7.81(d, J=8.7 Hz, 2H, PhH), 3.74(s, 8H, morpholine), 3.65(s, 8H, morpholine)
5b	13.38(s, 1H, SH), 9.45(s, 1H, NH), 8.05(d,J=8.7 Hz, 2H, PhH), 7.98(d, J=8.55 Hz, 2H, PhH), 3.51—3.48(m, 8H, pyrrolidine), 1.89(s, 8H, pyrrolidine)
5c	13.84(s, 1H, SH), 9.43(s, 1H, NH), 7.92(d,J=8.75 Hz, 2H, PhH), 7.78(d, J=8.7 Hz, 2H, PhH), 3.72(s, 8H, piperidine), 1.62—1.51(m, 12H, piperidine)

Table 4 Appearance, yields, melting points and HRMS data of compounds TZOA-1—TZOA-18

Compd.	Appearance	Yield(%)	m. p./℃	HRMS(positive-SIMS), m/z(calcd. ), [M+H]⁺
TZOA-1	White solid	67.6	279.8—280.8	660.1935(660.1923)
TZOA-2	White solid	68.9	282.9—283.7	674.2088(674.2080)
TZOA-3	Light pink solid	73.9	273.1—273.9	690.2025(690.2029)
TZOA-4	Brownish solid	65.1	259.7—260.5	694.1542(694.1534)
TZOA-5	Yellow solid	73.2	287.6—288.5	705.1782(705.1774)
TZOA-6	White solid	76.1	253.2—253.8	728.1787(728.1797)
TZOA-7	Yellow solid	75.8	250.7—251.5	628.2014(628.2025)
TZOA-8	White solid	66.9	269.8—270.3	642.2191(642.2182)
TZOA-9	White solid	73.9	255.5—256.3	658.2138(658.2131)
TZOA-10	White solid	79.9	265.1—265.7	662.1640(662.1635)
TZOA-11	Yellow solid	77.5	262.6—263.2	673.1883(673.1876)
TZOA-12	Yellow solid	79.1	284.2—285.0	696.1907(696.1899)
TZOA-13	Yellow solid	78.2	252.7—253.5	656.2331(656.2338)
TZOA-14	White solid	76.8	248.9—249.6	670.2489(670.2495)
TZOA-15	White solid	78.2	271.7—272.3	686.2453(686.2444)
TZOA-16	White solid	73.1	254.3—254.9	690.1952(690.1948)
TZOA-17	Yellow solid	77.3	>300	701.2195(701.2189)
TZOA-18	White solid	79.9	>300	724.2219(724.2212)

Table 5 1H NMR and 13C NMR data of compounds TZOA-1—TZOA-18

Compd.	¹H NMR(500 MHz, DMSO-d₆), δ	¹³C NMR(125 MHz, DMSO-d₆), δ
TZOA-1	13.17(s, 1H, NH), 9.54(s, 1H, NH), 7.91—7.85(m, 6H, PhH), 7.50—7.42(m, 3H, PhH), 4.32(s, 2H, CH₂), 3.72(d, J=4.15 Hz, 8H, morpholine), 3.64(d, J=4.05 Hz, 8H, morpholine)	168.13, 165.06, 164.64, 163.94, 162.89, 159.77, 143.78, 131.51, 129.54, 129.06, 126.96, 126.44, 119.33, 115.44, 65.96, 43.38, 37.71
Compd.	¹H NMR(500 MHz, DMSO-d₆), δ	¹³C NMR(125 MHz, DMSO-d₆), δ
TZOA-2	9.55(s, 1H, NH), 7.91(q,J=8.6 Hz, 4H, PhH), 7.73(d, J=7.65 Hz, 2H, PhH), 7.27(d, J=7.8 Hz, 2H, Ph), 4.18(s, 2H, CH₂), 3.74(s, 8H, morpholine), 3.66(s, 8H, morpholine), 2.35(s, 3H, CH₃)	169.90, 168.85, 164.71, 164.66, 163.96, 157.59, 143.64, 138.00, 130.27, 129.38, 126.91, 125.93, 119.36, 115.66, 65.97, 43.38, 20.80
TZOA-3	13.01(s, 1H, NH), 9.54(s, 1H, NH), 7.91(d,J=8.7 Hz, 2H, PhH), 7.86(d, J=8.6 Hz, 2H, PhH), 7.81(d, J=8.5 Hz, 2H, PhH), 7.04(d, J=8.5 Hz, 2H, Ph), 4.28(s, 2H, CH₂), 3.81(s, 3H, OCH₃), 3.72(d, J=3.6 Hz, 8H, morpholine), 3.64(d, J=3.55 Hz, 8H, morpholine)	168.53, 164.93, 164.63, 163.93, 163.25, 160.10, 158.93, 143.73, 127.73, 126.94, 124.62, 119.32, 115.50, 114.42, 65.96, 55.23, 43.36, 38.47
TZOA-4	13.16(s, 1H, NH), 9.55(s, 1H, NH), 7.92(t,J=8.4 Hz, 4H, PhH), 7.87(d, J=8.75 Hz, 2H, PhH), 7.58(d, J=8.05 Hz, 2H, PhH), 4.37(s, 2H, CH₂), 3.73(d, J=3.3 Hz, 8H, morpholine), 3.65(s, 8H, morpholine)	167.96, 165.09, 164.63, 163.94, 163.27, 162.79, 159.99, 143.80, 131.36, 129.66, 129.10, 126.97, 126.48, 119.32, 115.41, 65.96, 43.37, 37.49
TZOA-5	9.53(s, 1H, NH), 8.29(d,J=8.5 Hz, 2H, PhH), 8.09(d, J=8.5 Hz, 2H, PhH), 7.88(q, J=8.75 Hz, 4H, PhH), 4.22(s, 2H, CH₂), 3.72(d, J=4.05 Hz, 8H, morpholine), 3.64(d, J=3.9 Hz, 8H, morpholine)	167.75, 165.12, 164.63, 163.93, 162.68, 160.23, 143.81, 131.20, 129.76, 129.11, 126.96, 126.53, 119.31, 115.38, 65.96, 43.36, 37.27
TZOA-6	13.32(s, 1H, NH), 9.54(s, 1H, NH), 8.14(d,J=8.2 Hz, 2H, PhH), 7.90(d, J=8.75 Hz, 2H, PhH), 7.85(t, J=8.25 Hz, 4H, PhH), 4.43(s, 2H, CH₂), 3.71(s, 8H, morpholine), 3.64(d, J=3.5 Hz, 8H, morpholine)	167.59, 165.23, 164.62, 163.92, 162.36, 162.22, 159.26, 143.85, 134.62, 129.86, 129.61, 127.29, 126.97, 126.09, 126.07, 125.02, 122.85, 119.30, 115.32, 65.95, 43.36, 36.68
TZOA-7	13.18(s, 1H, NH), 9.38(s, 1H, NH), 8.05(d,J=8.65 Hz, 2H, PhH), 7.89(d, J=7.7 Hz, 2H, PhH), 7.83(d, J =8.65 Hz, 2H, PhH), 7.50—7.43(m, 3H, PhH), 4.33(s, 2H, CH₂), 3.51—3.47(m, 8H, pyrrolidine), 1.89(s, 8H, pyrrolidine)	168.16, 164.75, 164.41, 163.04, 162.60, 159.01, 144.12, 131.44, 128.99, 128.67, 126.45, 126.01, 118.65, 114.55, 45.31, 37.79, 24.46, 24.29
TZOA-8	9.37(s, 1H, NH), 8.06(d,J=8.4 Hz, 2H, PhH), 7.84(d, J=8.35 Hz, 2H, PhH), 7.72(d, J=7.6 Hz, 2H, PhH), 7.26(d, J=7.8 Hz, 2H, PhH), 4.18(s, 2H, CH₂), 3.52—3.48(m, 8H, pyrrolidine), 2.33(s, 3H, CH₃), 1.89(s, 8H, pyrrolidine)	169.78, 164.83, 163.75, 163.39, 162.95, 157.75, 144.36, 138.10, 130.15, 129.40, 126.77, 125.97, 119.00, 115.05, 45.66, 24.82, 24.65, 20.82
TZOA-9	13.00(s, 1H, NH), 9.37(s, 1H, NH), 8.05(d,J=8.9 Hz, 2H, PhH), 7.83—7.79(m, 4H, PhH), 7.04(d, J=8.9 Hz, 2H, PhH), 4.28(s, 2H, CH₂), 3.81(s, 3H, OCH₃), 3.51—3.47(m, 8H, pyrrolidine), 1.89(s, 8H, pyrrolidine)	168.64, 165.01, 163.38, 163.17, 162.94, 160.06, 158.79, 144.43, 127.71, 126.79, 124.68, 118.99, 114.93, 114.41, 55.23, 45.64, 38.52, 24.81, 24.64
TZOA-10	9.37(s, 1H, NH), 8.06(d,J=8.3 Hz, 2H, PhH), 7.84(d, J=8.25 Hz, 4H, PhH), 7.50(d, J=8.3 Hz, 2H, PhH), 4.17(s, 2H, CH₂), 3.52—3.48(m, 8H, pyrrolidine), 1.89(s, 8H, pyrrolidine)	169.55, 168.12, 164.53, 163.22, 163.05, 162.62, 144.02, 132.73, 131.22, 128.59, 127.27, 126.44, 118.66, 114.69, 45.33, 24.47, 24.31
TZOA-11	9.36(s, 1H, NH), 8.31(d,J=8.65 Hz, 2H, PhH), 8.14(d, J=8.65 Hz, 2H, PhH), 8.04(d, J=8.65 Hz, 2H, PhH), 7.82(t, J=8.45 Hz, 2H, PhH), 4.31(s, 2H, CH₂), 3.50—3.47(m, 8H, pyrrolidine), 1.88(s, 8H, pyrrolidine)	169.89, 168.97, 164.47, 163.39, 163.04, 162.60, 155.91, 144.00, 132.55, 131.44, 128.55, 127.19, 126.43, 118.66, 114.71, 45.29, 24.48, 24.30
TZOA-12	13.23(s, 1H, NH), 9.38(s, 1H, NH), 8.12(d, J=8.25 Hz, 2H, PhH), 8.05(d, J=8.6 Hz, 2H, PhH), 7.85—7.81(m, 4H, PhH), 4.36(s, 2H, CH₂), 3.51—3.47(m, 8H, pyrrolidine), 1.88(s, 8H, pyrrolidine)	167.99, 164.86, 163.04, 162.60, 162.23, 158.04, 144.15, 134.81, 129.16, 128.90, 126.72, 126.47, 125.67, 125.64, 124.73, 122.57, 118.64, 114.49, 45.30, 37.14, 24.46, 24.29
TZOA-13	9.38(s, 1H, NH), 7.93(d, J=8.15 Hz, 2H, PhH), 7.87(d, J=8.55 Hz, 2H, PhH), 7.83(d, J=7.6 Hz, 2H, PhH), 7.44(t,J=7.65 Hz, 2H, PhH), 7.38—7.35(m, 1H, PhH), 4.17(s, 2H, CH₂), 3.73(t, J=4.75 Hz, 8H, piperidine), 1.63—1.51(m, 12H, piperidine)	167.79, 165.18, 164.35, 164.05, 162.62, 160.20, 144.18, 131.24, 129.73, 129.10, 126.91, 126.52, 119.04, 115.08, 43.65, 37.31, 25.33, 24.31
TZOA-14	9.38(s, 1H, NH), 7.92(d,J=7.55 Hz, 2H, PhH), 7.86(d, J=7.9 Hz, 2H, PhH), 7.71(d, J=6.95 Hz, 2H, PhH), 7.25(d, J=6.85 Hz, 2H, PhH), 4.16(s, 2H, CH₂), 3.72(s, 8H, piperidine), 2.33(s, 3H, CH₃), 1.62—1.51(m, 12H, piperidine)	169.90, 168.84, 164.75, 164.37, 164.07, 163.90, 157.58, 144.01, 137.98, 130.28, 129.38, 126.87, 125.93, 119.07, 115.34, 43.67, 25.33, 24.32, 20.80
Compd.	¹H NMR(500 MHz, DMSO-d₆), δ	¹³C NMR(125 MHz, DMSO-d₆), δ
TZOA-15	13.05(s, 1H, NH), 9.39(s, 1H, NH), 7.91(d,J=8.55 Hz, 2H, PhH), 7.83(q, J=5.45 Hz, 4H, PhH), 7.06(d, J=8.55 Hz, 2H, PhH), 4.37(s, 2H, CH₂), 3.82(s, 3H, OCH₃), 3.71(t, J=4.5 Hz, 8H, piperidine), 1.62—1.50(m, 12H, piperidine)	166.84, 164.89, 163.99, 163.69, 162.05, 160.30, 143.86, 127.79, 126.58, 123.15, 120.64, 118.68, 114.67, 114.24, 54.96, 43.30, 36.43, 24.98, 23.96
TZOA-16	9.38(s, 1H, NH), 7.92(d,J=8.7 Hz, 2H, PhH), 7.86(t,J=8.55 Hz, 4H, PhH), 7.50(d, J=8.3 Hz, 2H, PhH), 4.18(s, 2H, CH₂), 3.72(s, 8H, piperidine), 1.62—1.51(m, 12H, piperidine)	170.27, 169.41, 164.78, 164.37, 164.06,163.81, 156.23, 144.02, 132.89, 131.82, 128.89, 127.53, 126.86, 119.07, 115.32, 43.66, 25.33, 24.32
TZOA-17	9.38(s, 1H, NH), 8.29(d,J=8.85 Hz, 2H, PhH), 8.09(d, J=8.25 Hz, 2H, PhH), 7.92(d, J=8.25 Hz, 2H, PhH), 7.86(d, J=8.55 Hz, 2H, PhH), 4.20(s, 2H, CH₂), 3.73(t, J=4.8 Hz, 8H, piperidine), 1.63—1.51(m, 12H, piperidine)	167.30, 165.29, 164.38, 164.33, 164.07, 162.26, 159.71, 144.22, 143.58, 134.59, 129.67, 129.23, 128.30, 126.92, 126.03, 119.02, 118.00, 114.99, 43.62, 36.59, 25.33, 24.32
TZOA-18	13.30(s, 1H, NH), 9.39(s, 1H, NH), 8.15(d,J=8.1 Hz, 2H, PhH), 7.91(d, J=8.4 Hz, 2H, PhH), 7.87(d, J=8.1 Hz, 2H, PhH), 7.83(d, J=8.6 Hz, 2H, PhH), 4.43(s, 2H, CH₂), 3.71(t, J=4.65 Hz, 8H, piperidine), 1.61—1.50(m, 12H, piperidine)	167.18, 164.96, 164.00, 163.70, 161.89, 159.00, 143.88, 134.23, 129.57, 129.31, 126.98, 126.58, 125.73, 122.51, 118.69, 114.66, 43.31, 36.24, 24.98, 23.96

Table 5 1H NMR and 13C NMR data of compounds TZOA-1—TZOA-18

Compd.	¹H NMR(500 MHz, DMSO-d₆), δ	¹³C NMR(125 MHz, DMSO-d₆), δ
TZOA-1	13.17(s, 1H, NH), 9.54(s, 1H, NH), 7.91—7.85(m, 6H, PhH), 7.50—7.42(m, 3H, PhH), 4.32(s, 2H, CH₂), 3.72(d, J=4.15 Hz, 8H, morpholine), 3.64(d, J=4.05 Hz, 8H, morpholine)	168.13, 165.06, 164.64, 163.94, 162.89, 159.77, 143.78, 131.51, 129.54, 129.06, 126.96, 126.44, 119.33, 115.44, 65.96, 43.38, 37.71
Compd.	¹H NMR(500 MHz, DMSO-d₆), δ	¹³C NMR(125 MHz, DMSO-d₆), δ
TZOA-2	9.55(s, 1H, NH), 7.91(q,J=8.6 Hz, 4H, PhH), 7.73(d, J=7.65 Hz, 2H, PhH), 7.27(d, J=7.8 Hz, 2H, Ph), 4.18(s, 2H, CH₂), 3.74(s, 8H, morpholine), 3.66(s, 8H, morpholine), 2.35(s, 3H, CH₃)	169.90, 168.85, 164.71, 164.66, 163.96, 157.59, 143.64, 138.00, 130.27, 129.38, 126.91, 125.93, 119.36, 115.66, 65.97, 43.38, 20.80
TZOA-3	13.01(s, 1H, NH), 9.54(s, 1H, NH), 7.91(d,J=8.7 Hz, 2H, PhH), 7.86(d, J=8.6 Hz, 2H, PhH), 7.81(d, J=8.5 Hz, 2H, PhH), 7.04(d, J=8.5 Hz, 2H, Ph), 4.28(s, 2H, CH₂), 3.81(s, 3H, OCH₃), 3.72(d, J=3.6 Hz, 8H, morpholine), 3.64(d, J=3.55 Hz, 8H, morpholine)	168.53, 164.93, 164.63, 163.93, 163.25, 160.10, 158.93, 143.73, 127.73, 126.94, 124.62, 119.32, 115.50, 114.42, 65.96, 55.23, 43.36, 38.47
TZOA-4	13.16(s, 1H, NH), 9.55(s, 1H, NH), 7.92(t,J=8.4 Hz, 4H, PhH), 7.87(d, J=8.75 Hz, 2H, PhH), 7.58(d, J=8.05 Hz, 2H, PhH), 4.37(s, 2H, CH₂), 3.73(d, J=3.3 Hz, 8H, morpholine), 3.65(s, 8H, morpholine)	167.96, 165.09, 164.63, 163.94, 163.27, 162.79, 159.99, 143.80, 131.36, 129.66, 129.10, 126.97, 126.48, 119.32, 115.41, 65.96, 43.37, 37.49
TZOA-5	9.53(s, 1H, NH), 8.29(d,J=8.5 Hz, 2H, PhH), 8.09(d, J=8.5 Hz, 2H, PhH), 7.88(q, J=8.75 Hz, 4H, PhH), 4.22(s, 2H, CH₂), 3.72(d, J=4.05 Hz, 8H, morpholine), 3.64(d, J=3.9 Hz, 8H, morpholine)	167.75, 165.12, 164.63, 163.93, 162.68, 160.23, 143.81, 131.20, 129.76, 129.11, 126.96, 126.53, 119.31, 115.38, 65.96, 43.36, 37.27
TZOA-6	13.32(s, 1H, NH), 9.54(s, 1H, NH), 8.14(d,J=8.2 Hz, 2H, PhH), 7.90(d, J=8.75 Hz, 2H, PhH), 7.85(t, J=8.25 Hz, 4H, PhH), 4.43(s, 2H, CH₂), 3.71(s, 8H, morpholine), 3.64(d, J=3.5 Hz, 8H, morpholine)	167.59, 165.23, 164.62, 163.92, 162.36, 162.22, 159.26, 143.85, 134.62, 129.86, 129.61, 127.29, 126.97, 126.09, 126.07, 125.02, 122.85, 119.30, 115.32, 65.95, 43.36, 36.68
TZOA-7	13.18(s, 1H, NH), 9.38(s, 1H, NH), 8.05(d,J=8.65 Hz, 2H, PhH), 7.89(d, J=7.7 Hz, 2H, PhH), 7.83(d, J =8.65 Hz, 2H, PhH), 7.50—7.43(m, 3H, PhH), 4.33(s, 2H, CH₂), 3.51—3.47(m, 8H, pyrrolidine), 1.89(s, 8H, pyrrolidine)	168.16, 164.75, 164.41, 163.04, 162.60, 159.01, 144.12, 131.44, 128.99, 128.67, 126.45, 126.01, 118.65, 114.55, 45.31, 37.79, 24.46, 24.29
TZOA-8	9.37(s, 1H, NH), 8.06(d,J=8.4 Hz, 2H, PhH), 7.84(d, J=8.35 Hz, 2H, PhH), 7.72(d, J=7.6 Hz, 2H, PhH), 7.26(d, J=7.8 Hz, 2H, PhH), 4.18(s, 2H, CH₂), 3.52—3.48(m, 8H, pyrrolidine), 2.33(s, 3H, CH₃), 1.89(s, 8H, pyrrolidine)	169.78, 164.83, 163.75, 163.39, 162.95, 157.75, 144.36, 138.10, 130.15, 129.40, 126.77, 125.97, 119.00, 115.05, 45.66, 24.82, 24.65, 20.82
TZOA-9	13.00(s, 1H, NH), 9.37(s, 1H, NH), 8.05(d,J=8.9 Hz, 2H, PhH), 7.83—7.79(m, 4H, PhH), 7.04(d, J=8.9 Hz, 2H, PhH), 4.28(s, 2H, CH₂), 3.81(s, 3H, OCH₃), 3.51—3.47(m, 8H, pyrrolidine), 1.89(s, 8H, pyrrolidine)	168.64, 165.01, 163.38, 163.17, 162.94, 160.06, 158.79, 144.43, 127.71, 126.79, 124.68, 118.99, 114.93, 114.41, 55.23, 45.64, 38.52, 24.81, 24.64
TZOA-10	9.37(s, 1H, NH), 8.06(d,J=8.3 Hz, 2H, PhH), 7.84(d, J=8.25 Hz, 4H, PhH), 7.50(d, J=8.3 Hz, 2H, PhH), 4.17(s, 2H, CH₂), 3.52—3.48(m, 8H, pyrrolidine), 1.89(s, 8H, pyrrolidine)	169.55, 168.12, 164.53, 163.22, 163.05, 162.62, 144.02, 132.73, 131.22, 128.59, 127.27, 126.44, 118.66, 114.69, 45.33, 24.47, 24.31
TZOA-11	9.36(s, 1H, NH), 8.31(d,J=8.65 Hz, 2H, PhH), 8.14(d, J=8.65 Hz, 2H, PhH), 8.04(d, J=8.65 Hz, 2H, PhH), 7.82(t, J=8.45 Hz, 2H, PhH), 4.31(s, 2H, CH₂), 3.50—3.47(m, 8H, pyrrolidine), 1.88(s, 8H, pyrrolidine)	169.89, 168.97, 164.47, 163.39, 163.04, 162.60, 155.91, 144.00, 132.55, 131.44, 128.55, 127.19, 126.43, 118.66, 114.71, 45.29, 24.48, 24.30
TZOA-12	13.23(s, 1H, NH), 9.38(s, 1H, NH), 8.12(d, J=8.25 Hz, 2H, PhH), 8.05(d, J=8.6 Hz, 2H, PhH), 7.85—7.81(m, 4H, PhH), 4.36(s, 2H, CH₂), 3.51—3.47(m, 8H, pyrrolidine), 1.88(s, 8H, pyrrolidine)	167.99, 164.86, 163.04, 162.60, 162.23, 158.04, 144.15, 134.81, 129.16, 128.90, 126.72, 126.47, 125.67, 125.64, 124.73, 122.57, 118.64, 114.49, 45.30, 37.14, 24.46, 24.29
TZOA-13	9.38(s, 1H, NH), 7.93(d, J=8.15 Hz, 2H, PhH), 7.87(d, J=8.55 Hz, 2H, PhH), 7.83(d, J=7.6 Hz, 2H, PhH), 7.44(t,J=7.65 Hz, 2H, PhH), 7.38—7.35(m, 1H, PhH), 4.17(s, 2H, CH₂), 3.73(t, J=4.75 Hz, 8H, piperidine), 1.63—1.51(m, 12H, piperidine)	167.79, 165.18, 164.35, 164.05, 162.62, 160.20, 144.18, 131.24, 129.73, 129.10, 126.91, 126.52, 119.04, 115.08, 43.65, 37.31, 25.33, 24.31
TZOA-14	9.38(s, 1H, NH), 7.92(d,J=7.55 Hz, 2H, PhH), 7.86(d, J=7.9 Hz, 2H, PhH), 7.71(d, J=6.95 Hz, 2H, PhH), 7.25(d, J=6.85 Hz, 2H, PhH), 4.16(s, 2H, CH₂), 3.72(s, 8H, piperidine), 2.33(s, 3H, CH₃), 1.62—1.51(m, 12H, piperidine)	169.90, 168.84, 164.75, 164.37, 164.07, 163.90, 157.58, 144.01, 137.98, 130.28, 129.38, 126.87, 125.93, 119.07, 115.34, 43.67, 25.33, 24.32, 20.80
Compd.	¹H NMR(500 MHz, DMSO-d₆), δ	¹³C NMR(125 MHz, DMSO-d₆), δ
TZOA-15	13.05(s, 1H, NH), 9.39(s, 1H, NH), 7.91(d,J=8.55 Hz, 2H, PhH), 7.83(q, J=5.45 Hz, 4H, PhH), 7.06(d, J=8.55 Hz, 2H, PhH), 4.37(s, 2H, CH₂), 3.82(s, 3H, OCH₃), 3.71(t, J=4.5 Hz, 8H, piperidine), 1.62—1.50(m, 12H, piperidine)	166.84, 164.89, 163.99, 163.69, 162.05, 160.30, 143.86, 127.79, 126.58, 123.15, 120.64, 118.68, 114.67, 114.24, 54.96, 43.30, 36.43, 24.98, 23.96
TZOA-16	9.38(s, 1H, NH), 7.92(d,J=8.7 Hz, 2H, PhH), 7.86(t,J=8.55 Hz, 4H, PhH), 7.50(d, J=8.3 Hz, 2H, PhH), 4.18(s, 2H, CH₂), 3.72(s, 8H, piperidine), 1.62—1.51(m, 12H, piperidine)	170.27, 169.41, 164.78, 164.37, 164.06,163.81, 156.23, 144.02, 132.89, 131.82, 128.89, 127.53, 126.86, 119.07, 115.32, 43.66, 25.33, 24.32
TZOA-17	9.38(s, 1H, NH), 8.29(d,J=8.85 Hz, 2H, PhH), 8.09(d, J=8.25 Hz, 2H, PhH), 7.92(d, J=8.25 Hz, 2H, PhH), 7.86(d, J=8.55 Hz, 2H, PhH), 4.20(s, 2H, CH₂), 3.73(t, J=4.8 Hz, 8H, piperidine), 1.63—1.51(m, 12H, piperidine)	167.30, 165.29, 164.38, 164.33, 164.07, 162.26, 159.71, 144.22, 143.58, 134.59, 129.67, 129.23, 128.30, 126.92, 126.03, 119.02, 118.00, 114.99, 43.62, 36.59, 25.33, 24.32
TZOA-18	13.30(s, 1H, NH), 9.39(s, 1H, NH), 8.15(d,J=8.1 Hz, 2H, PhH), 7.91(d, J=8.4 Hz, 2H, PhH), 7.87(d, J=8.1 Hz, 2H, PhH), 7.83(d, J=8.6 Hz, 2H, PhH), 4.43(s, 2H, CH₂), 3.71(t, J=4.65 Hz, 8H, piperidine), 1.61—1.50(m, 12H, piperidine)	167.18, 164.96, 164.00, 163.70, 161.89, 159.00, 143.88, 134.23, 129.57, 129.31, 126.98, 126.58, 125.73, 122.51, 118.69, 114.66, 43.31, 36.24, 24.98, 23.96

Table 6 Inhibitory activities of compounds 1—6 and TZOA-1—TZOA-18 against Cdc25B and PTP1B

Compd.	Cdc25B^a		PTP1B^c
Compd.	Inhibition rate(%)^b	IC₅₀/(μg·mL^-1)	Inhibition rate (%)^b	IC₅₀/(μg·mL^-1)
1a	1.55±1.34	NA^d	2.99±3.88	NA
1b	0.16±0.66	NA	1.01±0.05	NA
1c	18.62±2.83	NA	24.47±1.22	NA
2a	0.67±0.17	NA	4.77±6.25	NA
2b	53.53±2.79	10.37±0.63	38.79±5.97	NA
2c	37.76±7.95	NA	22.35±0.77	NA
3a	4.85±0.23	NA	5.45±0.39	NA
3b	53.48±1.06	5.62±1.52	84.63±4.76	9.18±0.43
3c	0.32±1.52	NA	24.07±1.96	NA
4a	1.64±0.69	NA	4.91±0.60	NA
4b	8.93±3.84	NA	1.21±0.52	NA
4c	1.41±3.43	NA	6.63±3.14	NA
5a	61.81±3.58	12.82±1.46	31.13±4.69	NA
5b	60.00±1.00	6.64±1.04	60.53±2.00	19.71±2.84
5c	64.49±1.60	6.41±0.49	84.47±0.52	6.64±0.16
6a	0.34±0.39	NA	15.64±5.71	NA
6b	36.68±2.83	NA	85.71±2.80	12.24±0.11
6c	0.02±0.35	NA	85.22±1.87	20.58±0.06
Compd.	Cdc25B^a		PTP1B^c
Compd.	Inhibition rate(%)^b	IC₅₀/(μg·mL^-1)	Inhibition rate (%)^b	IC₅₀/(μg·mL^-1)
6d	14.99±1.04	NA	91.00±1.53	7.21±0.11
6e	64.59±0.69	9.92±0.74	87.74±2.21	17.28±2.24
6f	25.69±2.93	NA	88.47±1.38	11.81±0.47
TZOA-1	4.28±0.98	NA	31.91±0.81	NA
TZOA-2	44.10±0.00	NA	31.77±0.32	NA
TZOA-3	0.37±1.02	NA	31.85±1.09	NA
TZOA-4	69.32±2.77	6.66±1.77	40.60±1.18	NA
TZOA-5	70.23±3.06	3.32±0.06	44.83±4.20	NA
TZOA-6	77.53±1.20	3.01±0.19	48.10±0.92	NA
TZOA-7	74.97±0.17	3.36±0.13	84.42±1.00	7.04±0.73
TZOA-8	24.30±4.25	NA	86.75±1.65	15.11±0.98
TZOA-9	57.61±0.91	9.38±0.99	84.66±0.90	9.32±1.86
TZOA-10	63.73±4.13	5.49±0.48	84.70±8.06	3.24±0.06
TZOA-11	92.25±0.21	0.71±0.04	93.40±0.39	2.37±0.38
TZOA-12	89.07±1.18	1.12±0.13	89.16±6.93	8.50±0.07
TZOA-13	90.28±0.07	1.04±0.25	77.33±0.73	26.18±6.77
TZOA-14	93.37±1.09	0.88±0.15	88.15±0.14	4.78±0.24
TZOA-15	94.54±1.50	0.86±0.50	88.78±0.56	4.22±0.64
TZOA-16	91.13±0.06	1.02±0.12	89.73±3.35	4.36±0.78
TZOA-17	96.18±0.16	0.66±0.33	92.71±0.74	6.12±0.58
TZOA-18	99.23±0.09	0.46±0.34	91.52±0.39	3.04±0.02

Table 6 Inhibitory activities of compounds 1—6 and TZOA-1—TZOA-18 against Cdc25B and PTP1B

Compd.	Cdc25B^a		PTP1B^c
Compd.	Inhibition rate(%)^b	IC₅₀/(μg·mL^-1)	Inhibition rate (%)^b	IC₅₀/(μg·mL^-1)
1a	1.55±1.34	NA^d	2.99±3.88	NA
1b	0.16±0.66	NA	1.01±0.05	NA
1c	18.62±2.83	NA	24.47±1.22	NA
2a	0.67±0.17	NA	4.77±6.25	NA
2b	53.53±2.79	10.37±0.63	38.79±5.97	NA
2c	37.76±7.95	NA	22.35±0.77	NA
3a	4.85±0.23	NA	5.45±0.39	NA
3b	53.48±1.06	5.62±1.52	84.63±4.76	9.18±0.43
3c	0.32±1.52	NA	24.07±1.96	NA
4a	1.64±0.69	NA	4.91±0.60	NA
4b	8.93±3.84	NA	1.21±0.52	NA
4c	1.41±3.43	NA	6.63±3.14	NA
5a	61.81±3.58	12.82±1.46	31.13±4.69	NA
5b	60.00±1.00	6.64±1.04	60.53±2.00	19.71±2.84
5c	64.49±1.60	6.41±0.49	84.47±0.52	6.64±0.16
6a	0.34±0.39	NA	15.64±5.71	NA
6b	36.68±2.83	NA	85.71±2.80	12.24±0.11
6c	0.02±0.35	NA	85.22±1.87	20.58±0.06
Compd.	Cdc25B^a		PTP1B^c
Compd.	Inhibition rate(%)^b	IC₅₀/(μg·mL^-1)	Inhibition rate (%)^b	IC₅₀/(μg·mL^-1)
6d	14.99±1.04	NA	91.00±1.53	7.21±0.11
6e	64.59±0.69	9.92±0.74	87.74±2.21	17.28±2.24
6f	25.69±2.93	NA	88.47±1.38	11.81±0.47
TZOA-1	4.28±0.98	NA	31.91±0.81	NA
TZOA-2	44.10±0.00	NA	31.77±0.32	NA
TZOA-3	0.37±1.02	NA	31.85±1.09	NA
TZOA-4	69.32±2.77	6.66±1.77	40.60±1.18	NA
TZOA-5	70.23±3.06	3.32±0.06	44.83±4.20	NA
TZOA-6	77.53±1.20	3.01±0.19	48.10±0.92	NA
TZOA-7	74.97±0.17	3.36±0.13	84.42±1.00	7.04±0.73
TZOA-8	24.30±4.25	NA	86.75±1.65	15.11±0.98
TZOA-9	57.61±0.91	9.38±0.99	84.66±0.90	9.32±1.86
TZOA-10	63.73±4.13	5.49±0.48	84.70±8.06	3.24±0.06
TZOA-11	92.25±0.21	0.71±0.04	93.40±0.39	2.37±0.38
TZOA-12	89.07±1.18	1.12±0.13	89.16±6.93	8.50±0.07
TZOA-13	90.28±0.07	1.04±0.25	77.33±0.73	26.18±6.77
TZOA-14	93.37±1.09	0.88±0.15	88.15±0.14	4.78±0.24
TZOA-15	94.54±1.50	0.86±0.50	88.78±0.56	4.22±0.64
TZOA-16	91.13±0.06	1.02±0.12	89.73±3.35	4.36±0.78
TZOA-17	96.18±0.16	0.66±0.33	92.71±0.74	6.12±0.58
TZOA-18	99.23±0.09	0.46±0.34	91.52±0.39	3.04±0.02

Fig.2 Molecular docking of compound TZOA-13, TZOA-18 with Cdc25B and PTP1B, respectively(A, B) TZOA-13 with Cdc25B; (C, D) TZOA-18 with Cdc25B; (E, F) TZOA-13 with PTP1B; (G, H) TZOA-18 with PTP1B.

References 35

[1]	Kmar R., Kmar A., Jain S., Kaushik D., Eur. J. Med. Chem., 2011, 46(9), 3543-3550
[2]	Husain A., Ahmad A., Alam M. M., Ajmal M., Ahuja P., Eur. J. Med. Chem., 2009, 44(9), 3798-3804
[3]	Zhang X. M., Qiu M., Sun J., Zhang Y. B., Yang Y. S., Wang X. L., Tang J. F., Zhu H. L., Bioorg. Med. Chem., 2011, 19(21), 6518-6524
[4]	Shingalapur R. V., Hosamani K. M., Keri R. S., Hugar M. H., Eur. J. Med. Chem.,2010, 45(5), 1753-1759
[5]	Wang F. H., Qin Z. L., Huang Q., Front. Chem. China,2006, 1(1), 112-114
[6]	Naresh K. R., Poornachandra Y., Nagender P., Santhosh K. G., Krishna S. D., Ganesh K. C., Narsaiah B., Bioorg. Med. Chem. Lett., 2016, 26, 4829-4831
[7]	Almasirad A., Mousavi Z., Tajik M., Assarzadeh M. J., Shafiee A., DARU-J. Pharm. Sci., 2014, 22(22), 1-8
[8]	Chaudhary S. K., Chaudhary M., Chaudhari A., Parmar S. S., J. Pharm. Sci., 1978, 67(11), 1507-1509
[9]	El-Emam A. A., Al-Deeb O. A., Al-Omar M., Lehmann J., Bioorg. Med. Chem., 2004, 12(19), 5107-5113
[10]	Dolman S. J., Gosselin F., O’Shea P. D., Davies I. W., J. Org. Chem., 2006, 71(25), 9548-9551
[11]	Biftu T., Feng D. D., Liang G. B., Kuo H., Qian X., Naylor E. M., Colandrea V. J., Candelore M. R., Cascieri M. A., Colwell L. F., Forrest M. J., Hom G. J., Maclntyre D. E., Stearns R. A., Strader C. D., Wyvratt M. J., Fisher M. H., Weber A.E., Bioorg. Med. Chem. Lett., 2000, 10(13), 1431-1434
[12]	Velázquez C., Rao P. N. P., McDonald R., Knaus E. E., Bioorg. Med. Chem., 2005, 13(8), 2749-2757
[13]	Era M., Adachi C., Tsutsui T., Saito S., Chem. Phys. Lett., 1991, 178(56), 488-490
[14]	Bentiss F., Traisnel M., Lagrenee M., Corros. Sci., 2000, 42(1), 127-146
[15]	Yang X. H., Wen Q., Zhao T. T., Sun J., Li X., Xing M., Lu X., Zhu H. L., Bioorg. Med. Chem.,2012, 20, 1181-1187
[16]	Liu T. T., Wan Y. C., Liu R. S., Ma L., Li M. Y., Fang H., Chem. Res. Chinese Universities,2016, 32(5), 768-774
[17]	Wang C. X., Song H. L., Liu W. Q., Xu C. L., Chem. Res. Chinese Universities,2016, 32(4), 615-620
[18]	Gür M., Muglu H., Çavus M. S., Güder A., Sayiner H. S., Kandemirli F., J. Mole. Struct.,2017, 1134, 40-50
[19]	Tang J. Y., Liu J. B., Wu F. Y., Bioorg. Chem., 2016, 69, 29-36
[20]	Solankee A., Kapadia K., C’iric A., Sokovic M., Doytchinova I., Geronikaki A., Eur. J. Med. Chem., 2010, 45(2), 510-518
[21]	Saczewski F., Bułakowska A., Bednarski P.,Grunert R., Eur. J. Med. Chem., 2006, 41(2), 219-225
[22]	Zacharie B., Abbott S. D., Bienvenu J. F., Cameron A. D., Cloutier J., Duceppe J. S., Ezzitouni A., Fortin D., Houde K., Lauzon C., Moreau N., Perron V., Wilb N., Asselin M., Doueet A., Fafard M. E., Gaudreau D., Grouix B., Sarra B. F., St A. N., Gagnon L., Penney C. L., J. Med. Chem., 2010, 53(3), 1138-1145
[23]	Singla P., Luxami V., Puai K., Eur. J. Med. Chem., 2016, 117, 59-69
[24]	Mishra A., Kaushik N. K., Verma A. K., Gupta R., Eur. J. Med. Chem.,2008, 43(10), 2189-2196
[25]	Guo Y., Synthesis and Activity of Novel Bicyclic Heterocycle Modified Amide Sulfide/Mannich Base Derivatives, Liaoning Normal University, Dalian, 2016
	(国阳. 新型双杂环修饰酰胺硫醚/曼尼希碱衍生物的合成及活性研究, 大连: 辽宁师范大学, 2016)
[26]	Rakse M., Karthikeyan C., Deora G. S., Moorthy N. S. H. N., Rathore V., Rawat A. K., SrivastavaA. K., Trivedi P., Eur. J. Med. Chem., 2013, 70, 469-476
[27]	Zhang J., Ji F. J., Gu Y., Zhang X. Y., Qiao S. X., Pharmacol. Rep., 2014, 66(3), 515-519
[28]	Hu M., Design and Synthesis of Potential PTP1B/SHP2/Cdc25B Carbohydrate Small Molecule Inhibitor Based on CuAAC, East China University of Science and Technology, Shanghai, 2011
	(胡敏. 基于CuAAC的潜在PTP1B/SHP2/Cdc25B糖类小分子抑制剂的设计与合成, 上海: 华东理工大学, 2011)
[29]	Cao X. R., Yang X. Y., Wang P. X., Liang Y., Liu F., Tuerhong M., Jin D. Q., Xu J., Lee D. H., Ohizumi Y., Guo Y. Q., Bioorg. Chem.,2017, 75, 139-148
[30]	Matsuno T., Kato M., Tsuchida Y., Takahashi M., Yaguchi S., Terada S., Chem. Pharm. Bull., 1997, 45(2), 291-296
[31]	Zhu C.A., Synthesis and Properties of Novel Y-Type 1,2,4-Triazole/Triazolothiadiazole-1,3,5-Triazine Derivatives, Liaoning Normal University, Dalian, 2015
	(朱长安. 新Y型1,2,4-三唑/三唑并噻二唑-1,3,5-三嗪衍生物的合成及其性能研究, 大连: 辽宁师范大学, 2015)
[32]	Zhang C. L., Li C. Y., Yang M., Zhu C. A., Sun X. N., Li Y. Z., Chinese J. Appl. Chem.,2017, 34(4), 385-393
	(张成路, 李传银, 杨蒙, 朱长安, 孙晓娜, 李益政. 应用化学, 2017, 34(4), 385-393)
[33]	Li D. J., Long D. Q., Fu H. Q., Chem. Inform., 2006, 181(3), 519-526
[34]	Karaman N., Sıcak Y., Tok T. T., Öztürk M., Karaküçük I. A., Dikmen M., Koçyiği K. B., Oruç-EmreE. E., Eur. J. Med. Chem., 2016, 124, 270-283
[35]	Ábrahámi R. A., Kiss L., Barrio P., Fülöp F., Tetrahedron,2016, 72(47), 7526-7535