Synthesis and Cytotoxicity of Thieno[2,3-b]Pyridine Derivatives Toward Sensitive and Multidrug-Resistant Leukemia Cells

(1)

Supporting Information

Synthesis and Cytotoxicity of Thieno[2,3-b]Pyridine Derivatives Toward Sensitive and Multidrug-Resistant Leukemia Cells

Salah A. Al-Trawneh

^1,*

, Amer H. Tarawneh

²

, Anastassiya V. Gadetskaya

³

, Ean-Jeong Seo

⁴

, Mohammad R. Al-Ta’ani

¹

, Samir A. Al-Taweel

¹

, Mustafa M. El-Abadelah

⁵

1

Chemistry Department, Faculty of Science, Mu'tah University, Karak 61710, Jordan

2

Chemistry and Chemical Technology Department, Faculty of Science, Tafila Technical University, Tafila 61610, Jordan

3

School of Chemistry and Chemical Technology, Al-Farabi Kazakh National University, Almaty 050040, Kazakhstan

4

Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany

5

Chemistry Department, Faculty of Science, The University of Jordan, Amman 11942, Jordan

* Corresponding author: E-mail: laratr@mutah.edu.jo Phone: +96232372380/4561

List of contents

1. The structural representative of skeleton for 3a-e compounds S2 2.

¹

H and

¹³

C NMR spectra of compound 3a S3-S9 3. DEPT-135 NMR spectrum of compound 3a S10 4. 2D NMR (HMBC, HMQC, COSY) spectra of compound 3a S11-S18 5.

¹

H and

¹³

C NMR spectra of compound 3b S19-S26 6. DEPT-135 NMR spectrum of compound 3b S27 7. 2D NMR (HMBC, HMQC, COSY) spectra of compound 3b S28-S38 8.

¹

H and

¹³

C NMR spectra of compound 3c S39-S45 9. DEPT-135 NMR spectra of compound 3c S46-S48 10. 2D NMR (HMBC, HMQC, COSY) spectra of compound 3c S49-S57 11.

¹

H and

¹³

C NMR spectra of compound 3d S58-S65 12. DEPT-90 and DEPT-135 NMR spectra of compound 3d S66-S67 13. 2D NMR (HMBC, HMQC, COSY) spectra of compound 3d S68-S70 14.

¹

H and

¹³

C NMR spectra of compound 3e S71-S75 15. DEPT-135 NMR spectrum of compound 3e S76 16. 2D NMR (HMBC, HMQC, COSY) spectra of compound 3e S77-S89

17. HRMS spectra of compound 3a S90-S91

18. HRMS spectra of compound 3b S92-S93

19. HRMS spectra of compound 3c S94-S95

20. HRMS spectra of compound 3d S96-S98

21. HRMS spectra of compound 3e S99-S100

(2)

(3)

18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 ppm

−0.02870.78231.19341.22621.25571.34111.35521.36941.52171.9754

3.39044.32454.33864.35284.3669

7.01967.17487.19107.23177.24867.26357.38047.39597.41208.32988.3479

H NMR

MP

(4)

7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 8.0 8.1 8.2 8.3 8.4 8.5 8.6

8.7 ppm

7.0196

7.17487.19107.23177.24867.2635

7.38047.39597.4120

8.32988.3479

H NMR

(5)

7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 8.0 8.1 8.2 8.3 8.4 8.5 8.6

8.7 ppm

7.0196

7.17487.19107.23177.24867.2635

7.38047.39597.4120

8.32988.3479

H NMR

MP

(6)

5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

−0.0287

0.7823

1.19341.22621.25571.34111.35521.36941.5217

1.9754

3.3904

4.32454.33864.35284.3669

H NMR

(7)

5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

−0.0287

0.7823

1.19341.22621.25571.34111.35521.36941.5217

1.9754

3.3904

4.32454.33864.35284.3669

H NMR

MP

(8)

0.8 0.9

1.0 1.1

1.2 1.3

1.4 1.5

1.6 1.7

1.8 1.9

2.0 2.1 ppm

0.7823

1.19341.22621.2557

1.34111.35521.3694

1.5217

1.9754

H NMR

(9)

220 200 180 160 140 120 100 80 60 40 20 ppm

7.826514.3483

36.5923

61.2750

76.766677.020177.2747

118.4140

126.2610130.3681

141.4408145.7028

157.1669

c13 MP

(10)

220 200 180 160 140 120 100 80 60 40 20 ppm

7.574914.0927

36.3342

61.030861.0693

118.1525

126.0050130.1132

145.4466

dept135

(11)

13 12 11 10 9 8 7 6 5 4 3 2 1

ppm ppm

180 160 140 120 100 80 60 40 20

hmbc MP

(12)

6.5 7.0

7.5 8.0

8.5 ppm 9.0 ppm

40

60

80

100

120

140

160

180 hmbc

(13)

5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5

ppm ppm

180

160

140

120

100

80

60

40

20 hmbc MP

(14)

13 12 11 10 9 8 7 6 5 4 3 2 1 0

ppm ppm

180

160

140

120

100

80

60

40

20 hmqc

(15)

−0.5

4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0

ppm ppm

70

60

50

40

30

20

10

0 hmqc MP

(16)

6.2 6.4

6.6 6.8

7.0 7.2

7.4 7.6

7.8 8.0

8.2 8.4

8.6 ppm 8.8 ppm

70

80

90

100

110

120

130

140

150

160

170 hmqc

(17)

13 12 11 10 9 8 7 6 5 4 3 2 1 0

ppm ppm

12

10

8

6

4

2

0 cosy MP

(18)

−0.5

4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0

ppm ppm

8

7

6

5

4

3

2

1

0 cosy

(19)

18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 ppm

1.10041.11431.12861.14321.18981.21531.22961.24371.94152.31542.45442.58893.26103.62993.63673.64343.97633.99044.16314.17724.19144.20557.38257.39917.44347.45847.47347.74697.76187.77667.89427.90848.319510.2592

H NMR

MA

(20)

0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3 2.4 2.5

2.6 ppm

0.8072

1.04161.05371.10041.11431.12861.14321.18981.21531.22961.2437

1.9415

2.3154

2.4544

2.5889

H NMR

(21)

3.1 3.2

3.3 3.4

3.5 3.6

3.7 3.8

3.9 4.0

4.1 4.2

4.3 4.4 ppm

3.2610

3.62993.63673.6434

3.97633.9904

4.16314.17724.19144.2055

H NMR

MA

(22)

6.8 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 8.0 8.1 8.2 8.3 8.4

8.5 ppm

7.38257.39917.44347.45847.4734

7.74697.76187.7766

7.89427.9084

8.3195

H NMR

(23)

9.6 9.8

10.0 10.2

10.4 10.6

10.8 11.0

11.2 11.4

11.6 11.8 ppm

10.2592

H NMR

MA

(24)

220 200 180 160 140 120 100 80 60 40 20 ppm

7.683314.654037.156039.509639.676439.843340.010240.098840.177140.267240.344140.434240.511040.601960.8287

116.0572118.6572119.9122126.4802126.9034130.4909131.4355137.0605143.7213146.1476149.3293158.2434164.3930167.5581

188.9255

c13

(25)

110 115

120 125

130 135

140 145

150 155

160 165 ppm

116.0572

118.6572119.9122

126.4802126.9034

130.4909131.4355

137.0605

143.7213

146.1476

149.3293

158.2434

164.3930

167.5581

c13 MA

(26)

70 65 60 55 50 45 40 35 30 25 20 15 10 5 0 ppm

7.6833

14.6540

37.156039.509639.676439.843340.010240.098840.177140.267240.344140.434240.511040.6019

60.8287

c13

(27)

200 180 160 140 120 100 80 60 40 20 ppm

7.6836

14.6554

37.158839.930840.097940.264240.430240.5991

60.8312

118.6575

126.9063130.4949

137.0641

146.1509

188.9089188.9432

dept135

MA

(28)

12 11 10 9 8 7 6 5 4 3 2 1

ppm ppm

200

180

160

140

120

100

80

60

40

20 hmbc

(29)

1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3 2.4 2.5

ppm 2.6 ppm

20

40

60

80

100

120

140

160

180 hmbc MA

(30)

7.4 7.5

7.6 7.7

7.8 7.9

8.0 8.1

8.2 8.3

8.4 8.5

ppm 8.6 ppm

40 60 80

100 120 140

160 180

200 hmbc

(31)

8.15 8.20

8.25 8.30

8.35 8.40

8.45 8.50

ppm 8.55 ppm

40 60 80

100 120 140

160 180

200 hmbc MA

(32)

12 11 10 9 8 7 6 5 4 3 2 1

ppm ppm

180

160

140

120

100

80

60

40

20

0 hmqc

(33)

4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5

ppm ppm

70

60

50

40

30

20

10

0 hmqc MA

(34)

7.3 7.4

7.5 7.6

7.7 7.8

7.9 8.0

8.1 8.2

8.3 ppm 8.4 ppm

120

125

130

135

140

145 hmqc

(35)

12 11 10 9 8 7 6 5 4 3 2 1

ppm ppm

12

10

8

6

4

2 cosy MA

(36)

5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5

ppm ppm

1

2

3

4

5

6

7 cosy

(37)

7.4 7.5

7.6 7.7

7.8 7.9

8.0 8.1

8.2 8.3

ppm 8.4 ppm

7.2

7.4

7.6

7.8

8.0

8.2

8.4

8.6

8.8 cosy MA

(38)

1.5 2.0

2.5 3.0

3.5 4.0

4.5 ppm 5.0 ppm

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5 cosy

(39)

18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 ppm

0.08880.96891.29841.31131.34651.39861.44071.45461.46882.13112.37082.42642.50143.57133.65663.76954.21574.39524.40944.42364.43767.27527.29207.35827.42437.53337.54927.83608.29948.42888.4635

10.4807

H NMR

MB

(40)

7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7

8.8 ppm

7.27527.2920

7.3582

7.4243

7.53337.5492

7.8360

8.2994

8.42888.4635

H NMR

(41)

3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8

4.9 ppm

3.5713

3.6566

3.7695

4.2157

4.39524.40944.42364.4376

H NMR

MB

(42)

2.6 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 ppm

0.0888

0.9689

1.29841.31131.34651.39861.44071.45461.4688

2.1311

2.37082.42642.5014

H NMR

(43)

220 200 180 160 140 120 100 80 60 40 20 ppm

7.80517.857714.342220.6898

29.6829

36.7011

61.2999

76.776377.030477.2846

116.0356118.2356121.2145126.2452129.5974131.4551136.6493136.8374141.9861145.8835146.1781149.5847156.6301164.4936167.6325

187.6608

c13 MB

(44)

120 130

140 150

160 170

180 190

200 ppm

116.0356118.2356

121.2145

126.2452

129.5974131.4551

136.6493136.8374

141.9861

145.8835146.1781

149.5847

156.6301

164.4936

167.6325

187.6608

c13

(45)

100 90 80 70 60 50 40 30 20 10 ppm

7.80517.8577

14.3422

20.6898

29.6829

36.7011

61.2999

76.776377.030477.2846

c13 MB

(46)

220 200 180 160 140 120 100 80 60 40 20 ppm

7.48767.838714.323920.6710

36.6901

61.2783

118.2235

129.5794

136.8217

145.8688

154.7522

162.2482

187.6439

dept135

(47)

15 20

25 30

35 40

45 50

55 60

65 70 ppm

7.48767.8387

14.3239

20.6710

36.6901

61.2783

dept135

MB

(48)

110 120

130 140

150 160

170 180

190 ppm

118.2235

129.5794

136.8217

145.8688

154.7522

162.2482

187.6439

dept135

(49)

15 14 13 12 11 10 9 8 7 6 5 4 3 2 1

ppm ppm

180

160

140

120

100

80

60

40

20 hmbc MB

(50)

1.5 2.0

2.5 3.0

3.5 4.0

4.5 ppm 5.0 ppm

180

160

140

120

100

80

60

40

20 hmbc

(51)

7.0 7.5

8.0 8.5

9.0 9.5

10.0 10.5

ppm 11.0 ppm

180

160

140

120

100

80

60

40

20 hmbc MB

(52)

15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0

ppm ppm

180

160

140

120

100

80

60

40

20 hmqc

(53)

5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5

ppm ppm

70

60

50

40

30

20

10

0 hmqc MB

(54)

15 14 13 12 11 10 9 8 7 6 5 4 3 2 1

ppm ppm

14

12

10

8

6

4

2

0 cosy

(55)

10 9 8 7 6 5 4 3 2 1

ppm ppm

11

10

9

8

7

6

5

4

3

2

1

0 cosy MB

(56)

2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5

ppm 8.0 ppm

8

7

6

5

4

3

2

1 cosy

(57)

7.2 7.4

7.6 7.8

8.0 8.2

8.4 8.6

ppm 8.8 ppm

7.2

7.4

7.6

7.8

8.0

8.2

8.4

8.6

8.8 cosy MB

(58)

18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 ppm

0.83630.84960.86181.11491.17591.22671.24021.26391.27961.32391.33771.35141.36541.46281.47681.72822.01162.13792.32692.34193.43103.47723.50504.06834.08264.09694.11114.29414.30854.32714.34154.35576.94156.98206.99867.01667.18897.20607.23117.26327.27707.29247.38797.40547.43697.45517.50587.55577.56957.63007.88168.19478.21038.33538.36359.821710.291810.3582

H NMR

(59)

0.6 0.8

1.0 1.2

1.4 1.6

1.8 2.0

2.2 2.4

2.6 ppm

0.83630.84960.8618

1.11491.17591.22671.24021.26391.27961.32391.33771.35141.36541.46281.4768

1.7282

2.0116

2.1379

2.32692.3419

H NMR

MD

(60)

3.4 3.5 3.6 3.7 3.8 3.9 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9

5.0 ppm

3.3351

3.43103.47723.5050

3.6178

3.68263.6970

3.8794

4.00234.06834.08264.09694.1111

4.29414.30854.32714.34154.3557

H NMR

(61)

6.6 6.8

7.0 7.2

7.4 7.6

7.8 8.0

8.2 8.4

8.6 8.8 ppm

6.2444

6.82176.92396.94156.98206.99867.01667.05047.18897.20607.23117.26327.27707.29247.38797.40547.43697.45517.50587.55577.56957.6300

7.8816

8.14308.19478.2103

8.33538.3635

H NMR

MD

(62)

9.8 10.0

10.2 10.4

10.6 10.8

11.0 11.2 ppm

9.8217

9.8746

10.1692

10.2918

10.3582

10.540910.5666

10.8794

H NMR

(63)

7.837.92

14.35

29.70

36.7336.79

MD

c 13

(64)

116.12

119.21

120.91121.04

122.60

127.16

128.99

132.11132.59

135.89

142.61

146.12146.22147.34147.76

157.06

164.21164.37

167.26167.67

c 13

(65)

7.837.92

14.35

29.70

36.7336.79

61.41

76.7377.0477.36

116.12119.21120.91121.04122.60127.16128.99132.11132.59135.89142.61146.12146.22147.34147.76

157.06

164.21164.37167.26167.67

186.22

MD

c 13

(66)

7.837.92

14.35

29.70

36.7336.79

61.41

77.25

119.22

128.99

135.90

146.13146.22

186.22

dept 90

(67)

7.837.92

14.35

29.70

36.7336.79

61.41

77.25

119.21

128.99

135.89

146.12146.22

186.22

MD

dept135

(68)

F2 [ppm]

10 8 6 4 2

F1 [ppm] 200 150 100 50

hmbc

(69)

F2 [ppm]

10 8 6 4 2

F1 [ppm] 140 120 100 80 60 40 20

MD

hmqc

(70)

ppm

11

10

9

8

7

6

5

4

3

2

1

0 cosy

(71)

18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 ppm

1.32861.34261.45391.66852.09442.30242.53942.55392.74332.80953.11373.23463.24493.40433.41203.59524.01924.27134.28534.29954.31356.98146.99737.01407.14007.19917.23117.25807.27127.28677.30687.35597.36237.36787.48797.49447.50107.50607.66618.07568.2602

H NMR

MT1

(72)

6.8 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 8.0 8.1 8.2 8.3 8.4 8.5 8.6

8.7 ppm

6.98146.99737.0140

7.14007.19917.23117.25807.27127.28677.30687.35597.36237.36787.48797.49447.50107.5060

7.6661

8.0756

8.2602

H NMR

(73)

2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 ppm

0.0375

0.6813

0.80950.83230.84530.85820.88690.9678

1.07431.14681.16001.17091.20411.21191.22111.31451.32861.34261.4539

1.6685

2.0944

H NMR

MT1

(74)

3.0 3.2

3.4 3.6

3.8 4.0

4.2 4.4

4.6 4.8

5.0 5.2 ppm

3.1137

3.23463.2449

3.40433.4120

3.5952

4.0192

4.27134.28534.29954.3135

H NMR

(75)

220 200 180 160 140 120 100 80 60 40 20 ppm

7.781014.3481

29.6930

36.5027

61.3383

76.781777.035277.2900

129.5590129.8981130.0131132.2414132.5048144.3657145.6676

c13 MT1

(76)

220 200 180 160 140 120 100 80 60 40 20 ppm

7.5243

14.0910

29.4384

36.2478

61.0819

129.3057129.6428132.2498

145.4167

dept135

(77)

12 11 10 9 8 7 6 5 4 3 2 1

ppm ppm

180

160

140

120

100

80

60

40

20 hmbc MT1

(78)

0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9

ppm 2.0 ppm

180

160

140

120

100

80

60

40

20 hmbc

(79)

3.4 3.6 3.8 4.0

4.2 4.4 4.6

4.8 5.0 5.2

5.4 5.6 5.8

ppm 6.0 ppm

180

160

140

120

100

80

60

40

20 hmbc MT1

(80)

6.4 6.6

6.8 7.0

7.2 7.4

7.6 7.8

8.0 8.2

8.4 ppm 8.6 ppm

40

60

80

100

120

140

160

180 hmbc

(81)

12 11 10 9 8 7 6 5 4 3 2 1

ppm ppm

180

160

140

120

100

80

60

40

20 hmqc MT1

(82)

3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4

ppm ppm

60

55

50

45

40

35

30

25

20

15

10

5 hmqc

(83)

3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8

ppm 4.9 ppm

25

30

35

40

45

50

55

60

65

70

75 hmqc MT1

(84)

7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 8.9

ppm 9.0 ppm

105

110

115

120

125

130

135

140

145

150

155 hmqc

(85)

7.1 7.2

7.3 7.4

7.5 7.6

7.7 7.8

ppm 7.9 ppm

120

125

130

135

140

145 hmqc MT1

(86)

12 11 10 9 8 7 6 5 4 3 2 1

ppm ppm

12

11

10

9

8

7

6

5

4

3

2

1 cosy

(87)

12 11 10 9 8 7 6 5 4 3 2 1 0

ppm ppm

12

10

8

6

4

2

0 cosy MT1

(88)

5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5

ppm ppm

7

6

5

4

3

2

1

0 cosy

(89)

6.5 7.0

7.5 8.0

8.5 9.0

9.5 ppm 10.0 ppm

1

2

3

4

5

6

7

8

9

10

11 cosy MT1

(90)

(91)

(92)

(93)

(94)

(95)

(96)

(97)

(98)

(99)

(100)