Chapter V

Synthesis, Characterization and Biological

Evaluation of Pyrazolyl Carbothioamide
Derivatives
 Chapter- V

5.1. Introduction

Carbothioamide derivatives displayed various pharmacological activity including

antimicrobial, neuroprotective, antitubercular, anti-inflammatory and anticancer

activity. Compound 80 showed significant antiproliferative activity against MCF-7

with IC50 of 0.08 µM [1].

N
N
O
H2N S

80

Motivated by our previous findings of anticancer chalcones [2], we report herein the

synthesis and in vitro cytotoxicity evaluation of some pyrazole tethered

carbothioamide derivatives.

5.2. Results and Discussion

5.2.1. Chemistry

Base catalyzed reaction of thiosemicarbazide with chalcones afforded carbothioamide

derivatives in poor yield [3, 4]. Better yield for the preparation was achieved when

cyclization of chalcones with thiosemicarbazide were carried out in acidic medium

[5]. Treatment of chalcones 4a-i with thiosemicarbazide in presence of concentrate

H2SO4 in acetic acid afforded pyrazolylcarbothioamide derivatives 9a-i. The

formation of pyrazoline ring involves a Michael addition of thiosemicarbazide on

chalcone followed by cyclization and dehydration. Synthesis of target compounds is

outlined in Scheme 5.1.

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R N
O R

(i)
N
N N N
N N N
S NH2

4a-i 9a-i
a: R= H d: R= 3-Br g: R= 4-NO2
b: R= 4-F e: R= 4-Br h: R= 4-CH3
c: R= 4-Cl f: R= 3-NO2 i: R= 4-OCH3

Scheme 5.1: General procedure for the synthesis of pyrazolyl thiocarbomide

derivatives (i) Thiosemicarbazide, H2SO4, AcOH, reflux.

All the synthesized compounds were characterized by detailed 1H and 13C NMR

(Figure 5.1a-i), IR, mass spectral data and elemental analysis. IR spectrum of the

compound 9a showed strong absorption bands at 3424 and 3242 cm-1 due to presence

of primary amine group. The characteristic signal in 1H NMR spectra of 9a was due to

presence of three pyrazoline protons which displayed an interesting AMX pattern of

doublet of doublet. Methine proton of pyrazolines displayed signal at 6.06 ppm as a

doublet of doublet with coupling constants of 11.6 and 4.4 Hz. The methylene proton

displayed doublet of doublet at 3.96 ppm with coupling constants of nearly 18.0 Hz

and 11.6 Hz. The peak for another methylene proton has not been observed clearly

because of merging of this particular proton with DMSO-d6 solvent peak at 3.29-3.34

ppm. 13C NMR spectrum of compound 9a displayed a signal at 176.01 ppm assigned

to thiocarbamoyl carbon (C=S). Carbon of methine showed a chemical shift at 55.68

ppm. Carbon of methylene displayed a chemical shift at 42.04 ppm. Furthermore, the

mass spectrum and elemental analysis supported the structure of compound 9a.

Spectroscopic data supported the structure of other carbothioamide derivatives.

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5.2.2. Biology

In vitro cytotoxicity of all the synthesized compounds 9a-i was determined by the

MTT [(3-(4, 5-dimethyl-2-thiazolyl)2,5-diphenyl-2H-tetrazolium bromide)] assay

against a panel of three different human cancer cell lines namely; MCF-7 (human

breast), NCI-H460 (human lung), HeLa (human cervix) and HEK-293T (Human

embryonic kidney cells) normal cell line [6]. IC50 values were calculated from the

dose effect curve (Figure 5.2) and expressed as concentration (µM) of drug activity.

Etoposide was taken as reference compound and the results are summarized in terms

of IC50 values (Table 5.1). From the IC50 values, it is clear that most of these

compounds showed moderate to good cytotoxicity against lung, cervix and breast

cancer cell lines and weak toxicity towards normal human embryonic kidney cells.

Analogues 9d, 9e and 9g showed significant cytotoxicity as compared to standard

drug Etoposide.

Table 5.1: In vitro cytotoxicity of compounds 9a-i and etoposide against a panel of

three human cancer cell lines and a normal cell line in terms of IC50 value in µM.

Compounds MCF-7 NCI-H460 Hela Hek-293T

N
N N 64.60±4.25 68.42±2.10 59.68±1.05 112.04±1.10
N
H2N S

9a
F

N 44.89±1.27 20.91±0.97 54.06±2.39 159.70±3.01

N N
N
H2N S

9b
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Cl

N
N N 87.60±2.98 38.93±1.94 57.13±3.70 115.03±2.74
N
H2N S

9c

Br
N

N
N N 13.51±1.01 8.75±0.69 8.30±0.67 94.44±2.95
N
H2N S

9d
Br

N 24.81±1.05 17.28±2.88 19.67±3.32 119.23±3.47

N N
N
H2N S

9e
O2N
N

N
N N 23.39±0.68 16.54±0.68 48.90±1.49 91.10±2.47
N
H2N S

9f
O2N

N 23.04±1.52 9.74±0.35 8.50±0.98 109.22±3.16

N N
N
H2N S

9g

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H3C

N 76.10±2.39 61.06±3.06 46.22±1.27 176.42±3.71

N N
N
H2N S

9h
H3CO

N 21.85±1.69 17.13±1.18 25.92±0.51 182.92±4.78

N N
N
H2N S

9i

O O

O
O
O O 32.50±0.67 16.01±2.02 11.43±0.35 12.32±0.99
O

O OH
O O
Etoposide

Subsequently, structure activity relationship (SAR) studies were performed to

determine the effect of substituents on cytotoxic activities of the synthesized

compounds. Heterocyclic analogue 9d with meta substituted Br group in the benezene

ring showed most significant cytotoxic activity. Substituents Br and NO2 present in

the benzene ring of compounds 9e and 9g showed good effect, which is clearly seen

in Table 5.1. Compounds with meta substituted electron-withdrawing group, the

cytotoxic activity order for the cancerous cell lines is Br > NO2. The cytotoxic

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strength is NO2 > Br > F > Cl for the compounds with para substituted electron-

withdrawing in cancerous cell lines. Finally, compounds with electron-donating

substituent present in para position of the benzene ring, cytotoxic strength order for

the cancerous cell line is OCH3 > CH3.

5.3. Experimental Section

5.3.1. General procedure for the synthesis of compounds 9a-i

A mixture of (E)-3-(3-(aryl)-1-phenyl-1H-pyrazol-4-yl)-1-(pyridin-3-yl)prop-2-en-1-

ones 4a-i (2 mmol) and thiosemicarbazide (3 mmol) in acetic acid (10 ml) was added

0.5 ml of Conc. HCl and the reaction mixture was refluxed for 12 h. On completion,

the reaction mixture was allowed to attain room temperature, poured into crushed ice

and neutralized by dilute NaOH. The precipitate obtained was filtered off, washed

with water and ethanol, and dried, affording compounds 9a-i. The compounds 9a-i

were crystallized in DMF:MeOH.

5-(1,3-diphenyl-1H-pyrazol-4-yl)-3-(pyridin-3-yl)-4,5-dihydropyrazole-1-

carbothioamide (9a)

White solid; Yield: 86%; m.p. 258-260 °C; IR (neat, νmax cm-1): 3424, 3242, 3089,

1599, 1510, 1339; 1H NMR (400 MHz, DMSO-d6): δ 9.04 (d, J = 1.6 Hz, 1H), 8.60-

8.62 (m, 1H), 8.15-8.23 (m, 3H), 7.96 (s, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.78 (d, J =

7.2 Hz, 2H), 7.38-7.49 (m, 6H ), 7.27 (t, J = 7.2 Hz, 1H), 6.06 (dd, J = 11.6 Hz, 4.4

Hz, 1H), 3.96 (dd, J = 18.0 Hz, 11.6 Hz, 1H), 13C NMR (100 MHz, DMSO-d6):

176.24, 152.79, 150.95, 149.37, 148.36, 139.32, 134.35, 129.49, 128.59, 127.96,

127.21, 126.20, 125.99, 124.21, 123.76, 118.17, 55.73, 42.04; Anal. Calcd. for

C24H20N6S: C, 67.90; H, 4.75; N, 19.80. Found: C, 67.86; H, 4.68; N, 19.78; MS

(ESI) [M + H]+ Calcd for C24H20N6S: 425.2. Found: 425.5 [M + H]+.

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5-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(pyridin-3-yl)-4,5-

dihydropyrazole-1-carbothioamide (9b)

White solid; Yield: 89%; m.p. 270-172 °C; IR (neat, νmax cm-1): 3263, 3138, 1601,

1508, 1337; 1H NMR (400 MHz, DMSO-d6): 9.03 (d, J = 1.6 Hz, 1H), 8.61-8.62 (m,

1H), 8.17-8.22 (m, 3H), 7.95 (s, 1H), 7.25-7.86 (m, 10H), 6.02 (dd, J = 11.6 Hz, 4.0

Hz, 1H), 3.94 (dd, J = 17.6 Hz, 11.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6):

176.11, 152.62, 151.03, 148.55, 148.24, 139.33, 134.19, 130.07, 129.51, 127.17,

126.26, 126.16, 124.16, 123.77, 118.10, 115.38, 55.96, 42.00; Anal. Calcd. for

C24H19FN6S: C, 65.14; H, 4.33; N, 18.99. Found: C, 65.98.05; H, 4.36; N, 18.86; MS

(ESI) [M + H]+ Calcd. for C24H19FN6S: 443.1. Found: 443.1 [M + H]+.

5-(3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(pyridin-3-yl)-4,5-

dihydropyrazole-1-carbothioamide (9c)

White solid; Yield: 85 %; m.p. 280-282 °C; IR (neat, νmax cm-1): 3265, 3129, 1601,

1505, 1330; 1H NMR (400 MHz, DMSO-d6): 9.04 (s, 1H), 8.62 (d, J = 3.6 Hz, 1H),

7.93-8.23 (m, 3H), 7.85 (d, J = 8 Hz, 2H), 7.79 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.4

Hz, 2H), 7.43-7.48 (m, 3H ), 7.27 (t, J = 7.2 Hz, 1H), 6.03 (dd, J = 11.2 Hz, 3.6 Hz,

1H), 3.95 (dd, J = 18.0 Hz, 12.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): 175.74,

152.94, 150.77, 148.26, 139.30, 134.15, 132.70, 132.11, 129.83, 129.56, 128.64,

127.09, 126.30, 124.19, 123.59, 118.05, 55.48, 41.92; Anal. Calcd. for C24H19ClN6S:

C, 62.81; H, 4.17; N, 18.31. Found: C, 62.79; H, 4.24; N, 18.28; MS (ESI) [M + H]+

Calcd. for C24H19ClN6S: 459.1. Found: 459.0 [M + H]+.

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5-(3-(3-bromophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(pyridin-3-yl)-4,5-

dihydropyrazole-1-carbothioamide (9d)

White solid; Yield: 88 %; m.p.: 242-244 °C; IR (neat, νmax cm-1): 3423, 3235, 3084,

1598, 1508, 1341; 1H NMR (400 MHz, DMSO-d6): 9.04 (d, J = 1.6 Hz, 1H), 8.61-

8.62 (m, 1H), 7.95-8.26 (m, 5H), 7.86 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 7.6 Hz, 1H),

7.60 (d, J = 8.0 Hz, 1H), 7.42-7.49 (m, 4H), 7.28 (t, J = 7.2 Hz, 1H), 6.03 (dd, J =

11.6 Hz, 4.0 Hz, 1H), 3.96 (dd, J = 17.6 Hz, 11.6 Hz, 1H); 13C NMR (100 MHz,

DMSO-d6): 176.22, 152.77, 151.00, 148.34, 147.81, 139.14, 135.46, 135.00, 130.77,

130.40, 129.52, 127.20, 127.05, 126.45, 124.55, 123.61, 121.96, 118.24, 55.42, 42.05;

Anal. Calcd. for C24H19BrN6S: C, 57.26; H, 3.80; N, 16.69. Found: C, 57.34; H, 3.74;

N, 16.75; MS (ESI) [M + H]+ Calcd. for C24H19BrN6S: 503.1. Found: 505.1 ([M +

H]++2).

5-(3-(4-bromophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(pyridin-3-yl)-4,5-

dihydropyrazole-1-carbothioamide (9e)

White solid; Yield: 84 %; m.p. 282-284 °C; IR (neat, νmax cm-1): 3267, 3131, 1601,

1505, 1330; 1H NMR (400 MHz, DMSO-d6): 9.04 (s, 1H), 8.61-8.62 (d, J = 4.4 Hz,

1H), 8.15-8.23 (m, 3H), 7.97 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.4 Hz,

2H), 7.65 (d, J = 8.4 Hz, 2H), 7.43-7.49 (m, 3H ), 7.27 (t, J = 7.6 Hz, 1H), 6.03 (dd, J

= 10.8 Hz, 3.2 Hz, 1H), 3.95 (dd, J = 18.0 Hz, 11.6 Hz, 1H); 13C NMR (100 MHz,

DMSO-d6): 176.45, 152.66, 150.91, 148.23, 139.22, 134.22, 132.32, 131.48, 129.96,

129.48, 127.16, 126.26, 124.23, 123.63, 121.35, 118.10, 55.49, 41.96; Anal. Calcd.

for C24H19BrN6S: C, 57.26; H, 3.80; N, 16.69. Found: C, 57.18; H, 3.74; N, 16.73;

MS (ESI) [M + H]+ Calcd. for C24H19BrN6S: 503.1. Found: 505.2 ([M + H]++2).

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5-(3-(3-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(pyridin-3-yl)-4,5-

dihydropyrazole-1-carbothioamide (9f)

Pale yellow solid; Yield: 76 %; m.p.: 272-274 °C; IR (neat, νmax cm-1): 3261, 3131,

1600, 1505, 1344; 1H NMR (400 MHz, DMSO-d6): 9.02 (s, 1H), 8.61-8.62 (m, 2H),

8.36 (s, 1H), 8.17-8.26 (m, 4H), 7.96 (s, 1H), 7.89 (d, J = 7.6 Hz, 2H), 7.77 (t, J = 7.6

Hz, 1H), 7.45-7.49 (m, 3H), 7.30 (t, J = 7.2 Hz, 1H), 6.07 (dd, J = 11.6 Hz, 4.0 Hz,

1H), 3.96 (dd, J = 17.6 Hz, 11.2 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): 176.05,

152.61, 150.87, 148.16, 147.96, 147.34, 139.13, 134.63, 134.37, 134.19, 130.18,

129.54, 127.07, 126.81, 126.56, 124.61, 123.66, 122.72, 122.38, 118.31, 55.33, 41.91;

Anal. Calcd. for C24H19N7O2S: C, 61.39; H, 4.08; N, 20.88. Found: C, 61.34; H, 4.15;

N, 20.91; MS (ESI) [M + H]+ Calcd. for C24H19N7O2S: 470.1. Found: 470.1 [M + H]+.

5-(3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(pyridin-3-yl)-4,5-

dihydropyrazole-1-carbothioamide (9g)

Greenish yellow solid; Yield: 79 %; m.p.: 292-294 °C; IR (neat, νmax cm-1): 3263,

3138, 1600, 1510, 1335; 1H NMR (400 MHz, DMSO-d6): 9.04 (d, J = 1.6 Hz, 1H),

8.61-8.63 (m, 1H), 8.32 (d, J = 8.0 Hz, 3H), 8.19-8.24 (m, 2H), 8.08 (d, J = 8.8 Hz,

2H), 7.99 (s, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.45-7.49 (m, 3H ), 7.31 (t, J = 7.2 Hz,

1H), 6.11 (dd, J = 11.2 Hz, 4.0 Hz, 1H), 4.00 (dd, J = 18.4 Hz, 12.0 Hz, 1H); 13C

NMR (100 MHz, DMSO-d6): 176.01, 152.61, 150.89, 148.22, 146.78, 139.61, 139.11,

134.23, 129.48, 128.91, 127.14, 126.90, 126.68, 125.11, 123.87, 123.65, 118.31,

55.50, 41.88; Anal. Calcd. for C24H19N7O2S: C, 61.39; H, 4.08; N, 20.88. Found: C,

61.47; H, 4.11; N, 20.76; MS (ESI) [M + H]+ Calcd. for C24H19N7O2S: 470.1. Found:

470.4 [M + H]+.

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5-(1-phenyl-3-p-tolyl-1H-pyrazol-4-yl)-3-(pyridin-3-yl)-4,5-dihydropyrazole-1-

carbothioamide (9h)

White solid; Yield: 86 %; m.p. 266-268 °C; IR (neat, νmax, cm-1): 3263, 3119, 1600,

1506, 1330; 1H NMR (400 MHz, DMSO-d6): 9.03 (d, J = 1.2 Hz, 1H), 8.60-8.62 (m,

1H), 8.21 (d, J = 8.0 Hz, 1H), 8.16 (s, 2H), 7.96 (s, 1H), 7.83 (d, J = 8.0 Hz, 2H),

7.65 (d, J = 8.0 Hz, 2H), 7.24-7.48 (m, 6H), 6.05 (dd, J = 11.6 Hz, 4.0 Hz, 1H), 3.94

(dd, J = 18.0 Hz, 11.6 Hz, 1H); 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3): 176.33,

152.66, 150.85, 149.23, 148.15, 139.31, 137.37, 134.27, 130.14, 129.48, 129.15,

127.86, 127.22, 126.13, 125.91, 124.04, 123.62, 118.03, 55.58, 41.98, 20.89; Anal.

Calcd. for C25H22N6S: C, 68.47; H, 5.06; N, 19.16. Found: C, 68.42; H, 5.08; N,

19.24; MS (ESI) [M + H]+ Calcd. for C25H22N6S: 439.2. Found: 439.2 [M + H]+.

5-(3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(pyridin-3-yl)-4,5-

dihydropyrazole-1-carbothioamide (9i)

White solid; Yield: 81 %; m.p. 264-266 °C; IR (neat, νmax cm-1): 3425, 3239, 3045,

1596, 1506, 1335; 1H NMR (400 MHz, DMSO-d6): 9.03 (d, J = 1.6 Hz, 1H), 8.60-

8.61 (m, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.15 (s, 2H), 7.96 (s, 1H), 7.83 (d, J = 8.0 Hz,

2H), 7.70 (d, J = 8.8 Hz, 2H), 7.41-7.48 (m, 3H ), 7.25 (t, J = 7.6 Hz, 1H), 7.01 (d, J =

8.8 Hz, 2H), 6.03 (dd, J = 11.6 Hz, 4.4 Hz, 1H), 3.93 (dd, J = 18.0 Hz, 12.0 Hz, 1H),

3.78 (s, 3H); 13C NMR (100 MHz, DMSO-d6): 176.11, 159.08, 152.63, 150.82,

148.19, 139.35, 134.24, 129.46, 129.24, 127.18, 126.02, 125.86, 123.81, 123.63,

117.97, 113.98, 55.69, 55.14, 41.98; Anal. Calcd. for C25H22N6OS: C, 66.06; H, 4.88;

N, 18.49. Found: C, 66.13; H, 4.94; N, 18.46; MS (ESI) [M + H]+ Calcd. for

C25H22N6OS: 455.2. Found: 455.2 [M + H]+.

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5.3.2. Evaluation of in vitro cytotoxicity of compounds 9a-i

The NCI-H460 (human lung), HeLa (human cervix) and MCF-7 (human breast) and a

normal HEK-293T (Human embryonic kidney) cells were grown as per the standard

protocol (37°C, 5% CO2 in water jacketed incubator shell) using DMEM media with

10% FBS (Foetal bovine serum) and seeded onto a single 96 well plate (Falcon Plate,

Corning costar, USA) and allowed to adhere for 18 h for the assays. The plate was

treated with increasing concentration of the compounds to be tested at 1, 10, 25, 50,

100, 150 and 200 µM of the synthesized compounds dissolved in DMSO. These

concentrations were added in triplicates to the 96 well tissue culture plates. After 24 h

of treatment, the MTT assay was performed to check cell viability. For the MTT

assay, the media was removed from all the wells and 10 µl of MTT reagent (Sigma

Aldrich, USA) per well from a working stock of 5 mg/ml was added and the plates

were incubated (37°C and 5% CO2) for 2-3 h. Then the solution from the plates was

removed and the crystals were solubilised using equal volume (100µl) of dimethyl

sulfoxide (DMSO) in each well. The DMSO converts the phenol red in the tissue

culture medium to a yellow colour that does not interfere with the MTT formazan

measurement. The DMSO dissolves the formazan crystals to give a homogeneous

blue solution. The absorbance was measured at a test wavelength of 570 nm using an

ELISA plate reader (Tecan, Switzerland). The percentage inhibition was calculated by

the formulae (1) Each assay was repeated for three times. IC50 values were calculated

and expressed as concentration (µM) of drug.

5.4. Conclusions

As a part of our current research work focused on the development of some anticancer

heterocyclic compounds, the synthesis and in vitro cytotoxicity evaluation of the

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pyrazolyl thiocarboamide derivatives 9a-i have been performed. All the synthesized

compounds displayed moderate to good effects against the tested cancer cell line and

weak toxicity towards normal cell line. The cytotoxicity evaluation data revealed that

among all the synthesized compounds studied, analogues 9d, 9e and 9g showed

significant cytotoxicity as compared to standard drug etoposide. The compound 9g

exhibited superior activity with IC50 values of 9.74±0.35 µM against NCI-H460

cancer cell line.

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N
N N
N
H2N S

N
N N
N
H2N S

Figure 5.1a 1H NMR and 13C NMR spectra of compound 9a in DMSO-d6

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N
N N
N
H2N S

N
N N
N
H2N S

Figure 5.1b 1H NMR and 13C NMR spectra of compound 9b in DMSO-d6

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Cl

N
N N
N
H2N S

Cl

N
N N
N
H2N S

Figure 5.1c 1H NMR and 13C NMR spectra of compound 9c in DMSO-d6

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Br
N

N
N N
N
H2N S

Br
N

N
N N
N
H2N S

Figure 5.1d 1H NMR and 13C NMR spectra of compound 9d in DMSO-d6

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Br

N
N N
N
H2N S

Br

N
N N
N
H2N S

Figure 5.1e 1H NMR and 13C NMR spectra of compound 9e in DMSO-d6

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O2N
N

N
N N
N
H2N S

O2N
N

N
N N
N
H2N S

Figure 5.1f 1H NMR and 13C NMR spectra of compound 9f in DMSO-d6

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O2N

N
N N
N
H2N S

O2N

N
N N
N
H2N S

Figure 5.1g 1H NMR and 13C NMR spectra of compound 9g in DMSO-d6

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H3C

N
N N
N
H2N S

H3C

N
N N
N
H2N S

Figure 5.1h 1H NMR and 13C NMR spectra of compound 9h in DMSO-d6

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H3CO

N
N N
N
H2 N S

H3CO

N
N N
N
H2 N S

Figure 5.1i 1H NMR and 13C NMR spectra of compound 9i in DMSO-d6

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Figure 5.2: Dose effect curves of the synthesized compounds 9a-i and etoposide

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5.5. References

1. P. C. Lu, H. Q. Li, J. Suan, Y. Zhou, H. L. Zhu, Bioorg. Med. Chem., 2010, 18,

4606-4614.

2. R. Alam, M. A. Alam, A. K. Panda, Rahisuddin, Heterocycl. Commun., 2016,

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Department of Chemistry, Jamia Millia Islamia, New Delhi

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