American Chemical Science Journal

15(3): 1-13, 2016, Article no.ACSJ.26694

ISSN: 2249-0205

SCIENCEDOMAIN international
www.sciencedomain.org

Synthesis, Spectral Properties and Anti-tumor

Evaluations of Some Novel 2-substituted-
1,3-Thiazole Derivatives
Asmaa S. Salman1*
1
Department of Chemistry, Faculty of Science, Al-Azhar University, Girls’ Branch, Nasr City, Cairo,
Egypt.

Author’s contribution

The sole author designed, analyzed and interpreted and prepared the manuscript.

Article Information

DOI: 10.9734/ACSJ/2016/26694
Editor(s):
(1) Anonymous.
Reviewers:
(1) Nitulescu George Mihai, University of Medicine and Pharmacy, Romania.
(2) F. M. A. El-Taweel, University of Damietta, Egypt.
(3) Nadeem Siddiqui, Hamdard University, New Delhi, India.
(4) Awatef Mohamed Elmaghraby, South Valley University, Egypt.
Complete Peer review History: http://sciencedomain.org/review-history/15351

th
Received 29 April 2016
Original Research Article Accepted 29th June 2016
th
Published 9 July 2016

ABSTRACT
4
Reaction of N -(4-chlorophenyl)-1,3-thiazole-2,4-diamine 1 with ammonium thiocyanate, phenyl
isothiocyanate, acetic anhydride, phenacyl bromide, 2-chloro -N- (4-chlorophenyl) acetamide and
acetic anhydride / cyanoacetic acid afforded the corresponding N-[ 4-(4-chlorophenyl)amino-1,3-
thiazol-2-yl]thiourea 2, N-[4-(4-chlorophenyl)amino-1,3-thiazol-2-yl]-N'-phenylthiourea 3, N-acetyl-
N-[4-(4-chlorophenyl)amino-1,3-thiazol-2-yl]acetamide 7,2-(1,3-thiazol-2-ylamino)-1
phenylethanone derivative 8, 2-(1,3-thiazol-2-ylamino)- N-(4-chlorophenyl)acetamide derivative 9
and N-(1,3-thiazol -2-yl)-2-cyanoacetamide derivative 11. Reaction 1 with phenyl isothiocyanate in
basic DMF yielded the intermediate potassium salt 14, then treatment of intermediate 14 with α-
halocarbonyl compounds such as ethyl chloroacetate and/ or 2-chloro-N-(4-chlorophenyl)
acetamide afforded ethyl {N'-(1,3-thiazol-2-yl)-N-phenyl-carbamimidoyl)thio}acetate15 and 2-[(4-
chlorophenyl)amino]-2-oxoethyl N'-(1,3-thiazol-2-yl)-N-phenyl-imidothiocarbamate16 respectively.
Reaction 1 with 1H-pyrazole-4-carboxaldehyde 17 or 1H-indole-3-carboxaldehyde 18 afforded N2-
[(1H-pyrazol-4-yl) methylene]-1,3-thiazole-2,4-diamine19 and N2-[(1H-indol-3-yl)methylene]-1,3-
_____________________________________________________________________________________________________

*Corresponding author: E-mail: [email protected];

 Salman; ACSJ, 15(3): 1-13, 2016; Article no.ACSJ.26694

thiazol-2,4-diamine 20 respectively. Structures of the newly synthesized compounds have been

confirmed by elemental analysis and spectra data. Some of the newly synthesized compounds
were screened in vitro for their anti-tumor activities against human cancer cell line MCF-7.

Keywords: 1,3-thiazole-2,4-diamine; thiourea; carbamimidothioate; pyrazole; anti-tumor activities.

1. INTRODUCTION IR, NMR and Mass spectrometry techniques.

Some synthesized compounds were also
The main objectives of medicinal chemistry are screened for their anti-tumor evaluation against
the design and synthesis, compounds having the breast cancer cell line (MCF-7).
value as human therapeutic agents. In recent
years, cancer is the biggest health issue in the 2. MATERIALS AND METHODS
world. Cancer disease which the control of cell
growth and nuclear proliferation lost in one or 2.1 General Conditions
more cells and end leading either to the tumor
such as breast, prostate cancer, and therapeutic
Melting points were measured on a Gallenkamp
options include surgery, chemotherapy, and
apparatus and are uncorrected. IR spectra were
radiotherapy. The major goal of cancer treatment
measured using KBr discs on Pye Unicam SP-
is to attain maximum therapeutic damage of
1000 spectrophotometer. The 1H-NMR and 13C
tumor cells in a collection with the minimum
NMR spectra were determined in DMSO-d6 at
concentration of the drug. This can be carried out
400 MHz on a Varian Mercury VX 300 NMR
by selective antitumor preparation, the cytostatic
spectrometer using TMS as an internal standard.
effects of which would be restricted within tumor
Mass spectra were measured on a GCMS-
tissue [1]. The find of new chemical structures
QP1000 EX spectrometer at 70 Ev. Elemental
that can act as more effective anticancer agents
analyses were carried out at the Microanalytical
is still the main challenge hard to medicinal
center of Cairo University and the main chemical
chemists. The important advances achieved over
warfare laboratories. N4-(4-chlorophenyl)-1,3-
recent decades in the research and development
thiazole-2,4-diamine 1 was prepared according
of multiple anticancer drugs, existing anticancer
to previously reported procedure [22].
drugs still have main limitations such as drug
resistance, lack of selectivity and unwanted side 2.2 Synthesis
effects. Thus, there is a strong request for the
find and development of effective new cancer 2.2.1 N-[4-(4-Chlorophenyl)amino-1,3-thiazol-
treatment devoid side effects [2-4]. 2-yl]thiourea 2
In recent years development antitumor chemical
drugs which including the heterocyclic ring which To N4-(4-chlorophenyl)-1,3-thiazole-2,4-diamine
has interesting biological activities [5,6].Thiazole 1 (0.0 1 mol), concentrated hydrochloric acid
is five-membered heterocyclic ring have many (0.01mol) was added and the solution was
biologically active Also, 2-amino-thiazoles offer a warmed. A saturated solution of ammonium
wide range of biological potencies including thiocyanate in water (5 gm in 3 mL) was added
antimicrobial [7], antiviral [8], anti-inflammatory slowly in above solution. The mixture was reflux
activities [9], anti-Alzheimer [10], anti-tubercular for 45 min. The reaction mixture was poured in
activity [11], anti-convulsant activity [12], anti- cold water. The solid obtained was filtered off
HIV-1 [13]. Antitumor activity of thiazole was and recrystallized from ethanol to give 2 as
easily based via being incorporated into a variety yellow powder. Yield: 70 %. m.p.: 140-142˚C. IR
of therapeutically active agents like bleomycin (KBr): υ/cm-1: 3340, 3269, 3250, 3200 (NH2,2
[14], epothilones [15] and dasatinib [16,17].From NH), 3066, 2931 (CH),1240 (C=S ),1608 (C=N).
1
literature survey, it was found that aminothiazole H-NMR (DMSO-d6) δ ppm: 4.27 (s, 2H, NH2
proved to have a broad spectrum of activity exchanged by D2O),7.03 (s,1H , C5-H thiazole) ,
against most of the tested tumor cell lines 7.30-7.57 (m, 4H, Ar-H), 10.12 (s,1H, NH
[18-21]. exchanged by D2O) ,10.50 (s,1H, NH exchanged
+
by D2O) . MS m/z (%): 285 (M , 21.3), 269 (4.6),
On the way of continuing our work on the 113 (10.5), 111(28), 60 (6.1), 57 (100). Anal.
synthesis of new heterocyclic compounds with Calcd. for C10H9ClN4S2 (284.79) : C, 42.17 ;H ,
expected biological activities, we report herein 3.19 ; Cl, 12.45 ; N ,19.67 ; S , 22.52.Found: C,
the synthesis of some new 1,3-thiazole-2,4- 42.07; H , 3.09 ; Cl , 12.25 ; N , 19.47 ; S,
diamine derivatives and their characterization by 22.32.

2
 Salman; ACSJ, 15(3): 1-13, 2016; Article no.ACSJ.26694

2.2.2 N-[ 4-(4- Chlorophenyl)amino-1,3-thiazol thiourea derivative 3 (0.01 mol) in ethanol (50
- 2-yl] -N'-phenylthiourea 3 mL) and sodium hydroxide (0.01 mol) dissolved
in minimum quantity of water was refluxed 6h.
4
A mixture of N -(4- chlorophenyl)-1,3-thiazole-2,4 The reaction mixture was allowed to cooled and
-diamine 1 (0.01 mol) and phenyl isothiocyanate then acidified with dilute hydrochloric acid. The
( 0.01 mol) in 1,4-dioxane (40 mL) was refluxed solid obtained was collected by filtration, washed
in the presence of few drops of triethylamine with water, and recrystallized from ethanol to
(TEA) for 8h.The solid product separated from give 6 as a yellow granule. Yield: 75%. m.p.:
-1
the hot mixture was filtered off, washed with 260-261°C. IR (KBr): υ/cm : 3217, 3166, 3116
water and recrystallized from pot. ether to give 3 (NH2, NH), 3035, 2985, 2936 (CH), 1254 (C=S).
1
as yellow powder .Yield : 55%. m.p.: 60 - 62˚C. H-NMR (DMSO-d6) δ ppm 4.48 (d, 1H, C4-H
-1
IR (KBr): υ/cm : 3217, 3186, 3116 ( 3 NH), 3005, pyrimidine), 6.60 (d,1H,C5-H pyrimidine), 5.02 (s,
2995 , 2935 ( CH ), 1250 (C= S ) , 1597 (C=N). 2H, NH2, exchanged by D2O-), 7.11–7.81 (m, 18
1
H-NMR (DMSO - d6) δ ppm : 7.11 ( s,1H, C5-H H, Ar-H and C5-H thiazole), 8.91 (s, 1H, NH,
thiazole), 7.29 - 7.61 (m, 9H, Ar-H ),10.02 (s ,1H, exchanged by D2O). Anal. Calcd. for C31 H23
NH exchanged by D2O), 11.03 (s,1H, NH Cl2 N5 S2 ( 600.58) : C ,61.99 ; H , 3.86 ; Cl
exchanged by D2O),11.54 (s,1H NH exchanged ,11.81 ; N, 11.66; S, 10.68. Found: C, 61.69; H,
by D2O) . MS m/z (%): 361 ( M+,1.1), 325 ( 3.8), 3.66; Cl, 11.61; N, 11.46; S, 10.48.
264 ( 9.3) , 230 ( 26.5) , 224 ( 7.2 ), 113 ( 26.4 ) ,
55 ( 100 ) . Anal. Calcd. for C16 H13 Cl N4 S2 2.2.5 N-Acetyl-N-[4-(4-chlorophenyl)amino-
(360.88): C, 53.25 ; H, 3.63 ; Cl, 9.82 ; N, 15.52 ; 1,3 - thiazol-2-yl] acetamide 7
S , 17.77. Found : C , 53.05 ; H , 3.43 ; Cl, 9.62 ;
4
N, 15.32 ; S ,17.57. A mixture of N -(4-chlorophenyl)-1,3-thiazole-2,4-
diamine 1 (0.01 mol) and acetic anhydride (5 mL)
2.2.3 3-[4-(4- Chlorophenyl )amino-1,3-thiazol was heated under reflux for 5h.Then, the reaction
-2-yl]-6-(4-methoxyphenyl)-4-oxo-1- mixture was cooled and poured into ice. The
phenyl-2-thioxo-1,2,3,4-tetrahydro- solid product was filtered off, washed with water,
pyrimidine-5-carbonitrile 4 dried and recrystallized from ethanol / DMF (2 :1)
to give compound 7 as a brown powder. Yield:
-1
A mixture of thiourea derivative 3 (0.01 mol), 70%. m.p.: 162-164°C. IR (KBr): υ/ cm : 3136
ethyl cyanoacetate (0.01 mol) and anisaldehyde (NH), 3055, 2981, 2877 (CH), 1670 (C=O) .1H-
(0.01 mol) in ethanol 30 mL was added few NMR (DMSO- d6) δ ppm: 2.70. (s, 3H, CH3),
drops of TEA. The reaction mixture was refluxed 2.86 (s , 3H , CH3) , 6.83 (s, 1H , C5- H thiazole),
for 6h. The solid product separated from the hot 7.48-7.61 (m, 4H, Ar-H), 8.91 (s, 1H, NH
13
mixture was filtered off, washed with water and exchanged by D2O). CNMR (DMSO-d6) δ ppm:
recrystallized from ethanol to give 4 as a yellow 21.09, 24.09 (2CH3), 130.34 , 131.49 , 134.24,
plate. Yield: 80%. m.p.: 309 - 310°. IR (KBr): υ / 138.83, 149.21,157.82 (C-N) ,168.42, 170.44 ( 2
cm-1: 3275 (NH), 3027.2904, 2839 (CH), 2214 C=O), 179 (C-S). Anal. Calcd. for C13 H12 Cl N3
1 O2 S (309.77): C, 50.40; H , 3.90 ; Cl ,11.44 ; N,
(CN), 1670 (C=O), 1246 (C=S). H-NMR (DMSO-
d6) δ ppm: 3.25 (s, 3H, OCH3), 7.04 (s, 1H , C5-H 13.56; S, 10.35. Found: C, 50.20; H, 3.60; Cl,
thiazole), 7.14 – 8.04 (m, 13H, Ar-H ),8.27 (s, 1H, 11.24; N, 13.36; S, 10.25.
13
NH exchanged by D2O). C NMR (DMSO-d6 ) δ
ppm:62.52 (OCH3),115.26,115.43,116.63 (CN), 2.2.6 2-[4-(4-Chlorophenyl)amino-1,3-thiazol-
124,41, 129.84, 132.13, 133.97, 154.91 (C-N), 2-ylamino]-1-phenylethanone 8
162.81 (C-O), 164 (C = O),180 (C-S), 186 (C=S).
Anal. Calcd. for C27H18ClN5O2S2 (544.04): C, To a mixture of N4-(4-chlorophenyl)-1,3-thiazole-
59.61 ; H , 3.33 ; Cl , 6.52 ; N, 12.87; S ,11.79. 2,4-diamine 1 (0.01 mol ) and phenacyl bromide
Found: C, 59.41; H, 3.13; Cl, 6.32; N, 12.67; S, (0.01 mol ) in ethanol (30 mL) was added few
11.69. drops of TEA. The reaction mixture was refluxed
for 6h.The solid product separated after cool was
2.2.4 6-(4-Aminophenyl)-1-[4-(4-chlorophenyl) filtered off, washed with water and recrystallized
amino-1,3-thiazol-2-yl]-4-(4-chloro- from ethanol to give 8 as brown plates. Yield:
phenyl)-3-phenyl-3,4-dihydropyrimidine- 70%. m.p.: 100-102°C. IR (KBr): υ/cm-1:3186,
2(1H)-thione 6 3147 (2 NH), 3059, 2924, 2850 (CH), 1685 (C =
O). 1H-NMR (DMSO-d6) δ ppm: 4.21 (s, 2H,
A mixture of 1-(4-aminophenyl)-3-(4-chloro- CH2), 6.84 (s, 1H, C5- H thiazole), 7.15-7.99
phenyl) prop-2-en-1-one 5 (0.01 mol) and (m,9H,Ar-H),8.07(s,1H, NH exchanged by D2O),

3
 Salman; ACSJ, 15(3): 1-13, 2016; Article no.ACSJ.26694

11.08 (s, 1H, NH exchanged by D2O) . MS m/z 2.2.9 N-[4-(4-Chlorophenyl)amino-1,3-thiazol-

+
(%): 344 (M , 15), 316 (12.5), 270 (28.9), 232 2-yl]-2-cyanoacetamide 11
(3.8), 113 (4.3), 105 (100), 77(41.6). Anal. Calcd.
for C17 H14 Cl N3 O S (343.83): C, 59.38; H, 4.10; A solution of cyanoacetic acid (0.05 mo l) in
Cl, 10.31; N, 12.22; S, 9.33.Found : C, 59.18; H, acetic anhydride (15 mL) was heated under
4.00 ; Cl, 10.11; N, 12.02; S, 9.23. reflux over water bath for 5 minutes , then
compounds 1 ( 0.05 mol) was added and the
2.2.7 2-(4-(4-Chlorophenyl)amino-1,3-thiazol- reaction mixture was heated for further 1h. at
2-ylamino)-N-(4-chlorophenyl)acetamide 60-70°C. The reaction mixture was cooled, and
9 the precipitate was filtered off and recrystallized
from ethanol to give 11 as a brown powder.
4
To a mixture of N -(4-chlorophenyl)-1,3-thiazole- Yield: 60%. m.p.: 141-143°C. IR (KBr): υ/cm-1:
2,4-diamine 1 (0.01 mol) and 2-chloro-N-(4- 3136, 3100 ( 2 NH ) , 3006, 2931 ( CH ), 2200
1
chlorophenyl) acetamide (0.01 mol) in ethanol (CN), 1670 (C=O ). H-NMR (DMSO-d6 ) δ ppm:
(30 mL) was added few drops of TEA. The 4.02 (s, 2H, CH2) , 6.83 (s,1H , C5- H thiazole ),
reaction mixture was refluxed for 6h.The solid 7.48 -7.61( m, 4 H, Ar-H), 10.22 (s, 1H , NH
product separated after cool was filtered off, exchanged by D2O),11.01(s ,1H , NH exchanged
+ +
washed with water and recrystallized from by D2O ).293 ( M , 90.7),294 (M +1, 19.8), 258
ethanol to give 9 as a white plat .Yield: 80 %. (4.9), 232 (4.9), 218 (11.5) , 190 (7.5),181 (16.5),
m.p.:145-147℃. IR (KBr): υ/cm-1: 3271 , 3197 , 153 (100), 113 (43.4),77(27.2). Anal. Calcd. for
3128 (3 NH) , 3082 , 2974 , 2931, 2893 ( CH), C12H9 Cl N4 OS ( 292.74): C,49.23 ; H , 3.10; Cl ,
1 12.11 ; N, 19.14; S ,10.95. Found: C,49.03 ; H
1678 ( C=O) . H-NMR (DMSO-d6 ) δ ppm: 4.22 (
s, 2H , CH2) , 6.85 ( s, 1H, C5 -H thiazole), 7.30 - 3.00; Cl , 12.01 ; N, 19.04 ; S,10.65.
7.64 (m, 8 H, Ar-H), 8.27 (s, 1H, NH exchanged
2.2.10 General procedure for the Synthesis of
by D2O) ,10.36 (s, 1H, NH exchanged by D2O) ,
13 12 and 13
10.93 (s, 1H, NH, exchanged by D2O). C NMR
(DMSO-d6) δ ppm: 33.18 (CH2) ,121.08, 123.21, Equimolecular mixture of N-[4-(4-chlorophenyl)-
127.50, 128.87, 129.20 ,130.24, 134.45, 137.97, amino -1,3- thiazol – 2 -yl] -2- cyanoacetamide11
138.01, 140.72, 147,02, 156.28 (C-N), 164.36 (0.01 mol ) and the selected aldehydes such as
(C=O), 184.01 ( C-S ). Anal. Calcd. For C17H14 benzaldehyde and salicylaldehyde (0.01 mol) in
Cl2N4OS(393.29) : C, 51.92; H, 3.59; Cl ,18.03; 1,4-dioxane (20 mL) containing piperidine (0.5
N,14.25; S, 8.15. Found: C, 51.62; H, 3.39; Cl, mL) was heated under reflux for 6h. The reaction
18.00; N, 14.05; S, 8.00. mixture was left to cool then poured onto ice /
water containing few drops of hydrochloric acid
2.2.8 4-(4-Chlorophenyl)amino-1-[4-(4-chloro- and the formed solid product was collected by
phenyl)amino-1,3-thiazol-2-yl]-1H- filtration and recrystallized from the appropriate
imidazole-2(3H)-thione 10 solvent.
A mixture of acetamide derivative 9 (0.01mol) 2.2.10.1 N-[4-(4-Chlorophenyl)amino-1,3-thiazol-
and ammonium thiocyanate (0.015 mol) in glacial 2-yl]-2-cyano-3-phenylacrylamide 12
acetic acid (20 mL) was refluxed for 6h. After
cooling, the separated solid was filtered off and Yield: 60%. m.p.:170 - 172°C. IR (KBr): υ/cm-1:
recrystallized from ethanol to give 10 as brown 3170, 3124 (2 NH), 3047 , 2924 , 2877 (CH) ,
plates. Yield: 60 %.m.p.:170-172°C. IR (KBr): υ/ 2222(CN), 1693 (C=O ).1H-NMR (DMSO-d6 ) δ
cm-1: 3302, 3263, 3190 (3 NH), 3066, 2927(CH), ppm : 6.94 (s ,1H ,C 5-H thiazole ), 7.29 – 7.71
1 (m, 10 H, Ar-H and C=CH), 11.24 (s, 1H, NH,
1261(C=S). H-NMR (DMSO-d6) δ ppm: 7.29 ( s ,
1H, C5- H thiazole), 7.35 (s,1H , C4-H imidazole), exchanged by D2O),11.78 (s,1H, NH exchanged
7.40 -7.71 (m, 8 H, Ar-H), 8.61 (s, 1H, NH by D2O).Anal.Calcd. for C19H13 Cl N4 OS(380.85):
exchanged by D2O),10.02(s,1H, NH , exchanged C, 59.92 ; H , 3.44 ; Cl, 9.31; N, 14.71; S, 8.42.
by D2O),11.21(s ,1H , NH exchanged by D2O). Found: C, 59.62; H , 3.24; Cl, 9.01; N ,14.51; S,
13 8.22.
C NMR (DMSO-d6) δ ppm: 120.12, 120.89,
126.90, 127.14, 127.56, 129.09, 129.19, 129.22,
2.2.10.2 N-[4-(4-Chlorophenyl)amino-1,3-thiazol-
137.59, 138.71 , 155.12 (C-N) , 170.70 (C-S),186
2-yl]-2-imino-2H-chromene-3-carbox-
(C=S).Anal. Calcd. for C18 H13 Cl2 N5 S2 (434.36 ):
amide 13
C , 49.77 ; H, 3.02 ; Cl, 16.32 ; N ,16.12 ; S,
14.76. Found: C, 49.57; H, 3.00; Cl, 16.12; N, -1
Yield: 75 %. m.p.: 308 - 310°C. IR (KBr): υ/cm :
16.02; S, 14.46. 3209, 3190, 3170 (3NH) , 3051,2962 (CH) ,1689

4
 Salman; ACSJ, 15(3): 1-13, 2016; Article no.ACSJ.26694

(C=O).1H-NMR (DMSO-d6) δ ppm: 6.83 (s,1H, exchanged by D2O),10.36(s ,1H , NH exchanged

C5-H thiazole),7.02 -7.59 (m, 9 H, Ar-H and C4-H, by D2O ),10.39 (s ,1H , NH exchanged by D2O).
13
coumarin),10.05 (s ,1H, NH exchanged by D2O), C NMR (DMSO-d6) δ ppm:33.18 (CH2),121.14,
11.01( s,1H, NH exchanged by D2O), 12.27 (s, 123.22,124.02, 127.38 , 127.50, 128.70 ,128.87,
1H, NH exchanged by D2O).13C NMR (DMSO-d6) 128.91, 129.08, 129.48, 129.75, 130.24, 130.81,
δ ppm: 116.61 , 120.06 ,120.69 , 120.52, 123.61, 137.97, 138.01, 138.33, 138.88, 140.72, 147.02,
125.35 ,128.41,129.28 ,129.53 , 129.83, 132.11 , 156.27(C - N) , 164.83 (C=O), 184 , 187 (2 C-S).
157.34 (C-N) , 157.57 (C-O), 162.74 (C=O),180 Anal.Calcd. for C24H19Cl2N5OS2 (528.47) : C ,
(C-S). Anal. Calcd. for C19H13 Cl N4O2S ( 396.85): 54.54 ; H , 3.62 ; Cl ,13.42 ; N, 13.25 ; S ,12.13.
C , 57.50 ; H , 3.30 ; Cl , 8.93; N , 14.12; S, 8.08. Found: C, 54.24; H, 3.42; Cl, 13.22; N, 13.05; S,
Found : C , 57.30 ; H , 3.20 ; Cl , 8.63 ; N, 14.02 12.03.
; S , 8.00 .
2.2.12 General Procedure for the Synthesis of
2.2.11 General procedure for the synthesis of 19 and 20
compounds 15 and 16
A mixture of compound 1 (0.01 mol) and 1,3-
To a cold suspension of powdered potassium diphenyl-1H- pyrazole-4-carboxaldehyde 17 or 2-
hydroxide (0.01 mol) in DMF (20 mL) was added (4-bromophenyl)-1H-indole-3-carboxaldehyde 18
compound 1(0.01 mol) and phenyl isothiocyanate (0.01 mol) was refluxed in ethanol (30 mL) for
(0.01 mol). The reaction mixture was stirred at 15h.The reaction mixture was cooled and poured
room temperature for 6h, and then treated with into crushed ice and filtered. The product
ethyl chloroacetate and /or 2-chloro -N-(4-chloro- obtained was recrystallization from ethanol/ DMF
phenyl)acetamide (0.01 mol) and the stirring was (1:3) to obtain schiff bases 19 and 20.
continued at room temperature for further 10h.
The reaction mixture was poured into 50 mL of 2.2.12.1 N4-(4-Chlorophenyl)-N2-(1,3-diphenyl-
cold water. The result solid products were 1H-pyrazol-4-yl)methylene)-1,3-thiazole
collected by filtration and recrystallized from a -2,4-diamine 19
mixture of ethanol / DMF (1:1) to give
compounds 15 and 16. -1
Yield: 75 %. m.p.: 302 - 304 ℃. IR (KBr): υ/cm :
2.2.11.1 Ethyl {N'- [4-(4-chlorophenyl)amino-1,3- 3124 ( NH ) , 3005 , 2993 , 2812 ( CH ).1H- NMR
thiazol-2-yl]-N-phenyl-carbamimidoyl) (DMSO- d6 ) δ ppm: 7.04 (s , 1H , C5- H thiazole),
thio} acetate 15 7.36 -7.98 ( m , 15 H, Ar-H and C5- H pyrazole ),
8.85 (s, 1H, N = CH), 12.15 (s, 1H, NH
13
Yield: 60%. m.p.:166-168℃.IR(KBr): υ/cm :
-1 exchanged by D2O). C NMR (DMSO-d6) δ ppm :
3283, 3201 (2 NH), 1670 (C=O ). H-NMR
1 119.70, 119.93 ,122.59 , 128.19 ,129.01 ,129.14
(DMSO-d6 ) δ ppm: 1.02 ( t , 3 H, CH2CH3) ,4.06 ,129.38, 129.64, 129.89, 130, 130.17,135.27,
(q , 2H, CH2 CH3),4.25 (s, 2H, CH2),6.81(s, 1H, 152.01 (C-N ), 185.09 (C-S). Anal. Calcd. for
C5-H thiazole) , 6.98 - 7.70 (m , 9H, Ar-H ), 11.23 C25H18ClN5S (455.96) : C, 65.85 ; H, 3.98 ; Cl,
(s, 1H, NH exchanged by D2O) ,11.74 (s, 1H, 7.78 ; N, 15.36; S, 7.03. Found: C, 65.65; H,
13
NH exchanged by D2O). C NMR (DMSO-d6) δ 3.68; Cl, 7.58; N, 15.16; S, 7.00.
ppm: 19 (CH3) , 33.29(CH2),110, 120.67 ,121.09
,122.20 ,123.51,124.07 ,124.63, 125.10 ,128.91 , 2.2.12.2 N2-(2-(4-Bromophenyl)-1H-indol-3-yl)
4
129.43, 129.69 ,135.73 ,148.61,156.35 (C-N) methylene)-N -(4-chlorophenyl)-1,3-
,172.08 (C= O), 182 (C - S) . Anal. Calcd. for C20 thiazole - 2,4-diamine 20
H19 Cl N4 O2 S2 (446.97): C, 53.74 ; H, 4.28 ; Cl,
7.93 ; N, 12.53 ; S, 14.35. Found: C, 53.54; H, Yield: 75%. m.p.: 280-282°C. IR (KBr): υ/cm-1:
4.08; Cl, 7.63; N, 12.33; S, 14.15. 3208 , 3167 (2 NH) , 3020 , 2974, 2904 , 2866
1
(CH). H-NMR ( DMSO - d6 ) δ ppm : 7.11 - 7.30
2.2.11.2 2-[(4-Chlorophenyl)amino]-2-oxoethyl ( m, 9 H , Ar-H and C5- H thiazole) , 7.50 (d, 1H,
N'-(4-(4-chlorophenyl)amino- 1,3-thiazol indole ), 7.70 - 7.80 (m , 2H, indole ), 8.18 (d ,1H,
-2-yl)-N-phenyl–imidothiocarbamate 16 indole ), 9.94 (s,1H ,N= CH) ,11.01 (s, 1H, NH,
exchanged by D2O), 12.42 (s, 1H, NH
13
Yield: 60%. m.p.: 125-126°C. IR (KBr): υ/cm-1: exchanged by D2O). C NMR (DMSO-d6) δ ppm :
3275 , 3190 , 3116 ( 3 N H) , 3055 , 2978 , 2923 , 112.52 ,114.09 ,121.51 ,122.51, 122.99, 123.95;
2839 ( CH ), 1670 (C=O) .1H-NMR (DMSO-d6 ) δ 124.33, 126.20 ,129.43, 132.24, 132.38, 136.37,
ppm:4.52 (s,2H, CH2), 6.84 (s,1H, C5- H thiazole) 147.90 (C-N), 185.48 (C-S). Anal. Calcd. for
,6.59-7.64 (m,13H, Ar-H) ,10.24 (s, 1H, NH C24H16BrClN4S (507.83) : C, 56.76 ; H, 3.18 ; Br,

5
 Salman; ACSJ, 15(3): 1-13, 2016; Article no.ACSJ.26694

15.73 ; Cl, 6.98 ; N, 11.03; S, 6.31.Found : C, (4-chlorophenyl)-1,3-thiazole-2,4-diamine 1 was

56.56 ; H ,3.08 ; Br ,15.63 ; Cl , 6.68 ; N , 11.00 ; prepared by heating a mixture of equimolar
S , 6.01. amounts of the 2- chloro –N -(4 - chlorophenyl)-
acetamide and thiourea according to the reported
2.3 In vitro Antitumor Screening method [22]. Reaction N4-(4-chlorophenyl)-1,3-
thiazole-2,4-diamine 1 with ammonium thiocyan-
In vitro anti-tumor activity of newly synthesized ate in the presence of HCl [24] afforded N-[1,3-
compounds 3, 4, 6, 7, 9, 10, 11, 13, 15, 16 and thiazol-2-yl]thiourea derivative e 2 (Scheme 1).
19 were evaluated against human breast cancer The structure of 2 was supported on the basis of
cell line (MCF-7. Breast cancer cell line (MCF-7) elemental analyses and spectral data. The 1H-
was obtained from the American type Cultures NMR spectrum (DMSO-d6) of compound 2
Collection (ATCC, Rockyille, MD) were kindly showed a D2O- exchangeable single signals at δ
provided by Regional Center for Mycology and 4.27 ppm, δ 10.12 ppm and δ 10.50 ppm
Biotechnology, Al-Azhar University, Cairo, Egypt. assigned to NH2 and two NH protons
Cell viability was determined by the crystal violet respectively. Its mass spectrum showed a
assay [23]. molecular ion peak at m/z 485 corresponding to
a molecular formula C10 H9 Cl N4 S2..
They grow as monolayer and routinely 4
maintained in RPMI-1640 medium supplemented The reaction of N -(4-chlorophenyl)-1,3-thiazole-
with 10 % inactivated fetal calf serum (FBS) and 2,4-diamine 1 with phenyl isothiocyanate in 1,4-
50 µg/mL gentamycin at 37°C in a dioxane in the present of TEA [25] to give the N-
humidified atmosphere containing 5%CO2.Three [1,3-thiazol-2-yl]-N'-phenylthiourea derivative 3
hours after seeding, vehicle or cannabinoids at (Scheme1). The IR spectrum displayed
-1 -1
different concentrations were added to the absorption bands at 3217 cm , 3186 cm , 3116
medium and then daily with each change of cm-1 and 1250 cm-1 due to 3 NH and C=S
1
medium for 4 days. After the treatment, cells groups respectively. The H-NMR spectrum
were fixed by 4 % paraformaldehyde solution in (DMSO–d6) showed a D2O-exchangeable three
FBS. Then crystal violet solution (0.5 % crystal signals at δ 10.02 ppm, δ 11.03 ppm and δ 11.54
violet in 20 % methanol / water) was added .The ppm assigned to three NH protons. The mass
excess crystal violet solution was washed away spectrum showed a molecular ion peak at m/z
with distilled water and the remaining crystals 361 corresponding to a molecular formula
were dissolved in Sorenson's buffer (0.1 M C16H13ClN4S2.Further structure elucidation of
sodium citrate in 50% ethanol/water pH 4.2). compound 3 was obtained through the study of
Viability was determined by absorbance at 540 its reactivity towards chemical reagents. Thus,
nm wavelength using Spectra Max M5 microplate the reaction of 3 with ethyl cyanoacetate and
reader. anisaldehyde in the present of TEA as catalysis
[26] to give 4-oxo-2-thioxo-1,2,3,4-tetra-
hydropyrimidine-5-carbonitrile 4. A plausible
Number of viable cells was determined using
mechanism for the formation 4 which the
ELISA reader as previously mentioned before
intermediate A and B are obtained first, then
and the percentage of viability was calculates as:
intrarmolecular cyclization to give 4 (Scheme 2).
The IR spectrum of 4 displayed absorptions band
[1-(ODt / ODc )] x 100 % −1 −1 −1
at 3275 cm (NH) , 2214 cm (CN) ,1670 cm
-1 1
(C=O) and 1246 cm (C=S). The H-NMR
Where ODt is mean optical density of well treated
spectrum (DMSO-d6) showed a D2O- exchange-
with the test sample, ODc is mean optical density
able signal at δ 8.27 ppm assigned to NH proton
of untread cell. IC50 values the concentration
and signal at δ 3.25 ppm for OCH3 proton.13C
required to cause toxic effects in 50% if intact
NMR spectrum showed signal at δ 62.52 ppm
cells was estimated from graphic plots.
(OCH3 ), δ 116.63 ppm (CN), δ 162.81 ppm (C =
Experiments were carried out in triplicate, and
O) and δ 186 ppm ( C = S ). The reaction of
results are reported in Table 1.
thiourea derivatives 3 with 1-(4-aminophenyl)-3-
3. RESULTS AND DISCUSSION (4-chlorophenyl)prop-2-en-1-one 5 in the
presence of sodium hydroxide to give pyrimidine-
3.1 Chemistry 2(1H)-thione derivative 6. The IR spectrum
−1
displayed absorptions band at 3217 cm , 3166
−1 −1 −1
The synthesis of the new compounds is outlined cm , 3116 cm , 1254 cm to NH2 , NH and
in Schemes 1- 4. The key starting compound N4- C=S groups respectively. The 1H-NMR spectrum

6
 Salman; ACSJ, 15(3): 1-13, 2016; Article no.ACSJ.26694

(DMSO–d6) showed a D2O-exchangeable signals NH protons and the signal at δ 4.48 ppm, δ 6.60
at δ 5.02 ppm , δ 8.91 ppm assigned to NH2 and ppm assigned to C4-H and C5-H pyrimidine.

NH NH2
N
N NH2 NH
S S
NH
S NH4SCN / HCl

2
Cl
Cl 1
S Ph
NH N N
OCH3
PhNCS CNCH2COOEt N
Cl S
4- OCH3C6H4CHO /TEA CN
O

NH NH 4
N Ph
NH O
S S
S Ph
NH N N
H2N Cl N Cl
3
Cl Cl S
5

H2N
6

Scheme 1. Synthesis of compounds 1-6

R N
NH
CN NHPh
S
TEA S
R1 CHO + CNCH2COOEt R1 COOEt
1

R
R R
S S S
O N N N
S S
N Aromatization NH
NH
NC S OEt
-H2 Ph NH
N Ph N
O- O
R1 Ph
R1 R1 OEt
CN CN

4
B
A

R= 4- Cl C6H4NH ,R1= 4- OCH3C6H4

Scheme 2. Proposed mechanism of formation of compound 4

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 Salman; ACSJ, 15(3): 1-13, 2016; Article no.ACSJ.26694

O
NH CH3
N
Ac2O N
S CH3
Cl
O
N NH2
NH 7
S

NH N
NH O
Cl PhCOCH2 Br
1
Cl S
Ph

4- ClC6H4NHCOCH2Cl 8

NH N
O NH
NH N NH
NH4SCN / AcOH
S Cl N
Cl NH S NH
Cl
S

9 10
Cl

Scheme 3. Synthesis of compounds 7-10

Diacylation of thiazole derivative 1 using acetic and δ 11.21 ppm assigned to the 3 NH protons.
anhydride under reflux condition [27] gave N- In addition 13C NMR spectrum showed the signal
acetyl-N-1,3-thiazol-2-yl] acetamide derivative 7 at δ 186 to C=S.
(Scheme 3). The structure of compound 7 was
4
established based on both elemental analysis Reaction, of N -(4-chlorophenyl)-1,3-thiazole-2,4-
and spectral data. The 1H-NMR showed singlet diamine 1 with mixture of acetic anhydride and
signals at δ 2.70 ppm , δ 2.86 ppm for acetyl cyanoacetic acid [30] to yield the corresponding
13
protons. C NMR spectrum showed the signal at N-[1,3-thiazol-2-yl]-2-cyanoacetamide derivative
δ 168.42 ppm , δ 170.44 ppm to (2 C=O ). 11 ( Scheme 4 ).The structure of 11 has been
assigned as a reaction product on the basis of
Condensation of thiazole derivative 1 with analytical and spectral data. The IR spectrum
phenacyl bromide and /or 2-chloro-N-(4-chloro- -1
displayed absorption bands at 3136 cm , 3100
phenyl)acetamide in the presence of catalytic -1 -1
cm and 2200 cm due to 2 NH and CN groups
amount of TEA in ethanol [ 28 ] afforded 2-(1,3- respectively .The mass spectrum showed a
thiazol-2-ylamino)-1-phenyl- ethanone derivative molecular ion peak at m/z 293 corresponding to
8 and /or 2-(1,3-thiazol-2-ylamino)-N-(4-chloro- a molecular formula C12 H9 Cl N4OS.
phenyl)acetamide 9. The structure of the
compound 8 and 9 were based on their The reaction of cyanoacetamide derivatives 11
1
elemental analysis and spectral data. H NMR with benzaldehyde [ 31 ] gave the benzalidine
spectrum of 8 exhibited a singlet signal at δ 4.21 derivative 12 , while its reaction with salicyl-
ppm due to CH2.The mass spectrum of 8 aldehyde [32] produced the coumarin derivative
displayed the molecular ion peak at m/z 344 13. The plausible mechanism for the formation of
corresponding to the molecular formula C17H14Cl compound 13 may be attributed to the initial,
N3OS. Cyclocondensation of 2-(1,3-thiazol-2-yl- through the formation of the arylidine derivative C
amino)-N-(4-chlorophenyl)acetamide 9 with followed by intarmolecular cyclization to give
ammonium thiocyanate in glacial acetic acid 13.The structure of compounds 12 and 13 were
[29] afforded 1- (1,3-thiazol-2-yl) -1H-imidazole- as signed on the basis of the elemental analysis
2( 3H ) - thione derivative 10 (Scheme 3).The 1H and spectral data. The IR spectrum of compound
NMR spectrum (DMSO–d6) of 10 showed a D2O- 13 revealed the absence of CN absorption band
exchangeable signal at δ 8.61 ppm, δ 10.02 ppm and the presence of new absorption bands at

8
 Salman; ACSJ, 15(3): 1-13, 2016; Article no.ACSJ.26694

3209 cm−1, 3190 cm-1, 3170 cm-1 assignable to 3 ppm, δ 33.29 ppm, δ 172.08 ppm to CH3 ,CH2
−1
NH groups and band at 1689 cm due to C= O and C= O respectively.
13
group. C NMR data showed signals at δ162.74
ppm to C= O. Moreover, the reaction of compounds 1 with 1,3-
4 diphenyl–1H- pyrazole-4-carboxaldehyde 17 or
Reaction of N -(4-chlorophenyl)-1,3-thiazole-2,4- 2-(4-bromophenyl)-1H-indole-3-carboxaldehyde
diamine 1 with phenyl isothiocyanate in dry DMF 2
18 [34,35] afforded N -(substituted methylene)-
at room temperature yielded the non-isolable 4
N -(4-chlorophenyl)-1,3-thiazol-2,4-diamine 19
intermediate 14 and then reaction with α-halo- and 20 respectively (Scheme 5).The structures of
carbonyl compounds [33] such as ethyl chloro- 19 and 20 were elucidated by microanalysis and
acetate and / or 2 – chloro - N- (4-chlorophenyl) spectral data. For example IR spectrum of 20
acetamide afforded ethyl {N'- [1,3-thiazol- 2-yl]- -1
showed absorption bands at 3208 cm , 3167cm
-
N-phenyl-carbamimidoyl)thio} acetate 15 and 2- 1
corresponding to 2 NH groups. The 1H-NMR
[(4-chlorophenyl) amino] -2 - oxoethyl N'-(1,3- spectrum of 20 showed a single signal at δ 9.94
thiazol-2-yl)-N-phenyl–imidothiocarbamate 16 ppm corresponds to N=CH proton.
(Scheme 5 ).The structures of compounds 15
and 16 were established and confirmed by their
elemental analysis and spectral data. For 3.2 In Vitro Anti-Tumor Activity
example IR spectrum of 15 showed absorption
bands at 3283 cm-1, 3201cm-1 and 1670 cm−1 The in vitro anticancer activity of the newly
corresponding to 2 NH and C=O groups synthesized compounds 3, 4, 6, 7,9, 10, 11, 13,
respectively. The 1H-NMR spectrum of 15 15, 16 and 19 are evaluated against human
showed a triplet at δ 1.02 ppm, a quartet at δ breast cancer cell line (MCF- 7) and cell viability
4.06 ppm correspond to CH2CH3 group and was determined by the crystal violet assay.
singlet at δ 4.25 ppm correspond to CH2 protons. Cisplatin used as a reference drug. The results
13 are presented in (Table 1; Figs. 1 and 2).
In addition, C NMR data showed signals at δ 19

N NH2
NH
S

1
Cl
NH O
N
CNCH2COOH /Ac2O NH
PhCHO S CN
Ph
12
NH O Cl
N O
NH
S NH
CN
N
S
11 NH
Cl 2 - OH C6H4CHO O
N
H

Cl C

O
NH N
NH O
Cl S HN

13

Scheme 4. Synthesis of compounds 11 – 13

9
 Salman; ACSJ, 15(3): 1-13, 2016; Article no.ACSJ.26694

NH N
ClCH 2 COOEt N
S SCH 2 COOEt
Cl
PhHN
N Sk
N
NH NHPh
S 15

14 O
NH N
Cl 4 -- ClC 6 H 4 NHCOCH 2 Cl N
S NH
Cl S
PhHN

16 Cl
PhNCS/KOH/ DMF

Ph
N Ph
N Ph NH N
N N
OHC
Cl S N
N NH 2 Ph
17
NH
S
19
OHC
Cl
R NH
1
N N
H NH N
S
18
Cl
Br

20

Scheme 5. Synthesis of compounds 14-20

120
100
80
60
40
20
0
3 4 6 7 9 10 11 13 15 16 19

1.56 (μg/ml) 3.12 (μg/ml) 6.25 (μg/ml) 12.5 (μg/ml) 25 (μg/ml) 50 (μg/ml)

Fig. 1. Cell viability % of human breast cancer MCF- 7 with different

concentrations of the tested compounds

The results indicated that compounds 6, 9 and activity towards human breast cancer cell line
16 showed the highest inhibitory effect against (MCF- 7 ).
breast cancer cell line (MCF-7) than control drug
cisplatin. Compounds 3, 7,10 and 11 showed Comparing compound 6 with 9 and 16, it is
moderated growth inhibitory effect and obvious that the presence of the pyrimidine ring
compounds 4, 13, 15 and 19 showed very low at position 2 of thiazole ring, in compound 6

10
 Salman; ACSJ, 15(3): 1-13,
13, 2016; Article no.ACSJ.26694
no.

Table 1. In vitro anticancer activities of synthesis compounds against human breast cancer
MCF- 7 cell line
Compd Compound concentration (μg/ml)
No. 1.56 (μg/ml) 3.12 (μg/ml) 6.25 (μg/ml) 12.5 (μg/ml) 25 (μg/ml) 50 (μg/ml) IC50 (μg/ml)
Cell viability %
3 98.12±0.19 91.75±0.12 84.52±0.34 69.78±1.44 31.63±0.33 24.17±021 19±0.43
4 100±0.12 100±0.14 99.63±0.02 97.28±0.12 91.13±0.08 82.85±014 170±3.8
6 57.09±1023 45.93±0.39 37.18±0.2 28.06±0.04 22.37±0.08 18.29±0.23
0.23 2.55±0.07
7 99.71±0.07 96.18±0.14 89.04±0.25 78.93±0.13 60.22±1.46 39.35±0.17 37.2±0.8
9 65.13±1.73 48.65±0.54 32.94±0.32 24.13±0.09 18.26±0.08 14.31±0.15 2.99±0.17
10 100 99.61±0.04 92.73±0.15 84.68±0.24 72.95±1.71 34.26±0.44 39.8±0.6
11 98.24±0.12 92.31±0.25 86.95±0.21 71.66±1.94 45.91±0.75 34.06±0.42 23±0.8
13 100 100 100 100 100 98.76±0.02 >400
15 98.72±0.08 96.04±0.21 89.72±0.44 80.63±0.39 69.18±1.24 43.84±0.98 43.9±1.3
16 69.41±0.31 56.29±0.39 48.12±0.32 37.54±0.75 28.04±0.42 20.87±0.26 5.53±0.25
19 100 98.12±0.08 91.45±0.23 80.75±0.16 63.82±0.24 50.67±1.25 52.5±1.3
Cisplatin 70.88±0.16 61.74±0.36 52.85±.98 46.71±1.37 34.62±0.89 23.79±0.41 5.71±0.21
IC50 value: corresponds to the concentration required required to cause toxic effects in 50% if intact

IC50
400
400
350
300
250
200 170
150
100 37.2 39.8 23 43.9 52.5
50 19 2.55 2.99 5.53 5.71
0

Fig. 2. Evaluation of IC50 of test compounds

resulted in a higher inhibitory effect than 9 which crystal violet assay ,cisplatin
cisplatin used as a reference
has a N- (4- chlorophenyl) acetamide group at drug. Compounds 6, 9 and 16 showed best
position 2 of thiazole ring and 16 which has a 2- 2 cytotoxic activity against cancer cell higher than
[(4-chlorophenyl) amino]-2-oxoethyl
oxoethyl N-phenyl- that of cisplatin .Hence it can be suggested that
imidothiocarbamate group at position 2 of 6, 9 and 16 could be used as leads in the design
thiazole ring. The antiproliferative activity of the and development of new anticancer drugs.
test compounds against tumor cell to measure by
IC50 g / mL which is concentration require COMPETING INTERESTS
causing toxic effects in 50% if intact.
intact
Author has declared that no competing interests
4. CONCLUSION exist.
In this work, variety of heterocyclic systems have
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