Thiazole containing nitrogen mustards: Synthesis, structural evaluation, cytotoxicity and DNA binding studies

Article abstract of DOI:10.2174/157018011797200812

The present anticancer research demands more potent anticancer agents with fewer side effects than the existing ones. A series of novel substituted thiazole and benzothiazole containing nitrogen mustards (5-8; 15-17; 22-23) were synthesized and the structures of the compounds were analyzed by IR, NMR and mass spectras. Their in-vitro cytotoxicity against human lung carcinoma (A549) was investigated by MTT Assay. The compounds 16, 8 showed promising activity against A549 human lung carcinoma cell lines with % CPI 52 (More than Cisplatin) and 45.9 respectively. The DNA binding properties of the compounds were also evaluated based on their affinity or intercalation with CT-DNA measured with absorption titration. The compounds 22 and 5 showed the highest binding affinity with binding constant (Ki) 48.34 and 41.8 respectively.

Full text of DOI:10.2174/157018011797200812

8
38
Letters in Drug Design & Discovery, 2011, 8, 838-842
Thiazole Containing Nitrogen Mustards: Synthesis, Structural Evaluation,
Cytotoxicity and DNA Binding Studies
Nulgulmnalli Manjunathiah Raghavendra*, Surampudi Renuka, Sayan Dutta Gupta and
Pingili Divya
Department of Pharmaceutical Chemistry, Gokaraju Rangaraju College of Pharmacy, Osmania University, Hyderabad,
Andhrapradesh, India
Received April 29, 2011: Revised June 14, 2011: Accepted July 11, 2011
Abstract: The present anticancer research demands more potent anticancer agents with fewer side effects than the exist-
ing ones. A series of novel substituted thiazole and benzothiazole containing nitrogen mustards (5-8; 15-17; 22-23) were
synthesized and the structures of the compounds were analyzed by IR, NMR and mass spectras. Their in-vitro cytotoxicity
against human lung carcinoma (A549) was investigated by MTT Assay. The compounds 16, 8 showed promising activity
against A549 human lung carcinoma cell lines with % CPI 52 (More than Cisplatin) and 45.9 respectively. The DNA
binding properties of the compounds were also evaluated based on their affinity or intercalation with CT-DNA measured
with absorption titration. The compounds 22 and 5 showed the highest binding affinity with binding constant (Ki) 48.34
and 41.8 respectively.
Keywords: Anticancer activity, Benzothiazoles, Cytotoxicity, DNA binding, Nitrogen mustards, Thiazoles..
1
. INTRODUCTION
(Merck) with visualization by UV Light. Melting points
were determined in DBK-Prog-melting point apparatus. The
Cancer is becoming the biggest health hazard for the
-1
IR spectra (KBr, ꢀmax, and cm ) were run on Shimadzu IR
world. Development of resistance against the existing anti-
cancer drugs keeps research window open in search of newer
anticancer molecules. But the window passage has become
narrower because it is rather more difficult to search a mole-
cule that can selectively inhibit the proliferation of cancer
cells only with least or no affect on normal cells. Therefore
the search for novel, potent and safer anticancer agents con-
tinues at various research laboratories across the world. Thi-
azoles are an interesting group of compounds and biological
activities of this class of compounds that are reported in lit-
erature are anticancer [1-3], antibacterial activity [3,4], anti-
fungal [5-7] and anti-retroviral [6]. Research has established
that nitrogen mustard (chloroethylamine) attached to 4-
position of phenyl ring of second position of benzimidazole
and benzthiazole ring exhibits a promising anticancer activ-
ity [8], but further SAR is required to optimize the thiazole
containing mustards. Therefore a series of novel thiazole
containing nitrogen mustards were designed and synthesized.
These compounds were screened for cytotoxic activity on
human lung carcinoma (A549) cells through MTT assay.
The synthesized compounds were also investigated for DNA
binding study.
1
affinity-1 spectrophotometer. H-NMR (ppm ꢁ, CD
3
OD) was
recorded on a Bruker AC-80 spectrometer with TMS as in-
ternal standard. Mass spectra were recorded on Apex mass
spectrophotometer (API-Electrospray ion source). The syn-
thetic scheme is depicted in Fig. (1) and II. Microwave syn-
thesis was carried out using Biotage Initiator 2.5 microwave
synthesizer.
2.1.1. General Procedure for the Synthesis of Substituted
N-(2-chloroethyl)benzo[d]thiazol-2-amine (5-8)
Substituted 2-(benzo[d]thiazol-2-ylamino)ethanol (1-4,
0
.01 mol) was dissolved in 15ml of ethanol, to this thionyl
chloride (0.01 mol) was added drop wise and the mixture
was refluxed with stirring for 4h. It was neutralized with
sodium bicarbonate solution to precipitate the product. The
product was filtered, dried and recrystallized from ethanol.
The purity of the compound was checked on silica gel coated
aluminum TLC plates by using pet ether: ethyl acetate (2:8)
as the eluent and observed in UV light as a single spot.
2.1.2. General Procedure for the Synthesis of Substituted
N-(benzo[d]thiazol-2-yl)-2-(bis(2-hydroxyethyl)amino)acet-
amide (12-14));(substituted 2-(bis(2-hydroxyethyl)amino)-
N-(thiazol-2-yl)acetamide (20-21)
2
2
. MATERIALS AND METHODS
To
benzo[d]thiazol-2-yl)-2-chloroacetamide (9-11, 0.004 mol)
and substituted 2-chloro-N-(thiazol-2-yl)acetamide (18-19,
.004 mol) in ethanol (15 ml), an equivalent amount of
0.004 mol) of diethanolamine and 2-3 drops of triethy-
a
solution of the respective substituted N-
.1. Synthesis of Compounds
(
All the chemicals were purchased from Merck specialties
0
(
Pvt. Limited, and Himedia laboratories pvt. limited, Mum-
bai. Analytical T.L.C was performed on silica gel plates
lamine was added and the mixture was refluxed with stirring
for 2h. The solvent was removed under reduced pressure and
the mixture was added to cold water to precipitate the corre-
sponding benzothiazole derivatives. The products were then
filtered, dried and recrystallized from ethanol. The purity of
the compound was checked on silica gel coated aluminum
*
Address correspondence to this author at the Department of Pharmaceuti-
cal Chemistry, Gokaraju Rangaraju College of Pharmacy, Osmania Univer-
sity, Hyderabad, Andhrapradesh, India; Tel: +91 8897915557; Fax: +91 40
2
3041700; E-mail: nmraghava@yahoo.in
1
570-1808/11 $58.00+.00
© 2011 Bentham Science Publishers

Thiazole Containing Nitrogen Mustards
Letters in Drug Design & Discovery, 2011, Vol. 8, No. 9 839
O
Cl
R
OH
S
R
S
NH
NH
N
N
Substituted N-(benzo[d]thiazol-2-yl)-2-chloroacetamide (9 -11)
Substituted 2-(benzo[d]thiazol-2-ylamino)ethanol (1- 4)
OH
SOCl2
i
ii
HN
OH
OH
HO
Cl
R
S
N
O
N
H
N
R
S
Substituted N-(2-chloroethyl)benzo[d]thiazol-2-amine (5- 8)
NH
N
Substituted N-(benzo[d]thiazol-2-yl)-2-(bis(2-hydroxyethyl)amino)acetamide (12-14)
SOCl2
iii
Substituent R:
R= OC H : 1,5,9,12,15
2 5
Reaction Conditions:
i. Reflux, 4h
Cl
R= CH : 2,6,10,13,16
3
ii. Reflux, 2h
iii. Reflux, 4h
R= NO : 3,7,11,14,17
R= H: 4,8
2
Cl
O
N
R
S
NH
N
Substituted N-(benzo[d]thiazol-2-yl)-2-(bis(2-chloroethyl)amino)acetamide (15-17)
Fig. (1). Synthesis of substituted N-(2-chloroethyl)benzo[d]thiazol-2-amine (5- 8) and substituted N-(benzo[d]thiazol-2-yl)-2-(bis(2-
chloroethyl)amino)acetamide (15-17).
TLC plates by using chloroform: methanol (1:1) as the elu-
ent and observed in UV light as a single spot.
2.2. Anticancer Activity
The cytotoxicity potential of the test compounds was
evaluated on A549 human lung carcinoma cells using MTT
[3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bro-
mide] based cell proliferation assay [9,10]. The carcinoma
cell lines were obtained from National Centre for Cell Sci-
ence (NCCS), Pune (India) and cultivated in Dulbecco’s
modified eagle red medium (DMEM) containing 10 % fetal
bovine serum. Equal number of cells were seeded in each
well of 96 well micro plates and incubated at 37 °C with 5 %
2
.1.3. General Procedure for the Synthesis of Substituted
N-(benzo[d]thiazol-2-yl)-2-(bis(2-chloroethyl)amino)acet-
amide (15-17); (substituted 2-(bis(2-chloroethyl)amino)-N-
(
thiazol-2-yl)acetamide (22-23)
To the respective solution of substituted N-(benzo[d] thi-
azol-2-yl)-2-(bis(2-hydroxyethyl)amino)acetamide (12-14)
and substituted 2-(bis(2-hydroxyethyl)amino)-N-(thiazol-2-
yl)acetamide (20-21) (0.01 mol) in ethanol (15 ml), an
equivalent amount of (0.01 mol) of thionyl chloride was
added drop wise and the mixture was refluxed with stirring
for 4h. It was neutralized with sodium bicarbonate solution
to precipitate the products. The product was filtered, dried
and recrystallized from ethanol. The purity of the compound
was checked on silica gel coated aluminum TLC plates by
using chloroform:methanol (1:1) as the eluent and observed
in UV light as a single spot. In case of compound 22, the
reaction mixture after neutralization was extracted with ethyl
acetate (3x30 ml). The ethyl acetate layer was then dried
over anhydrous magnesium sulphate and concentrated under
vacum to obtain the pure liquid product.
CO
2
. The cells were treated with test compounds and stan-
dard at a concentration of 100 ꢀg/ml for 72 h. Control were
supplemented with 0.5 % DMSO. After 72 h treatment, 5 ꢀl
of MTT reagent along with 45 ꢀl of phenol red and FBS free
DMEM was added to each well and plates were incubated at
3
2
7 °C (with 5 % CO for 4 h, thereafter 50 ꢀl of solubiliza-
tion buffer) was added to each well to solubilise the colored
formazan crystals produced by the reduction of MTT. After
2
4h the optical density was measured at 550 nm using spec-
trophotometer in a micro plate reader. The percentage cell
proliferation inhibition (% CPI) of the synthesized com-
pounds is shown in Table 1.

8
40 Letters in Drug Design & Discovery, 2011, Vol. 8, No. 9
Raghavendra et al.
Table 1. In-Vitro Cytotoxic Studies of Synthesized Thiazoles Containing Nitrogen Mustards
Compd code
% CPI
Compd code
% CPI
5
6
7
8
33.70
6.75
16
17
52
10.70
32.1
2.40
22
45.90
30.40
23
24.78
49.5
1
5
cisplatin
2
.3. DNA Binding Studies
The interaction of synthetic thiazole containing nitrogen
(C-H methyl stretching), 1637 (C=N stretching), 1543 (C=C
1
stretching), 720 (C-Cl stretching). H-NMR (CD
.26 (t, 3H, CH , J = 6.8 Hz), 3.18-3.19 (t, 2H, CH
Hz), 3.8-3.95 (m, 4H, OCH + CH Cl), 6.7-6.75 (d, 1H, Ar-
H, J = 8.3 Hz), 7.0-7.5 (d, 1H, Ar-H, J = 7.7 Hz), 7.10-7.15
3
OD): 1.23-
1
3
2
N, J = 7.7
mustards in phosphate buffer of pH7 with calf thymus DNA
was studied using UV absorption spectroscopy [11,12]. The
hypochromic effect observed in the absorption spectra of
synthetic compounds in the presence of increasing concen-
trations of DNA is shown in Fig. (1). The change in absor-
bance was measured at 280-330 nm for complex of synthetic
compounds-DNA. The binding isotherms were constructed
from these data using the Scatchard equation. The half recip-
rocal UV plot obtained on the basis of absorbance data for
synthetic compounds-DNA complex given in Fig. (2). These
linear plots indicate involvement of one binding process with
independent binding sites on DNA.
2
2
+
(
d, 1H, Ar-H, J = 8.6 Hz), MS m/z: 256 (M ).
3.1.2. N-(2-chloroethyl)-6-methylbenzo[d]thiazol-2-amine
(6)
ꢀ1
White solid, Yield (50 %), m.p. 193 °C, IR: (KBr, cm )
3
061 (C-H aromatic stretching), 3032 (N-H stretching), 2883
(
C-H methyl stretching), 1654 (C=N stretching), 1492 (C=C
1
stretching), 752 (C-Cl stretching), H-NMR: (CD
.19 (m, 7H, CH N + CH Cl + CH ), 7.29-7.31 (d, 1H, Ar-
H, J = 8.7 Hz), 8.024-8.052 (d, 1H, Ar-H, J = 8.5 Hz), 8.42-
3
OD): 3.18-
3
2
2
3
+
8
.43 (d, 1H, Ar-H, J = 8.1 Hz), MS m/z: 226 (M ).
3
3
3
. RESULTS AND DISCUSSION
3
.1.3 N-(2-chloroethyl)-6-nitrobenzo[d]thiazol-2-amine (7)
.1. Synthesis of Compounds
Yellow solid, Yield (50 %), m.p. 119 °C , IR: (KBr,
ꢀ1
cm ) 3030 (C-H aromatic stretching), 3149 (N-H, stretch-
ing), 1643 (C=N stretching), 1527 (C=C stretching), 1446
.1.1. N-(2-chloroethyl)-6-ethoxybenzo[d]thiazol-2-amine
(
5)
1
(
N-O stretching), 719 (C-Cl stretching). H-NMR (CD
3
OD):
ꢀ1
White solid, Yield (50 %), m.p. 170 °C, IR: (KBr, cm ):
149 (N-H stretching), 3061 (C-H aromatic stretching), 2892
2
.56 (d, 4H, CH
2 2
-Cl + CH N, J = 7.3 Hz), 7.04-7.28 (m, 3H,
3
+
Ar-H), MS m/z: 257 (M ).
O
Cl
R
S
NH
N
Substituted 2-chloro-N-(thiazol-2-yl)acetamide (18- 19)
OH
iv
HN
OH
O
OH
HN
N
S
N
R
OH
Substituted 2-(bis(2-hydroxyethyl)amino)-N-(thiazol-2-yl)acetamide (20-21)
v
SOCl2
O
Cl
Cl
Reaction Condition:
iv. Reflux, 2h
v. Reflux, 4h
Substituent:
R= NO : 18, 20, 22
HN
N
2
R= CH : 19, 21, 23
3
S
N
R
Substituted 2-(bis(2-chloroethyl)amino)-N-(thiazol-2-yl)acetamide (22-23)
Fig. (2). Synthesis of substituted 2-(bis(2-chloroethyl)amino)-N-(thiazol-2-yl)acetamide (22-23).

Thiazole Containing Nitrogen Mustards
Letters in Drug Design & Discovery, 2011, Vol. 8, No. 9 841
3
.1.4. N-(2-chloroethyl)benzo[d]thiazol-2-amine (8)
ing), 1590 (C=N stretching), 1498 (C=C stretching), 1420
1
ꢀ1
(N-O stretching), 761 (C-Cl stretching), H-NMR (CD
3
OD):
White solid, Yield (50%), m.p. 129 °C, IR: (KBr, cm )
030 (C-H aromatic stretching), 3520 (N-H stretching), 1637
3
.87-3.88 (d, 6H, (NCH
2 3
) ), J = 7.7 Hz), 3.23-3.24 (d, 4H,
3
(
CH Cl) , J= 4.5Hz), 6.9-7.2 (s, 1H, Ar-H), MS m/z: 327
2
2
(
C=N stretching) 1539 (C=C stretching), 720 (C-Cl stretch-
+
1
(M ).
ing), H-NMR (CD
3 2 2
OD): 3.18-3.19 (m, 4H, CH N- CH Cl),
6
.92-6.94 (d, 2H, Ar-H, J = 8.2 Hz), 7.12-7.25 (d, 2H, Ar-H,
3.1.9. 2-(bis(2-chloroethyl)amino)-N-(5-methylthiazol-2-yl)
acetamide (23)
+
J = 7.9 Hz), MS m/z: 212 (M ).
.1.5. 2-(bis(2-chloroethyl)amino)-N-(6-ethoxybenzo[d]
thiazol-2-yl)acetamide (15)
ꢀ1
3
White solid, Yield (33 %), m.p. 187 °C, IR: (KBr, cm )
3030 (C-H aromatic stretching), 3520 (N-H stretching), 2898
ꢀ
1
(C-H methyl stretching), 1590 (C=N stretching), 1485 (C=C
White solid, Yield (56 %), m.p. 200 °C, IR: (KBr, cm )
061 (C-H aromatic stretching), 3045 (N-H stretching), 2895
1
stretching), 730 (C-Cl stretching), H-NMR (CD
3
OD): 2.028
3
(
(
(
s, 3H, CH
s, 1H, Ar-H), MS m/z: 296 (M ).
3
), 3.18-3.19 (m, 10H, (NCH
2
)
3
+ (CH Cl) ), 7.2
2
2
C-H methyl stretching), 1606 (C=O stretching), 1637 (C=N
stretching), 1492 (C=C stretching), 721 (C-Cl stretching),
+
1
H-NMR (CD
.19 (t, 6H, CH
OCH ), 3.2-3.24 (s, 1H, CH
H), MS m/z: 376 (M ).
3
OD): 1.2-1.3 (t, 3H, CH
N, J = 7.2 Hz), 3.90-3.98 (m, 6H, (CH
-C-OH), 6.95-7.35 (m, 3H, Ar-
3
, J = 7.5 Hz), 3.18-
3
2
2
Cl)
2
3.2. Anticancer Activity
+
2
2
+
Compound-16 (% CPI = 52 %) showed more activity
when compared to the standard (% CPI = 49.5 %). Com-
pound-8 (% CPI = 45.9 %) exhibits moderate anticancer ac-
tivity. Compounds (5-7, 17 and 23) were exhibiting mild
anticancer activity. The percentage cell proliferation inhibi-
tion of the synthesized compounds is given in Table 1.
3
.1.6. 2-(bis(2-chloroethyl)amino)-N-(6-methylbenzo[d]
thiazol-2-yl)acetamide (16)
ꢀ1
White solid, Yield (50%), m.p. 200 °C, IR: (KBr, cm )
288 (C-H aromatic stretching), 3149 (N-H, stretching),
892 (C-H methyl stretching), 1620 (C=N stretching), 1571
3
2
(
C=O stretching) , 1448 (C=C stretching), 719 (C-Cl stretch-
3
.3. DNA Binding Studies
1
ing), H-NMR (CD
C-OH), 3.3-3.42 (t, 6H, CH
CH Cl, J = 5.9 Hz), 7.40-7.42 (d, 1H, Ar-H, J = 7.9 Hz), 8.1-
8
3
3
OD): 2.2 (s, 3H, CH
3 2
), 3.2 (s, 1H, CH
The absorption spectra of synthesized compounds in the
2
N, J = 7.5 Hz), 3.81-3.83 (t, 4H,
absence and presence of CT DNA is shown in Figs. (3 and
). The presence of increasing amounts of CT DNA showed
strong decrease in the peak intensity, which is indicated by
hypochromicity. DNA binding studies indicated that com-
2
4
.26 (d, 1H, Ar-H, J = 8.0 Hz), 8.5 (s, 1H, Ar-H), MS m/z:
+
46 (M ).
%
3
.1.7. 2-(bis(2-chloroethyl)amino)-N-(6-nitrobenzo[d]thia-
pound-5 (Ki = 41.98) and 16 (Ki = 37.87) exhibited good
binding affinity to DNA. Among substituted thiazoles / ben-
zothiazoles containing nitrogen mustards, compounds (6, 8
and 17) were exhibiting moderate DNA binding affinity,
while compounds (22, 23) were exhibiting less affinity.
zol-2-yl)acetamide (17)
ꢀ1
Yellow solid, Yield (52%), m.p. 190 °C IR: (KBr, cm )
030 (C-H aromatic stretching), 3155 (N-H, stretching),
3
1
649 (C=N stretching), 1606 (C=O stretching), 1575 (C=C
1
stretching), 1446 (N-O streching), 740 (C-Cl stretching), H-
NMR (CD
3 2 3 2 2
OD): 3.091-3.098 (m, 10H, (CH N) + (CH Cl) ),
4
. CONCLUSION
3
.7 (s, 1H, NH), 7.13-7.17 (d, 1H, Ar-H, J = 8.5 Hz), 8.2-8.3
(
(
d, 1H, Ar-H, J = 8.4 Hz), 8.5 (s, 1H, Ar-H), MS m/z: 400
M+ Na) .
Nine substituted thiazoles having nitrogen mustards are
+
synthesized and characterized. All the compounds were
screened for their anticancer potential against A549 human
lung carcinoma cells at Laila impex, R&D centre, A.P, India.
On the basis of results obtained it was found that compound-
16 (2-(bis(2-chloroethylamino)-N-(6-methylbenzo[d]thiazol-
2yl)acetamide) showed the highest cytotoxicity (more than
3
.1.8. 2-(bis(2-chloroethyl)amino)-N-(5-nitrothiazol-2-yl)
acetamide (22)
Yellow viscous liquid, Yield (30 %), b.p. 120 °C, IR:
ꢀ1
(
cm ) 3520 (N-H, stretching), 3030 (C-H aromatic stretch-
Table 2. Binding Constant, % Hypochromicity & Isobestic Points of DNA Complexes with Compounds 5-8, 15-17, and 32-23
Comp. code
Ki
ꢀ max (nm)
Hypochromicity (%)
Isobestic point
5
6
7
8
41.98
17.57
26.05
30.70
14.17
37.87
20.82
48.34
24.90
266
266
357
356
261
387
306
263
262
58.5
44.7
45.3
54.5
48.5
42.7
54.3
27.5
21.2
222
unclear
260
unclear
210
1
1
1
2
2
5
6
7
2
3
226
200
unclear
210

8
42 Letters in Drug Design & Discovery, 2011, Vol. 8, No. 9
Raghavendra et al.
azole (compound-22 (% CPI =32.1 %; Ki = 48.34)) increases
the anticancer activity and DNA binding affinity when com-
pared to the presence of methyl at position 5 of thiazole
(
compound 23 (% CPI =24.78 %; Ki = 24.9)).
ACKNOWLEDGEMENTS
We are thankful to DST (Fast track Scheme: SR/FT/CS-
0
1
79/2009) and AICTE (RPS Scheme: 8023/BOR/RID/RPS-
02/2009-10) for providing molecular modeling software
and other financial assistance for this project. We also thank
Gokaraju Rangaraju Educational Society for providing labo-
ratory facilities.
REFERENCES
[
1]
Lu, Y.; Li, C.M.; Wang, Z.; Ross, C.R.; Chen, J.; Dalton, J.; Li,
W.; Miller, D.M. Discovery of 4-substituted methoxybenzoyl-aryl-
thiazole as novel anticancer agents: synthesis, biological evaluation
and structure-activity relationships. J. Med. Chem., 2009, 52 (6),
Fig. (3). Effect of calf thymus DNA on the absorption spectrum of
synthesized compound-5.
1
701-1711.
[
2]
Chua, M.S.; Kashiyama, E.; Bradshaw, T.D.; Stinson, S.F.;
Brantley, E.; Sausville, E.A.; Stevens, M.F.G. Role of CYP1A1 in
modulation of antitumor properties of the novel agent 2-(4-
aminophenyl) benzothiazoles (DF 103 NSC 674495) in human car-
cinoma breast cancer cells. Cancer Res., 2000, 60 (18), 5196-5203.
Al-Saadi, M.S.; Faidallah, H.M.; Rostom, S.A. Synthesis and bio-
logical evaluation of some 2,4,5-trisubstituted thiazole derivatives
as potential antimicrobial and anticancer agents. Archiv der Phar-
mazie., 2008, 341 (7), 424-434.
[3]
[4]
[5]
Holla, B.S.; Malini, K.V.; Rao, B.S.; Sarojini, B.K.; Kumari, N.S.
Synthesis of some new 2,4-disubstituted thiazoles as possible anti-
bacterial and anti-inflammatory agents. Eur. J. Med. Chem., 2003,
3
8 (3), 313-318.
Narayana, B.; Vijaya Raj, K.K.; Ashalatha, B.V.; Kumari, N.S.;
Sarojini, B.K. Synthesis of some new 5-(2-substituted-1,3-thiazole-
5
-yl)-2-hydroxy benzamides and their 2-alkoxy derivatives as pos-
sible antifungal agents. Eur. J. Med. Chem., 2004, 39 (10), 867-
72.
8
[
6]
7]
Pandeya, S.N.; Sriram, D.; Nath, G.; DeClercq, E. Synthesis, anti-
bacterial, antifungal and anti-HIV activities of Schiff and Mannich
bases derived from isatin derivatives and N-[4-(4ꢀ-
chlorophenyl)thiazol-2-yl] thiosemicarbazide. Eur. J. Pharm. Sci.,
Fig. (4). A half reciprocal UV plots for the binding of synthesized
compound-5 to DNA.
1
999, 9, 25-31.
[
Sidoova, E.; Looos, D.; Bujdakova, H; Kallova, J. New antican-
didous 2-alkyl thio-6-amino benzothiazole. Molecules., 1997, 2,
cisplatin) and good DNA binding affinity among the series.
Structure activity relationship studies of the N-(2-
3
6-42.
[8]
Omar, A.M.M.E.; Habib, N.S.; Aboulwafa, O.M. Potential alkylat-
ing agents derived from benzimidazole and benzothiazole. J.
Pharm Sci., 1982, 71, 991-993.
Dutta Gupta, S.; Moorthy, N.S.H.N.; Sanyal, U. Synthesis, cyto-
toxic evaluation, in silico pharmacokinetic and QSAR study of
some benzothiazole derivatives. Int. J. Pharm. Pharm. Sci., 2010,
2(3), 57-62.
Mosmann, T. Rapid colorimetric assay for cellular growth and
survival: application proliferation and cytotoxicity assays. J. Im-
munol. Methods., 1983, 65, 55-63.
Mansuri, T.H., Ghadimy, S.; Akbarzadeh, N. Synthesis, characteri-
zation, DNA binding and cytotoxic studies of platinum(II) and pal-
ladium (II) complexes of the 2,2’- bipyridine and an anion of 1,1-
cyclobutanedicarboxylic acid. Chem. Pharm. Bull., 2001, 49, 1517-
chloroethyl)-6-substitutedbenzo[d]thiazol-2-amines
(5-8),
indicates the presence of hydrogen or ethoxy at position 6 of
benzothiazole increases the anticancer activity and DNA
binding affinity than nitro group at position 6 of benzothia-
zole as compound-8 (% CPI= 45.90 %; Ki = 30.70) and
Compund-5 (% CPI = 33.70 %; Ki = 41.98) are more active
than compound-7 (% CPI = 2.40 %; Ki = 26.05). Among 2-
[
9]
[
10]
11]
(
bis(2-chloroethyl)amino)-N-(6-substituedbenzo[d]thiazol-2-
[
yl)acetamides (15-17), the presence of methyl group (Com-
pound-16 (% CPI = 52 %; Ki = 37.87)) at position 6 of ben-
zothiazole increases the anticancer activity and DNA binding
affinity than nitro group (Compund-17 (% CPI = 10.70 %;
1
520.
[12]
Sathish, N.K.; Rajendra Prasad, V.V.S.; Raghavendra, N.M; Shanta
Kumar, S.M; Mayur,Y.C. Synthesis of novel 1,3-diacetoxy-
acridones as cytotoxic agents and their DNA-binding studies. Sci
Pharm., 2009, 77, 19-22.
2
0.82)) at position 6 of benzothiazole. SAR of 2-(bis(2-
chloroethyl)amino)-N-(5-substitutedthiazol-2-yl)acetamide
22-23) reveals the presence of nitro group position 5 of thi-
(