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Original Article

Synthesis of 1-[2 (substituted phenyl)-4-oxothiazolidin-3-yl]-3-(6-fluro-7-chloro-1,3-benzothiazol-2-yl)-ureas asanthelmintic agent

Sibaji Sarkar a,*, Jaya Dwivedi b, Rajani Chauhan c

aAssistant Professor, N. R Vekaria Institute of Pharmacy, C. L College Campus, Junagadh, Gujarat 362001, Indiab Professor, Department of Chemistry, Banasthali University, Rajasthan 304022, IndiacAssistant Professor, Department of Pharmacy, Banasthali University, Rajasthan 304022, India

a r t i c l e i n f o

Article history:

Received 1 April 2013

Accepted 9 May 2013

Available online 2 June 2013

Keywords:

Anthelmintic activity

Benzothiazole

Thiazolidinones derivatives

* Corresponding author. Tel.: þ91 9723512268E-mail addresses: sibajisarkar004@gmail.

0974-6943/$ e see front matter Copyright ªhttp://dx.doi.org/10.1016/j.jopr.2013.05.008

a b s t r a c t

Background/aim: Derivatives of thiazolidinones have attracted interest in recent years

because it exhibits broad spectrum of biological activities like anticonvulsant, analgesic,

anti-inflammatory. Thus we report the facile synthesis, characterization and biological

evaluation of novel 1-[2 (substituted phenyl)-4-oxothiazolidin-3-yl]-3-(6-fluro-7-chloro 1,3-

benzothiazol-2-yl)-ureas derivatives.

Method: The synthesis of novel potential anthelmintic agents of 1-[2 (substituted phenyl)-4-

oxothiazolidin-3-yl]-3-(6-fluro-7-chloro 1,3-benzothiazol-2-yl)-ureas (TH16eTH20) were

achieved by reaction with 2, 3, 4 (trisubstituted benzaldehyde) e N-(6-fluro-7-chloro-1,3-

benzothiazol-2-yl) semicarbazon (V) with DMF, thioglycolic acid and zinc chloride. The

products have been characterized by 1H NMR, mass spectrometry and elemental analysis.

Result: All the synthesized compounds show good to moderate anthelmintic activity

against Perituma posthuma. The best results were achieved with molecules that had methyl

and methoxy group at C-3 and C-2 position of phenyl ring, i.e., TH18 and TH20.

Conclusion: The results of novel 1-[2 (substituted phenyl)-4-oxothiazolidin-3-yl]-3-(6-fluro-7-

chloro 1,3-benzothiazol-2-yl)-ureas derivatives exhibits anthelmintic activity against

stander drug Albendazole. The modification of the heterocyclic ring of the parent com-

pound offers a promising prospect and active analogues are expected to be found.

Copyright ª 2013, JPR Solutions; Published by Reed Elsevier India Pvt. Ltd. All rights

reserved.

1. Introduction in the chemistry of benzothiazole ring systems, which is a

Benzothiazoles are bicyclic ring system. Benzothiazole ring

made from thiazole ring fused with benzene ring. Thiazole

ring is a five-member ring consists of one nitrogen and one

sulphur atom in the ring. There has been considerable interest

(mobile).com, sibajisarkar001@red2013, JPR Solutions; Publi

core structure in various synthetic pharmaceuticals display-

ing a broad spectrum of biological activities like antimicro-

bial,1 anticonvulsant,2 anti-inflammatory,3 anticancer,4

central dopaminergic,5choleratic,6 miscellaneous7 and anti-

fungal.8 Further thiazolidinones and its derivatives possess

iffmail.com (S. Sarkar).shed by Reed Elsevier India Pvt. Ltd. All rights reserved.

j o u rn a l o f p h a rma c y r e s e a r c h 7 ( 2 0 1 3 ) 4 3 9e4 4 2440

various biological activities such as anticonvulsant,9 anal-

gesic,10 and anti-inflammatory.11 In our present workwewere

interested to incorporate a thiazolidinones moiety in benzo-

thiazole ring. With the idea that if these two moieties are

joined together, themoleculemight exhibit superior biological

activity. The paper describes the synthesis of five new thia-

zolidinones derivatives (TH16eTH20) and their evaluation for

possible anthelmintic activity.

RCom. R1 R2

Scheme 1 e Out line for the synthesis of 1-[2 (substituted

phenyl)-4-oxothiazolidin-3-yl ]-3-( 6-fluro-7-chloro 1,3-

benzothiazol-2-yl )-ureas.

2. Experimental

All the chemicals and solvents were used laboratory grade.

Melting points were determined in open capillaries and are

uncorrected. IR spectra were recorded in KBr on Thermo

Scientific; NICOLET iS10 spectrophotometer. 1H NMR were

recorded on Bruker avance II 400 MHz spectrophotometer

using TMS as an internal standard. Thin layer chromatog-

raphy (TLC) was performed in precoated silica gel plates.

Visualization of the plates were done by exposing TLC plate to

iodine vapour and under UV light. Compound 2 amino

substituted benzothiazole was reported before in previous

literature.12

2.1. Synthesis of ethyl (6-fluro-7-chloro-1,3-benzothiazol-2-yl) carbamate (III)

2 Amino benzothiazole (0.327 mol) 13.5 g, in absolute alcohol

30 ml, anhydrous K2CO3 (2 g) were taken with ethyl chloro

formate (0.0327mol) 0.7 g, and refluxed for 7e8 h. The solution

was filtered and the residue washed with ethanol and the

solvent evaporated under reduce pressure to get the product

as solid which was recrystallized with ethanol.

2.2. Synthesis of N-(6-fluro-7-chloro-1,3-benzothiazol-2-yl)hydrazine carboxamide (IV)

Ethyl (6-fluro-7-chloro-1,3-benzothiazol-2-yl) carbamate was

treatedwith 4ml hydrazine hydrate in the presence of ethanol

(30 ml). The reaction mixture was refluxed for 5 h and cooled

to room temperature. The carbamoyl hydrazides separated

were filtered, wash with ethanol (2 ml), dried and recrystal-

lized with alcohol.

2.3. Synthesis of 2, 3, 4 (trisubstituted benzaldehyde)-N-(6-fluro-7-chloro-1,3-benzothiazol-2-yl) semicarbazone (V)

2.6 g of N-(6-fluro-7-chloro-1,3-benzothiazol-2-yl) hydrazine

carboxamide was treated with absolute ethanol (12.6 ml) in

the presence of different aldehyde and refluxed for 3 h. Sol-

vent was removed under reduce pressure to yield Schiff base,

which was recrystallized with alcohol.

2.4. Schiff base to thiazolidinones derivatives(TH16eTH20)

To a solution of Schiff base (0.10mol) in DMF, thioglycolic acid

(0.10mol) and zinc chloride (0.10mol) were added and content

was refluxed for 5 h. The reaction mixture was poured in

to cooled water and liberated compound was extracted

with chloroform. Evaporation of the compound afforded the

corresponding thiazolidinones derivatives

3. Analytical data

3.1. 1-[2-(3-methyl phenyl)-4-oxothiazolidin 3-yl]-3-(6-fluro-7-chloro-1,3-benzothiazol-2-yl)-ureas (TH18)

Mol. Wt: 436.91, M.P.: 150 �C; Yield 87%; Rf 0.47; IR (cm_1): 1652

(C]O), 3098 (NH), 1607 (C]N), 715 (CeCl), 1155 (CeF); 1H NMR

(d, ppm): 8.09 (m, 8H, AreH), 6.55 (S, IH, NH), 8.50 (S, IH, CONH),

Table 1 e Anthelmentic activity of synthesizedcompounds (TH16eTH20).

Sr.no

Name Time in minutes

For paralysis For death

% Concentration % Concentration

0.1 0.2 0.5 0.1 0.2 0.5

1 Control 0.9 e e e e e

2 Albendazole 30 25 14 50 35 27

3 TH16 6.2 5.7 3.5 10.4 9.4 5.8

4 TH17 5.5 4.8 3.8 10.5 9.8 5.6

5 TH18 19.4 14.4 12.8 25 18 14

6 TH19 4.9 3.7 2.5 5.9 5.8 3.9

7 TH20 16.8 12.9 10.5 19 14 9

j o u r n a l o f p h a rm a c y r e s e a r c h 7 ( 2 0 1 3 ) 4 3 9e4 4 2 441

2.38 (S, 3H, CH3),3.98 (S, 2H, CH2). Elemental analysis for

C18H14ClFN4O2S2; Calculated: C, 49.48; H 3.23; N, 12.82; Found:

C, 49.58; H, 3.26; N, 12.83, [M þ H]þ: 437.02.

3.2. 1-[2-(2-methoxy phenyl)-4-oxothiazolidin 3-yl]-3-(6-fluro-7-chloro-1,3-benzothiazol-2-yl)-ureas (TH20)

Mol. Wt: 452.91, M.P.: 145 �C; Yield 80%; Rf 0.58; IR (cm_1): 1659

(C]O), 3090 (NH), 1608 (C]N), 717 (CeCl), 1158 (CeF); 1H NMR

(DMSO): d (ppm) 7.27 (m, 8H, AreH), 6.25 (S, IH, NH), 8.51 (S, IH,

CONH), 2.35 (S, 3H, CH3), 3.73 (S, 3H, OCH3) 3.28 (S, 2H, CH2).

Elemental analysis for C18H14ClFN4O3S2; Calculated: C, 47.73;

H, 3.12; N, 12.37; Found: C, 47.89; H, 3.20; N, 12.40, [M þ H]þ:453.12.

4. Anthelmintic activity

The synthesized compounds (TH16eTH20) were screened for

anthelmintic activity in vitro against earth worms Perituma

posthuma using standard method13 at a concentration of 0.1%

w/v, 0.2% w/v and 0.5% w/v. The anthelmintic drug albenda-

zole was also tested under similar conditions against these

organisms.

5. Result and discussion

In the present investigation, a series of novel thiazolidinones

derivatives (TH16eTH20) have been synthesized (See

Scheme 1). All the synthesized derivatives were evaluated for

anthelmintic activity against earth worms Perituma posthuma.

The compounds have shown moderate to good anthelmintic

activity .The compound containing electron donating groups

such as CH3, OCH3 at 3 and 2 number position on phenyl ring,

i.e., the compound TH18 and TH20 (see Table 1) exhibited

good anthelmintic activity as compared with stander drug

albendazole.

6. Conclusion

A series of 1-[2 (substituted phenyl)-4-oxothiazolidin-3-yl]-3-

(6-fluro-7-chloro-1,3-benzothiazol-2-yl)-ureas were designed,

synthesized and evaluated for anthelmintic activity.

The results indicated that higher concentration of syn-

thesized derivatives exhibit paralytic effect much earlier.

Out of five synthesized compounds, two compounds (TH18

and TH20) showed good anthelmintic activity with all three

concentrations. Three compounds (TH16, TH17, TH19) contain

methoxy, methyl group at C-4, C-2 position of phenyl ring,

hence display less or comparable anthelmintic activity with

reference to albendazole. Among the tested new compounds,

better anthelmintic activity was reported for TH18 and TH20

which may probably due to attachment of methyl and

methoxy group at C-3, C-2 position of phenyl ring.

Conflicts of interest

All authors have none to declare.

Acknowledgement

The authors are grateful to principal, staff members of N.R

Vekaria Institute of Pharmacy, Junagadh for their support and

facilities provided to carry out this work. The authors are also

thankful to SAIF, Punjab University and ISFAL, Punjab for

recording data.

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