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Vol 1/Issue 6/Nov-December 2012 PhTechMed ISSN: 2278-1099

www.pharmtechmedica.com 210

Synthesis, Characterization and Biological Activity of Some New 2- Substituted Amino-
3-N- (M-Anisyl Carboxamido)-4, 5-Dimethyl Thiophene

Rekha Parmesh
*
, J. Saravanan and S. Mohan

Department of Pharmaceutical Chemistry, The Oxford College of Pharmacy, Hongasandra, Begur Road, Banglore,
India

Abstract
The synthesis of highly substituted thiophene has attracted a great deal of interest over the years due to their presence in
natural products. Our interest in this class of compounds was based on their use as novel antibacterial drugs. The new 2-
amino-3-N-(m-anisyl carboxamido)-4,5-dimethyl thiophene (MSR-4) was synthesized via a multi-component
condensation between sulphur, Ethyl methyl ketone and metametoxy cyano acetanalide adapting Gewald reaction. Later
it was condensed with different substituted aryl aldehydes to yield eleven new title compounds (MSR-4a-4k). The
synthesized compounds were characterized by preliminary laboratory techniques like MP, TLC, IR and further
confirmed by NMR and Mass spectra and were subjected to antibacterial screening at a concentration of 50mcg/ml
involving two gram positive and two gram negative bacteria using Ampicillin and Norfloxacin as standard at the same
concentration. From the antibacterial activity results, it was observed that both electron donating and electron
withdrawing groups on the aldehydic phenyl ring of the compounds influenced the activity. Among all the compounds
tested, MSR-4c was found to be most active against both Gram-positive and Gram-negative bacteria. The remaining
compounds of the series exhibited mild to moderate activities when compared to the standards.
Keywords Thiophene, Ampicillin Norfloxacin and Antibacterial activity.

Introduction
Among the approximately 20 million chemical
compounds identified by the end of the second
millennium, more than two third are fully are partially
aromatic and approximately half are heterocyclic, so we
have chosen the heterocyclic compound THIOPHENE.
Thiophene has exhibited an array of biological activities
like antibacterial & antifungal.
The current study describes the syntheses and biological
evaluation of novel series of condensed thiophenes
.Preparation of derivatives using microwave technique
rather than conventional methods. To carry out
purification of the newly synthesized compounds with
suitable solvents. To screen the synthesized compounds
for antimicrobial activity to evaluate their efficacy.
Experimental Methods
1. Syntheses of m-methoxy cyano acetanilide MSR-4
Reaction 1: A mixture of m-anisidine (m-methoxy aniline,
61.5 ml; 0.5 M) and ethyl cyano acetate (56.5 ml; 0.5 M)
was taken in a conical flask and heated on mantle for 5 hrs
at 160- 170C. Then the reaction mixture was transferred
into a beaker and kept at room temperature for overnight.
The solid obtained was washed with ethanol, dried &
recrystallized from acetone:water mixture.
2. Syntheses of 2-cyano-2-(alkylidene)m-anisyl
carboxamide:
Reaction 2: A mixture of m-methoxy cyano acetanilide
(7.6 g; 0.04 M), appropriate ethylmethyl ketone (0.04 M),
Address for Correspondence
E-mail: rekhaparmesh@gmail.com
Tel: Not Avilable
Received: 18/12/2012
Accepted: 21/12/2012

ammonium acetate (2 g) and glacial acetic acid (2 ml) in
benzene (100 ml) was refluxed with an arrangement for
continuous separation of water involving dean stark
apparatus. After 8 hrs the reaction mixture was cooled,
diluted with 10 ml benzene and washed succesively with
sodium carbonate solution (10% w/v in water) and water.
Dried over anhydrous sodiumsulphate. The solvent was
removed under vacuum and the intermediate crude
product obtained was immediately processed for next step.
3. Synthesis of 2-amino-3-(N-m-anisyl carboxamido)-4,5-
dimethyl thiophene MSR-4
Reaction 3: The intermediate obtained from the previous
step dissolved in alcohol (30 ml) sulphur(1.28g; 0.04M)
was added with stirring by maintaining the temperature
between 45-50C during addition. To the reaction mixture,
diethyl amine (6.0 ml) was added drop wise the stirring
was continued for 1hr at 45-50C and chilled overnight.
The solid obtained was filtered, washed with ethanol and
crystallized from benzene.
The formation of the parent compound was confirmed by
Lassingnes test, TLC, UV and IR spectra. The IR spectra
exhibit a distinct peak at 3339 cm
-1
(NH
2
group) confirms
the parent compound.
General method for the syntheses of 2-[(substituted
benzylidene) amino]-3-(N-m-anisylcarboxamido)-4,5
substitutedthiophenes (MSR-4a-4k): A mixture of the
starting compound (MSR-5) (0.005 M) and the required
aryl aldehydes (0.005 M) in isopropyl alcohol (30 ml) and
catalytic amount of glacial acetic acid (2 ml) was taken
into a conical flask and subjected to microwave irradiation
for 30 seconds. The mixture was cooled to room
temperature, the solid separated was filtered, washed with
isopropyl alcohol and recrystallised with DMF: Water
mixture (5:1)


Vol 1/Issue 6/ Nov-December 2012 Parmesh et al
www.pharmtechmedica.com 211

Reaction 1
CN CH
2
O
O
C
2
H
5
NH C
H
2
CN
O
-C
2
H
5
OH
NH
2
+
160 - 170 C
0
OCH
3 OCH
3

m- Anisidine Ethyl cyano acetate m-methoxy cyano acetanilide (m-methoxy aniline)

Reaction 2
HN
C

O
CN
NHCOCH
2
CN
CH
3
COOH/CH
3
COONH
4
O H
3
C
H
3
C
+
Benzene, refluxed for 8hrs
OCH
3
OCH
3
R
1
R
2

m-methoxy cyano Ethyl Methyl ketone 2-cyano-2-( alkylidine)
acetanilide m-anisyl carboxamide

Reaction 3
HN
C
O
S
2
HN
C
2
H
5
OH
S, (C
2
H
5
)
2
NH
HN
C

O
CN
45 - 50
0
C
MSR-4
OCH
3
OCH
3
R
1
R
2
R
1
R
2

2-cyano-2-(methylidine) 2-amino-3-(N-m-anisyl carboxamido)
m-anisyl carboxamide 4,5 disubstituted thiophenes

General Method
CH
3
COOH
C=N
O
H
R
HN
C
O
S
2
HN
HN
C
O
S
R
H
M.W.,IPA
+
MSR-4
OCH
3
OCH
3
a-k
R
1
R
2
R
1
R
2
MSR 4a-4k

2-amino-3-(N-m-anisyl Various aromatic Title compounds
Carboxamido) aldehydes



Substitution Comp. No.
Where R
=3,4,5-Trimethoxy benzaldehyde (MSR-4a)
= 3, 4-Dimethoxy benzaldehyde (MSR-4b)
= 2-Nitro benzaldehyde (MSR-4c)
= 3-Nitro benzaldehyde (MSR-4d)
= 2-Chloro benzaldehyde (MSR-4e)
= 4-Hydroxy benzaldehyde (MSR-4f)
= 4-Hydroxy-3-methoxy benzaldehyde (MSR-4g)
= 2-Hydroxy benzaldehyde (MSR-4h)
= 2-Methoxy benzaldehyde (MSR-4i)
= 4-Dimethyl amino benzaldehyde (MSR-4j)
= 4-Chloro benzaldehyde (MSR-4k)

Vol 1/Issue 6/ Nov-December 2012 Parmesh et al
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Table 1 Spectral data
X max.
(nm)
IR 1 H NMR
4-di methyl
amino
benzaldehyde
211 3736cm
-1
(NH);1667cm
-1
(C=O); 1610
cm
-1
,1526 cm
-1
(Ar-C=C) ; 1605 cm
-
1
(-N=CH); 1188 cm
-1
(C=N) 778.75
(C-S)

3,4,5-
trimethoxy
benzaldehyde
235 3226 cm
-1
(NH); 1669 cm
-1
(C=O);
1614 cm
-1
,1508 cm
-1
(ArC=C); 1665
cm
-1
(-N=CH); 1302 cm
-1
(CN);1099
cm
-1
(-C-0-C) 772.75 (C-S)
8.5(1H, s,of N=CH),7.3-
7.5(2H,m.aromatic H)7.4-
7.5(4H,m.aromaticH)7.4
(2H,s,NH
2
of
amide)6.9(1H,s H of
thiophene)3.8(9H,s,of
OCH
3
)
2-hydroxy
benzaldehyde


251


3400 cm
-1
(s)(OH); 3064 cm
-1
(NH);
1669.93 cm
-1
(C=O); 1676 cm
-1
(-
N=CH); 1614 cm
-1
,1522 cm
-1
(Ar-
C=C);1319 cm
-1
(C-N) 778.67 (C-S)



Table 2: Anti Bacterial Activity Data

Comp Code

R
ZONE OF INHIBITION IN mm.
S. Aureus B. Subtilis E. coli Klebsiella
MSR-5a 3,4,5-tri methoxy 03 02 NA NA
MSR-5b 3,4-dimethoxy 03 04 02 03
MSR-5c 2-nitro 05 04 05 06
MSR-5d 3-nitro 06 05 06 07
MSR-5e 2-chloro 07 09 07 10
MSR-5f 4-hydroxy 05 02 NA NA
MSR-5g 4-hydroxy,3-methoxy 05 05 NA NA
MSR-5h 2-hydroxy 06 03 02 07
MSR-5i 2-methoxy 07 05 NA NA
MSR-5 j p-dimethyl amino 04 02 04 03
MSR-5 k 4-chloro 11 09 08 11
Ampicillin ---------- 11 12 19 12
Norfloxacin ---------- 12 15 17 15

Result and Discussion
Based upon the fact, the present investigation was planned
and considerable interest has been shown in the synthesis
of 2-amino-3-(N-m-anisyl carboxamido)-4,5-di
substituted thiophene (MSR-4) was carried out by
Gewald reaction.
New series of title compounds were synthesized from 2-
amino-3-(N-m-anisyl carboxamido)-4,5-di substituted
thiophene (MSR-4) by heating in a microwave oven with
various substituted aromatic aldehydes in isopropyl
alcohol with glacial acetic acid as a catalyst to yield MSR
4a-4k.
The new series of title compounds synthesized were
confirmed preliminarily by M.P, TLC, UV, IR, and
further confirmed by NMR and Mass spectral analysis.
Conclusion
From the antibacterial activity results, it was observed that
both electron donating and electron withdrawing groups
on the aldehydic phenyl ring of the compounds influenced
the activity. Among all the compounds tested, MSR-4c
was found to be most active against both Gram-positive
and Gram-negative bacteria. The remaining compounds of
the series exhibited mild to moderate activities when
compared to the standards.
Acknowledgements
The author is thankful to Management, The Oxford
college of Pharmacy for giving the opportunity to
work, and PES College of Pharmacy for providing
necessary facilities.
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