Synthesis and evaluation of some new benzothiazole derivatives as potential antimicrobial agents

Article abstract of DOI:10.1016/j.ejmech.2010.03.019

As benzothiazole has proven to be good antimicrobial agent, a novel series of Schiff bases of benzothiazole derivatives were synthesized. Thus condensation of 5-[2-(1,3-benzothiazol-2-yl-amino) ethyl]-4-amino-3-mercapto-(4H)-1,2,4- triazole 5 with appropriate aromatic aldehydes afforded 5-[2-(1,3-benzothiazol- 2-yl-amino)ethyl]-4-(arylideneamino)-3-mercapto-(4H)-1,2,4-triazoles 6a-g. Structures of the synthesized compounds were elucidated on the basis of elemental analyses and spectral data. All the synthesized compounds were screened for their antimicrobial activity.

Full text of DOI:10.1016/j.ejmech.2010.03.019

European Journal of Medicinal Chemistry 45 (2010) 2938e2942
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and evaluation of some new benzothiazole derivatives as potential
antimicrobial agents
,
b
a
a
a
Balram Soni a , Mahendra Singh Ranawat , Rambabu Sharma , Anil Bhandari , Sanjay Sharma
*
a Faculty of Pharmaceutical Sciences, Jodhpur National University, Narnadi, Jodhpur, Rajasthan 342 003, India
b B.N.College of Pharmacy, Udaipur, Rajasthan 313001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
As benzothiazole has proven to be good antimicrobial agent, a novel series of Schiff bases of benzo-
thiazole derivatives were synthesized. Thus condensation of 5-[2-(1,3-benzothiazol-2-yl-amino)
ethyl]-4-amino-3-mercapto-(4H)-1,2,4-triazole 5 with appropriate aromatic aldehydes afforded 5-[2-(1,3-
benzothiazol-2-yl-amino)ethyl]-4-(arylideneamino)-3-mercapto-(4H)-1,2,4-triazoles 6aeg. Structures of
the synthesized compounds were elucidated on the basis of elemental analyses and spectral data. All the
synthesized compounds were screened for their antimicrobial activity.
Received 9 January 2010
Received in revised form
10 March 2010
Accepted 16 March 2010
Available online 25 March 2010
Ó 2010 Elsevier Masson SAS. All rights reserved.
Keywords:
Benzothiazole
Schiff’s base
1,2,4-triazole
Antimicrobial activity
1. Introduction
2. Chemistry
Despite numerous attempts to develop new structural prototype
in the search for more effective antimicrobials, benzothiazole still
remain as one of the most versatile class of compounds against
microbes [1e5] and therefore, are useful substructures for further
molecular exploration. Benzothiazole derivatives have attracted
continuing interest because of their varied biological activities viz.
antitumour [6e11], antitubercular [12], antimalarial [13], anticon-
vulsant [14], antihelmintic [15], analgesic [16], anti-inflammtory [17]
andantidiabetic[18]. Substituted2-arylbenzothiazoleshaveemerged
in recent years as an important pharmacophore in non-invasive
diagnosis of Alzheimer’s disease [6]. Recently, benzothiazole deriva-
tives have been evaluated as potential amyloid-binding diagnostic
agents inneurodegenerativedisease [19,20] and asselectivefattyacid
amide hydrolase inhibitors [21]. Azoles, in particular, 1,2,4-triazoles
have shownuseful antimicrobial activity [22,23]. Azomethine linkage
has also shown an array of biological activities viz. antimicrobial [24]
and anti-inflammatory [25]. These findings prompted us to synthe-
size 5-[2-(1,3-benzothiazol-2-yl-amino)ethyl]-4-(arylideneamino)-
3-mercapto-(4H)-1,2,4-triazoles 6aeg having different substitutions
onthearomaticringpossessingazomethinelinkageandevaluated for
their antimicrobial activity.
The reaction sequence for different title compounds is outlined
in Scheme 1. 2-Aminobenzothiazole 1 required as the starting
material was prepared according to the literature procedure [26]. 2-
aminobenzothiazole 1 on N-acrylation with methyl acrylate in the
presence of glacial acetic acid gave methyl-3-(1,3-benzothiazol-2-
yl-amino)propionate 2 which on treatment with hydrazine hydrate
in presence of alcohol resulted in the formation of 3-(1,3-benzo-
thiazol-2-yl-amino)propanoylhydrazine 3. Compound 3 on treat-
ment with carbon disulphide in presence of potassium hydroxide
gave potassium-2-[3-(1,3-benzothiazol-2-yl-amino)propanoylhy-
drazine]-1-carbodithionate 4 which on treatment with hydrazine
hydrate resulted in the formation of 5-[2-(1,3-benzothiazol-2-yl-
amino)ethyl]-4-amino-3-mercapto-(4H)-1,2,4-triazole 5. Conden-
sation of compound 5 with various selected aromatic aldehydes
furnished Schiff’s bases, 5-[2-(1,3-benzothiazol-2-yl-amino)ethyl]-
4-(arylideneamino)-3-mercapto-(4H)-1,2,4-triazoles 6aeg. The
physical and analytical characteristics of the synthesized
compounds are presented in Table 1. The purity of the compounds
was monitored by TLC and the structures of all the derivatives were
assigned by IR, 1H NMR spectroscopic data, which are consistent
with the proposed molecular structures.
3. Antimicrobial activity
The synthesized compounds 6aeg were screened for their
antibacterial activity against Bacillus subtilis MTCC 441, Escherichia
* Corresponding author. Tel.: þ91 94685 53979; fax: þ91 2931 281416.
E-mail address: brpharma@rediffmail.com (B. Soni).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.03.019

B. Soni et al. / European Journal of Medicinal Chemistry 45 (2010) 2938e2942
2939
N
S
gl. acetic acid
N
S
NH2
NHCH 2CH2COOCH 3
NH2NH2.H2O
CH2=CHCOOCH
3
1
2
N
S
N
S
SK+
CS2/KOH
NHCH 2CH2CONHNH
NH2NH2.H2O
C
NHCH 2CH2CONHNH 2
S
4
3
N
N
N
Ethanol,
Conc.H 2SO4
N
S
N
N
NHCH 2CH2
SH
HC
NHCH 2CH2
N
N
S
SH
OHC
6a-g
N
5
NH2
R
R
Compound
R
6a
6b
6c
H
4-OH
2-NO2
6d
6e
6f
3-NO2
2-Cl
4-N(CH3)2
3,4-OCH3
6g
Scheme 1. Synthetic pathway for the preparation of compounds 2e6.
coli MTCC 443 and Streptomyces griseus MTCC 1540 by cup-plate
method in nutrient agar medium with an incubation of 24 h at
37 ꢀC. The zone of inhibition was measured in millimeters using 1,
4. Results and discussion
The synthesized compounds 6aeg were evaluated for antibac-
terial and antifungal activity. All the compounds tested showed
some degree of antimicrobial activity. For all drugs, the minimum
inhibitory concentration (MIC) of the compounds was defined as
the lowest concentration at which there was 100% inhibition of
growth compared with the growth for a drug free control. The
minimum inhibitory concentration for Ciprofloxacin is approxi-
10, 100, 200 and 500 mg/ml concentrations of synthesized
compounds 6aeg. Ciprofloxacin was used as a reference standard
and dimethyl formamide was used both as a solvent and as
a control. No inhibition zone was observed in control (i.e.,
for DMF).
The antifungal activity of the compounds 6aeg was assayed
against Candida albicans MTCC 227 and Aspergillus niger MTCC
282 by cup-plate method in Sabouraud’s dextrose agar medium
with an incubation of 48 h at 28 ꢀC. The zone of inhibition was
mately 10
the lowest antibacterial activity against all bacterial species with
a MIC of 500 g/ml. Compounds 6b and 6f are the most effective
compounds against B. subtilis with a MIC of 100 g/ml. For activity
against E. coli, compounds 6f and 6g yielded better activity with
a MIC of 100 g/ml in comparison to other compounds synthesized.
mg/ml against all microbes used. Compound 6a showed
m
measured in millimeters using 30
mg/ml concentration of
m
synthesized compounds 6aeg. Fluconazole was used as reference
standard and dimethyl formamide was used both as a solvent and
as a control. No inhibition zone was observed in control (i.e.,
for DMF).
m
The antimicrobial spectrum of substituted benzothiazoles against S.
griseus demonstrated that compounds 6b, 6f and 6g were the most
Table 1
Physical and analytical data of the compounds 2, 3, 4, 5 and 6aeg.
Compounds
Yield (%)
M.p. (ꢀC)
Mol. formula
Elemental analysesa (calculated %/found %)
C
H
N
2
3
4
5
6a
6b
6c
6d
6e
6f
6g
85
70
66
75
70
68
73
70
71
69
66
101e102
200e202
226e228
202e204
185e187
195e197
210e212
220e222
231e233
260e262
250e252
C11H12N2O2S
C10H12N4OS
C11H11N4OS3K
C11H12N6S2
(55.91/55.82)
(50.83/50.80)
(37.69/37.57)
(45.19/45.08)
(56.82/56.61)
(54.53/54.42)
(50.81/50.75)
(50.81/50.75)
(52.10/52.07)
(56.71/56.63)
(54.53/54.41)
(5.12/5.33)
(5.12/5.37)
(3.16/3.34)
(4.14/4.28)
(4.24/4.36)
(4.07/4.26)
(3.55/3.65)
(3.55/3.65)
(3.64/3.69)
(5.00/5.10)
(4.58/4.63)
(11.86/11.99)
(23.71/23.91)
(15.98/15.78)
(28.74/28.53)
(22.09/21.98)
(21.20/21.31)
(23.04/23.16)
(23.04/23.16)
(20.25/20.45)
(23.15/23.40)
(19.08/19.26)
C18H16N6S2
C18H16N6OS2
C18H15N7O2S2
C18H15N7O2S2
C18H15N6S2Cl
C20H21N7S2
C20H20N6O2S2
a
Elemental analyses for C, H and N were within ꢁ0.4% of the theoretical value.

2940
B. Soni et al. / European Journal of Medicinal Chemistry 45 (2010) 2938e2942
Table 2
Table 4
Antibacterial activity of compounds 6aeg against Bacillus subtilis.
Antibacterial activity of compounds 6aeg against Streptomyces griseus.
Compounds Concentrations
Compounds Concentrations
1
m
g/ml 10
mg/ml 100
mg/ml 200
mg/ml 500
m
g/ml MIC (
mg/ml)
1
m
g/ml 10
m
g/ml 100
m
g/ml 200
m
g/ml 500
mg/ml MIC (mg/ml)
6a
6b
6c
6d
6e
6f
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þ
ꢂ
P
P
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
500
100
200
200
200
100
500
10
6a
6b
6c
6d
6e
6f
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þ
e
P
P
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
500
100
200
200
200
100
100
10
þ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
P
þ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
e
ꢂ
þ
þ
þþ
P
þþ
P
P
þ
ꢂ
þ
ꢂ
P
þ
ꢂ
e
ꢂ
þ
þ
6g
þþ
ꢂ
6g
þþ
ꢂ
Ciprofloxacin þ
ꢂ
Ciprofloxacin þ
Symbols: total inhibition (no growth of organism) ¼ (ꢂ); poor growth compared to
standard ¼ (P); medium growth compared to standard ¼ (þ); confluent growth ¼
(þþ).
Symbols: total inhibition (no growth of organism) ¼ (ꢂ); poor growth compared to
standard ¼ (P); medium growth compared to standard ¼ (þ); confluent growth ¼
(þþ).
maximum activity by compound 6f whereas compound 6g showed
overall maximum activity against both the C. albicans and A. niger.
effective ones with a MIC of 100 mg/ml. The results of antibacterial
activity screening of the tested compounds are summarized in
Tables 2e4. The results of antibacterial activity showed that
compounds with a 4-hydroxy, 4-dimethylamino and 3,4-dime-
thoxy group on the aromatic ring showed good antibacterial
activity among all the synthesized compounds. The compounds 6b,
6f and 6g exhibited somewhat less activity whereas compounds 6a,
6c, 6d and 6e exhibited poor activity in comparison to standard,
Ciprofloxacin. From the above discussion it is evident that
compounds 6b, 6f and 6g emerged as the most active antibacterial
6. Experimental section
Melting points were determined in open capillary tubes and are
uncorrected. The purity of the compounds was checked on a silica
gel-G plates and visualization was done using iodine/UV lamp. IR
spectra were recorded on a Schimadzu FTIR spectrophotometer
using KBr pellet technique. 1H NMR spectra were recorded on
a Brucker Avance II 400 NMR spectrometer in CDCl3 and DMSO-d6
using TMS as an internal standard. Elemental analyses were carried
out with Elementer-Vario EL III elemental analyzer.
benzothiazoles with a MIC of 100
ising candidates for novel drugs.
mg/ml thus they could be prom-
The results of antifungal activity of test compounds were found
to be somewhat different from their antibacterial activity. The
results of antifungal activity showed that substitution at position 2
on the aromatic ring by a chloro group retained the activity (i.e.,
similar to compound 6a). Substitution by 2-nitro or 3-nitro group
decreases the activity whereas substitution by 3,4-dimethoxy
group resulted in an increase in activity and it was found to be
equivalent to standard Fluconazole. Thus, Compounds 6a, 6b, 6e
and 6g have emerged as the most effective antifungal agents
against C. albicans whereas compound 6g was the most active one
against A. niger. The results of antifungal activity of the tested
compounds are depicted in Table 5.
6.1. Synthesis of methyl-3-(1, 3-benzothiazol-2-yl-amino)
propionate (2)
An equimolar solution of 2-aminobenzothiazole (25 g,
0.166 mol) and methyl acrylate (15 ml, 0.166 mol) was refluxed for
15 h in presence of glacial acetic acid (10 ml). After completion of
the reaction (as monitored by TLC), the contents were concen-
trated, cooled and poured into crushed ice. The resulting solid
which separated out, was filtered, washed with water, dried and
recrystallized from ethanol to obtain the compound 2. IR (KBr):
3320 (NeH str.), 3060 (aromatic CeH str.), 2926e2855 (aliphatic
CeH str.), 1723 (C]O str. of ester), 1540e1440 (aromatic C]C str.),
1650 (C]N str. in ring), 1515 (NeH def.), 1300e1016 (CeOeC str. in
ester), 1220e1076 (aliphatic CeN str.), 880e720 (aromatic CeH
5. Conclusion
def.), 721 (CeS str. in ring) cmꢂ1
.
Summarizingly, a series of benzothiazole derivatives have been
synthesized successfully in appreciable yields and screened for
their in vitro antimicrobial activity against bacterial strains B. sub-
tilis, E. coli, S. griseus and fungal strains C. albicans and A. niger. From
the activity studies, it was concluded that among all benzothiazole
derivatives, antibacterial activity decreases when there is a o-
substitution and it increases with p-substitution showing
6.2. Synthesis of 3-(1,3-benzothiazol-2-yl-amino)
propanoylhydrazine (3)
To the solution of compound 2 (39.22 g, 0.166 mol) in alcohol
(30 ml), hydrazine hydrate (99%, 0.25 mol) was added. The
Table 3
Table 5
Antibacterial activity of compounds 6aeg against Escherichia coli.
Antifungal activity of compounds 6aeg.
Compounds Concentrations
Compounds
Zone of inhibition (30 mg/ml)
1
m
g/ml 10
mg/ml 100
mg/ml 200
mg/ml 500
m
g/ml MIC (
mg/ml)
Candida albicans
Aspergillus niger
6a
6b
6c
6d
6e
6f
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þ
P
P
P
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
500
200
200
200
200
100
100
10
6a
6b
6c
6d
6e
6f
6g
þþþ
þþþ
ꢂ
þþ
þ
þ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
e
ꢂ
þþ
þ
þ
þ
þ
ꢂ
P
P
P
þþþ
þþ
þþ
þ
ꢂ
e
ꢂ
6g
þþ
þþþ
þþþ
þþþ
þþþ
Ciprofloxacin þ
ꢂ
Fluconazole
Symbols: total inhibition (no growth of organism) ¼ (ꢂ); poor growth compared to
standard ¼ (P); medium growth compared to standard ¼ (þ); confluent growth ¼
(þþ).
Symbols: zone diameter of growth inhibition: (ꢂ) ¼ Inactive (<10 mm); (þ) ¼
weakly active (10e15 mm); (þþ) ¼ moderately active (16e21 mm); (þþþ) ¼
highly active (22e28 mm); (þþþ) ¼ fluconazole.

B. Soni et al. / European Journal of Medicinal Chemistry 45 (2010) 2938e2942
2941
resulting mixture was refluxed on steam bath for 10 h. After
6.5.4. 5-[2-(1,3-Benzothiazol-2-yl-amino)ethyl]-4-(3-
completion of the reaction, the excess alcohol was distilled off. The
resulting residue was washed with cold water, dried and recrys-
tallized from ethanolewater mixture (2:1) to give the compound 3.
IR (KBr): 3400, 3378 (NeH str. in amide), 1680 (C]O str. of amide),
nitrobenzylideneamino)-3-mercapto-(4H)-1,2,4-triazole (6d)
IR (KBr): 3440 (NeH str.), 1519 (asym. N]O str.), 1340 (sym. N]
O str.) cmꢂ1 1H NMR (DMSO-d6):
;
d
7.26e7.98 (m, 8H, AreH), 5.71
(s, 1H, ]CeNH), 3.27 (t, 2H, eNeCH2), 2.54 (t, 2H, eCeCH2), 8.1 (s,
1H, eN]CH), 10.72 (s, 1H, eSH).
1650e1630 (N-H def. in amide) cmꢂ1
.
6.5.5. 5-[2-(1,3-Benzothiazol-2-yl-amino)ethyl]-4-(2-
6.3. Synthesis of potassium-2-[3-(1,3-benzothiazol-2-yl-amino)
propanoylhydrazine]-1-carbodithionate (4)
chlorobenzylideneamino)-3-mercapto-(4H)-1,2,4-triazole (6e)
IR (KBr): 3440 (NeH str.), 750 (aromatic CeCl str.) cmꢂ1 1H
;
NMR (DMSO-d6):
3.23 (t, 2H, eNeCH2), 2.57 (t, 2H, eCeCH2), 8.1 (s, 1H, eN]CH),
10.82 (s, 1H, eSH).
d 7.24e7.99 (m, 8H, AreH), 5.65 (s, 1H, ]CeNH),
To the compound 3 (4.72 g, 0.02 mol), a solution of potassium
hydroxide (1.12 g, 0.02 mol) in 26 ml of alcohol and 2 ml of carbon
disulfide was added. The reaction mixture was diluted with 40 ml of
absolute alcohol and agitated for 10 h. The mixture was diluted with
50 ml of diethyl ether. The solid obtained was filtered, washed with
dryether, dried,andrecrystallizedfromethanoltogivethecompound
4. IR (KBr): 3300e3200 (NeH str.), 1667 (C]O str. of amide),
6.5.6. 5-[2-(1,3-Benzothiazol-2-yl-amino)ethyl]-4-(4-
dimethylaminobenzylideneamino)-3-mercapto-(4H)-1,2,4-triazole
(6f)
1648e1628 (NeH def.), 1129 (C]S str.) cmꢂ1
;
1H NMR (DMSO-d6):
IR (KBr): 3440 (NeH str.), 1350-1190 (CeN str., N(CH3)2
group) cmꢂ1 1H NMR (DMSO-d6):
; d 7.26-7.91 (m, 8H, AreH),
d
7.29e7.85 (m, 4H, AreH), 5.65 (s,1H, ]CeNH), 3.1 (t, 2H, eNeCH2),
5.62 (s, 1H, ]CeNH), 3.22 (t, 2H, eNeCH2), 2.54 (t, 2H,
eCeCH2), 8.15 (s, 1H, eN]CH), 10.78 (s, 1H, eSH), 3.02 (s, 6H,
eN(CH3)2).
2.9 (t, 2H, eCH2eCO), 9.04 (s, 1H, eCONH), 4.6 (s, 1H, eNHeC]S).
6.4. Synthesis of 5-[2-(1, 3-benzothiazol-2-yl-amino) ethyl]-4-
amino-3-mercapto-(4H)-1,2,4-triazole (5)
6.5.7. 5-[2-(1,3-Benzothiazol-2-yl-amino)ethyl]-4-(3,4-
dimethoxybenzylideneamino)-3-mercapto-(4H)-1,2,4-triazole (6g)
A mixture of compound 4 (3.5 g, 0.01 mol) and hydrazine hydrate
(99%, 10 ml, 0.01 mol) was refluxed for 2 h with occasional shaking.
The solution was then cooled and poured into ice cold water. This
was acidified with dilute HCl. The precipitate obtained, was filtered,
dried and recrystallized from ethanol to obtain compound 5. IR
(KBr): 3400e3300 (NeH str.), 2900e2870 (CeH str.), 2625 (SeH str.)
IR (KBr): 3440 (NeH str.), 2807 (aromatic OCH3 str.) cmꢂ1 1H
;
NMR (DMSO-d6): d 7.26e7.9 (m, 8H, Ar-H), 5.61 (s, 1H, ]CeNH), 3.2
(t, 2H, eNeCH2), 2.52 (t, 2H, eCeCH2), 8.18 (s, 1H, eN]CH), 10.75
(s, 1H, eSH), 3.85 (s, 6H, eOCH3).
cmꢂ1; 1H NMR (DMSO-d6):
d 7.25e7.84 (m, 4H, AreH), 5.63 (s,1H, ]
Acknowledgement
CeNH), 3.2 (t, 2H, eNeCH2), 2.5 (t, 2H, eCeCH2), 5.84 (s, 2H,
eNeNH2), 10.22 (s, 1H, eSH).
The author is thankful to Department of Microbiology,
Lachoo Memorial College of Science and Technology, Jodhpur,
India, for helping in evaluating antimicrobial activity. Thanks are
due to CIL Punjab University, Chandigarh, India, for spectral
analysis.
6.5. General procedure for the synthesis of compounds (6aeg)
To a stirred solution of compound 5 (2.92 g, 0.01 mol) in ethanol
(15 ml) containing concentrated sulfuric acid (0.5 ml) was added
appropriate aromatic aldehydes (0.01 mol) and the mixture
refluxed for 1 h on a water bath. The solid obtained on cooling and
pouring in cold water, was filtered, dried and recrystallized from
ethanol to afford the title compounds.
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6.5.2. 5-[2-(1,3-Benzothiazol-2-yl-amino)ethyl]-4-(4-
hydroxybenzylideneamino)-3-mercapto-(4H)-1,2,4-triazole (6b)
IR (KBr): 3550 (aromatic OeH str.), 3440 (NeH str.), 2900e2870
(CeH str.), 2625 (SeH str.), 1657 (C]N str. in imine) cmꢂ1; 1H NMR
(DMSO-d6):
d 7.24e7.98 (m, 8H, AreH), 5.66 (s, 1H, ]CeNH), 3.23
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6.5.3. 5-[2-(1,3-Benzothiazol-2-yl-amino)ethyl]-4-(2-
nitrobenzylideneamino)-3-mercapto-(4H)-1,2,4-triazole (6c)
IR (KBr): 3440 (N-H str.), 1519 (asym. N]O str.), 1340 (sym. N]
O str.) cmꢂ1 1H NMR (DMSO-d6):
; d 7.26e7.99 (m, 8H, AreH), 5.70
(s, 1H, ]CeNH), 3.25 (t, 2H, eNeCH2), 2.55 (t, 2H, eCeCH2), 8.13 (s,
1H, eN]CH), 10.76 (s, 1H, eSH).

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