Synthesis and antibacterial activity of a novel series of 2,3-diaryl-substituted-imidazo(2,1-b)-benzothiazole derivatives

Article abstract of DOI:10.1002/ardp.200900260

Benzothiazole and imidazole compounds are extensively studied heterocyclics due to their wide spectrum of bioactivities. Among them, the imidazo(2,1-b)-benzothiazole derivatives are pharmacologically important because of their immunostimulant, anti-inflammatory, antifungal, antimicrobial, antitumor, and other activities. In the present research work, a novel series of 2,3-diaryl-substituted imidazo(2,1-b)-benzothiazoles 13a-o have been synthesized by reaction of substituted 2-aminobenzothiazoles 1-8 and an appropriately substituted a-bromo-1-(4″-substituted)-phenyl-2-(4′- substituted)-phenyl-1-ethanones 9-12 in the presence of anhydrous acetonitrile. They were characterized by physicochemical, elemental, and spectral (IR, ¹H-NMR, and Mass) data. All the synthesized compounds were screened for their in-vitro antibacterial activity against Gram-positive, Gram-negative bacteria. The investigation of antibacterial screening data revealed that most of the compounds tested have demonstrated congruent activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa as compared with the standard ampicillin. Among the series, compounds 13d, 13h, and 13m exhibited excellent an antibacterial activity profile as compared with the standard. In summary, preliminary results indicate that some of the newly synthesized title compounds exhibited promising antibacterial activities and they warrant more consideration as prospective antimicrobials.

Full text of DOI:10.1002/ardp.200900260

Arch. Pharm. Chem. Life Sci. 2010, 343, 353–359
M. Palkar et al.
353
Full Paper
Synthesis and Antibacterial Activity of a Novel Series of 2,3-
Diaryl-substituted-imidazo(2,1-b)-benzothiazole Derivatives
Mahesh Palkar1, Malleshappa Noolvi2, Ramappa Sankangoud1, Veeresh Maddi1,
Andanappa Gadad3, and Laxmi Venkat G. Nargund4
1 Department of Pharmaceutical Chemistry, K. L. E. University's College of Pharmacy, Vidyanagar, Hubli,
Karnataka, India
2 Department of Pharmaceutical Chemistry, ASBASJSM College of Pharmacy, Bela, Ropar, Punjab, India
3 RAK College of Pharmaceutical Sciences, RAK Medical and Health Sciences University, Ras Al Khaimah,
United Arab Emirates
4 Department of Pharmaceutical Chemistry, Nargund College of Pharmacy, Dattatreyanagar, Bangalore,
Karnataka, India
Benzothiazole and imidazole compounds are extensively studied heterocyclics due to their wide
spectrum of bioactivities. Among them, the imidazo(2,1-b)-benzothiazole derivatives are pharma-
cologically important because of their immunostimulant, anti-inflammatory, antifungal, anti-
microbial, antitumor, and other activities. In the present research work, a novel series of 2,3-di-
aryl-substituted imidazo(2,1-b)-benzothiazoles 13a–o have been synthesized by reaction of substi-
tuted 2-aminobenzothiazoles 1–8 and an appropriately substituted a-bromo-1-(499-substituted)-
phenyl-2-(49-substituted)-phenyl-1-ethanones 9–12 in the presence of anhydrous acetonitrile.
1
They were characterized by physicochemical, elemental, and spectral (IR, H-NMR, and Mass)
data. All the synthesized compounds were screened for their in-vitro antibacterial activity
against Gram-positive, Gram-negative bacteria. The investigation of antibacterial screening data
revealed that most of the compounds tested have demonstrated congruent activity against Staph-
ylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa as compared with the
standard ampicillin. Among the series, compounds 13d, 13h, and 13m exhibited excellent an
antibacterial activity profile as compared with the standard. In summary, preliminary results
indicate that some of the newly synthesized title compounds exhibited promising antibacterial
activities and they warrant more consideration as prospective antimicrobials.
Keywords: 2-Aminobenzothiazole / Antibacterial activity / Imidazo(2,1-b)benzothiazole /
Received: October 27, 2009; Accepted: December 31, 2009
DOI 10.1002/ardp.200900260
drug-resistant strains of the Gram-positive pathogens
like Streptococcus, Enterococcus, and Staphylococcus, and
Gram-negative pathogens like Escherichia, Salmonella, and
certain Pseudomonas strains. Especially the emergence of
multidrug-resistant strains of Gram-positive bacterial
pathogens such as methicillin-resistant Staphylococcus
aureus and Staphylococcus epidermis and vancomycin-
resistant Enterococcus is an alarming problem of ever-
increasing significance [1–4]. To meet this crisis success-
fully, many researchers across the globe are working to
unearth new compounds which can selectively attack
novel targets in microorganisms. Hence, the develop-
ment of novel, potent, and unique antibacterial agents is
Introduction
Bacterial resistance to antibacterial agents or antibiotics
is of grave concern in the medical community, as many
species of bacteria have evolved resistance to certain anti-
biotics and synthetic agents. Therefore, there could be a
rapidly growing global crisis in the clinical management
of life-threatening infectious diseases caused by multi-
Correspondence: Mahesh B. Palkar, M. Pharm., Assistant Professor,
Department of Pharmaceutical Chemistry, K. L. E. University's College of
Pharmacy, Vidyanagar, Hubli-580 031, Karnataka, India.
E-mail: bpmahesh1@gmail.com
Fax: 91-836-2371694
i 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

354
M. Palkar et al.
Arch. Pharm. Chem. Life Sci. 2010, 343, 353–359
Table 1. Physicochemical data of a novel series of 2,3-diaryl-substituted imidazo(2,1-b)-benzothiazoles 13a–o.
§
Compound R1
R2
R9
R99
Yield
(%)
M.p.
(8C)
Rf
Mol. Formula
Mol.
Weight
13a
13b
13c
13d
13e
13f
13g
13h
13i
13j
13k
13l
13m
13n
13o
7-Cl
7-F
7-H
7-NO2
7-Br
7-F
7-Cl
6-NO2
7-F
7-Cl
7-Cl
7-NO2
7-NO2
7-Br
6-NO2
8-Cl
8-Cl
8-H
8-H
8-H
8-H
8-H
8-H
8-H
8-H
8-Cl
8-H
8-H
8-H
8-H
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
Br
69%
71%
68%
75%
79%
62%
79%
65%
56%
71%
5%
205
186
168
212
135
155
190
205
160
300
300
230
236
121
196
0.62
0.54
0.43
0.76
0.61
0.88
0.81
0.27
0.40
0.98
0.84
0.28
0.56
0.55
0.69
C23H16SN2Cl2O2
C23H16SN2FClO2
C23H18SN2O2
C23H17SN3O4
C23H17SN2Br
C23H17SN2FO2
C23H17SN2O2Cl
C23H17SN3O4
C22H14SN2OFBr
C22H14SN2OCBr
C22H14SN2OCl2
C22H15SN3O3
C23H17SN3O
455.36
438.90
386.47
431.36
433.36
404.46
420.91
431.26
453.33
446.34
425.33
401.44
383.47
449.36
415.46
Br
OCH3
OCH3
CH3
CH3
CH3
H
67%
60%
73%
68%
OCH3
OCH3
OCH3
C23H17SN2OBr
C23H17SN3O3
§ All synthesized compounds were purified by column chromatography using n-hexane and ethyl acetate (6:4) as a mobile phase
and iodine vapors as visualizing agent.
the preeminent way to overcome bacterial resistance and
develop effective therapies [5].
Results and discussion
Chemistry
The benzothiazole and imidazole compounds are
extensively studied heterocyclics due to their wide spec-
trum of bioactivities. Despite numerous attempts to
develop new structural prototypes in the search for more
effective antimicrobials, the imidazo(2,1-b)-benzothi-
azoles still remain as one of the most versatile classes of
compounds against microbes and, therefore, are an
important component of molecules in drug discovery.
Literature survey revealed that various compounds con-
taining the imidazo(2,1-b)-benzothiazole moiety are well
acknowledged to possess immunostimulant, anti-inflam-
matory [6, 7], antifungal, antimicrobial [8], antitumor [9],
antituberculosis [10], anticonvulsant [11], and anthel-
mintic [12] activities. Therefore, such medicinal proper-
ties associated with these two heterocycles render them
as useful structural units in drug research. These find-
ings prompted us to synthesize imidazo(2,1-b)-benzothi-
azole derivatives as part of our ongoing research pro-
gram aiming at the synthesis of a variety of heterocyclic
systems for biological evaluation [13–15]. Herein, we
report the synthesis of a novel series of 2,3-diaryl substi-
tuted imidazo(2,1-b)-benzothiazoles 13a–o for the investi-
gation of an antibacterial activity profile.
The synthesis of 2,3-diaryl-substituted imidazo(2,1-b)ben-
zothiazoles 13a–o was achieved through the versatile
and efficient synthetic route outlined in Scheme 1. Reac-
tion of substituted 2-aminobenzothizoles 1–8 with substi-
tuted a-bromo-1-[49-substituted] phenyl-2-[499-substituted]
phenyl-1-ethanones 9–12 in the presence of anhydrous
acetonitrile at a temperature of 65–758C seemed to be a
convenient route for the synthesis of desired molecules.
Starting materials i.e., various substituted 2-aminobenzo-
thiazoles 1–8 were prepared by three different methods
with respect to the position of substitution. The 2-amino-
6,7-disubstituted benzothiazoles 1 and 2 were synthe-
sized by the reaction of substituted aniline and potas-
sium thiocyanate in the presence of glacial acetic acid at
08C by following the literature procedure [16]. In order to
produce the 2-amino-6-substituted benzothiazoles 3–7,
the literature procedure of Brewster et al. [17] was fol-
lowed. 2-Amino-5-nitro-benzothiazole 8 was prepared by
the reaction of 2,4-dinitrochlorobenzene and thiourea in
the presence of pyridine under a reflux condenser for 3 h
[18]. Synthesis of 1,2-(p-substituted)diaryl-1-ethanones
was carried out by reacting appropriate phenyl acetic
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Arch. Pharm. Chem. Life Sci. 2010, 343, 353–359
Antibacterial Activity of Imidazo(2,1-b)-benzothiazoles
355
Reagents and conditions: (a) CH3COOH, KSCN, Br2, NH3, 08C, stirring, 10 h; (b) thiourea, pyridine, reflux, stirring, 3 h; (c) H3PO4, (CF3CO)2O, 258C, 1 min; (d) Br2, CHCl3,
508C, 0.5 h; (e) anhydrous acetonitrile, methylcellosolve, P2O5, reflux, 4 h.
Scheme 1. Synthetic route of a novel series of 2,3-diaryl-substituted imidazo(2,1-b)-benzothiazoles.
acid with various substituted aromatic hydrocarbons in presence of anhydrous acetonitrile at a temperature of
the presence of orthophosphoric acid and trifluoroacetic 65–758C for 1 h with constant stirring. This way, we suc-
anhydride [15]. Subsequently, 1,2-(p-substituted)diaryl-1- cessfully obtained the hydrobromide salts, but the se-
ethanones were subjected to bromination using liquid cond step of the reaction was unsuccessful as per the lit-
bromine in chloroform to obtain a-bromo-1,2-(p-substitu- erature procedure [19]. Therefore, we modified the sec-
ted)diaryl-1-ethanones 9–12 as shown in Scheme 1. ond procedure by the addition of a trace quantity of phos-
Efforts to convert compounds 1–8 into the target mole- phorus pentoxide into the reaction mixture containing
cules 13a–o under a variety of conditions [6] were not suc- methylcellosolve and continued heating under reflux for
cessful. Hence, an alternative method was adopted. This 2–6 h. This resulted in the formation of the desired com-
involved the reaction of substituted 2-aminobenzothi- pounds 2,3-diaryl-substituted imidazo(2,1-b)benzothi-
zoles 1–8 with substituted a-bromo-1-[49-substituted] phe- azoles 13a–o. Structures of the synthesized compounds
nyl-2-[499-substituted] phenyl-1-ethanones 9–12 in the were established on the basis of physicochemical and ele-
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356
M. Palkar et al.
Arch. Pharm. Chem. Life Sci. 2010, 343, 353–359
Table 2. Spectral and elemental analysis data of a novel series of 2,3-diaryl-substituted imidazo(2,1-b)-benzothiazoles 13a–o.
Compound
IR (KBr, cm–1)
1H-NMR
Mass
Elemental (CHN) Analysis
(DMSO-d6, d, ppm)
3051.44 (aromatic C-H str),
2923.52 (methyl C-H str),
3.78 (s, 3H, OCH3), 3.86 (s, 3H, 454.01 (27.3%) [M+], 422.01
OCH3), 7.04–7.12 (d, 4H, Ar-H), (21.1%), 393.02 (19.2%),
Anal. calcd. for
C23H16SN2Cl2O2: C, 60.68; H,
1615.78 (aromatic C=C str), 7.52–7.62 (m, 4H, Ar-H), 7.75
383.01 (16.8%), 321.01 (100%), 3.53; N, 6.14. Found: C,
1290.83 (Ar-O-CH3 str)
(s, 1H, Ar-H), 7.93 (s, 1H, Ar-H) 276.03 (14.2%), 239.01 (25.1%), 60.63; H, 3.49; N, 6.08.
193.03 (35.7%), 134.01 (61.2%),
108.03 (29.4%), 90.02 (32.6%)
3087.77(aromatic C-H str),
2944.12 (methyl C-H str),
1628.99 (aromatic C=C str), 7.22 (s, 1H, Ar-H), 7.42–7.60 (d,
3.82 (s, 3H, OCH3). 3.85 (s, 3H,
OCH3), 7.03–7.16 (d, 4H, Ar-H),
Anal. calcd. for
C23H16SN2FClO2: C, 62.92; H,
3.69; N, 6.35. Found: C,
62.97; H, 3.69; N, 6.36.
1281.64 (Ar-O-CH3 str)
4H, Ar-H), 7.73 (s, 1H, Ar-H)
3047.24(aromatic C-H str),
2916.90 (methyl C-H str),
3.80 (s, 6H, OCH3), 7.15–7.23
(d, 4H, Ar-H), 7.47–7.57 (d, 4H, (18.4%), 385.03 (19.6%), 369.01 C, 64.02; H, 3.98; N, 9.76.
431.02 (33.4%) [M+], 399.02
Anal. calcd. for C23H17SN3O4:
1621.46 (aromatic C=C str), Ar-H), 7.88 (s,1H, Ar-H), 7.93– (28.2%), 324.01 (100%), 243.02 Found: C, 63.98; H, 3.94; N,
1249.66 (Ar-O-CH3 str)
8.08 (d, 2H, Ar-H)
(33.5%), 189.01 (26.1%), 134.02 9.72.
(67.3%), 108.02 (41.6%), 90.03
(38.6%)
3062.25 (aromatic C-H str),
2934.24 (methyl C-H str),
3.74 (s, 3H, OCH3). 3.79 (s, 3H, 406.02 (16.2%) [M + 1]+, 404.02 Anal. calcd. for C23H17SN2FO2:
OCH3), 7.11–7.19 (d, 4H, Ar-H), (13.3%) [M+], 370.02 (24.1%),
C, 68.33; H, 4.25; N, 6.92.
1606.59 (aromatic C=C str), 7.27 (s, 1H, Ar-H), 7.51–7.67
343.01 (19.4%), 322.02 (42.9%), Found: C, 68.42; H, 4.24; N,
1285.34 (Ar-O-CH3 str)
(d, 4H, Ar-H), 7.89–7.97 (d, 2H, 251.05 (28.3%), 179.02 (37.6%), 6.95.
Ar-H)
135.03 (19.2%), 134.01(100%),
107.07 (36.3%), 91.01 (31.9%)
3038.06 (aromatic C-H str),
2953.56 (methyl C-H str),
1635.13 (aromatic C=C str), 7.32 (s, 1H, Ar-H), 7.49–7.61
3.81 (s, 3H, OCH3). 3.84 (s, 3H,
OCH3), 7.07–7.18 (d, 4H, Ar-H),
Anal. calcd. for
C23H17SN2O2Cl: C, 65.65; H,
4.06; N, 6.64. Found: C,
65.63; H, 4.02; N, 6.68.
1279.75 (Ar-O-CH3 str)
(d, 4H, Ar-H), 7.94–8.05 (d, 2H,
Ar-H)
3072.11 (aromatic C-H str),
2941.53 (methyl C-H str),
3.79 (s, 3H, OCH3), 3.85 (s, 3H, 430.01 (24.1%) [M – 1], 395.02 Anal. calcd. for C23H17SN3O4:
OCH3), 7.18–7.26 (d, 4H, Ar-H), (14.9%), 388.02 (19.6%), 372.02 C, 64.07; H, 3.95; N, 9.73.
1614.67 (aromatic C=C str), 7.64–7.78 (d, 4H, Ar-H), 7.84 (s, (41.7%), 318.05 (100%), 273.03 Found: C, 64.1; H, 3.97; N,
1263.14 (Ar-O-CH3 str)
1H, Ar-H), 8.09–8.22 (m, 2H,
Ar-H)
(29.2), 225.02 (15.5%), 177.04 9.74.
(35.2%), 134.03 (78.6%), 108.01
(32.3%), 89.02 (15.8%)
3093.35 (aromatic C-H str),
2984.13 (methyl C-H str),
3.80 (s, 3H, OCH3), 7.06–7.13
(d, 2H, Ar-H), 7.31 (s, 1H, Ar-H), (26.7%), 420.01 (18.3%), 375.02 C22H14SN2OFBr: C, 58.31; H,
453.02 (22.5%) [M+], 431.03
Anal. calcd. for
1650.56 (aromatic C=C str), 7.52–7.58 (d, 2H, Ar-H), 7. 70– (17.4%), 327.04 (100%), 269.01 3.10; N, 6.20. Found: C,
1302.54 (Ar-O-CH3 str)
7.76 (d, 2H, Ar-H), 7.83–7.89
(d,2H, Ar-H), 8.08–8.15 (d, 2H, (17.5%), 135.02 (53.3%), 110.01
Ar-H) (44.9%), 88.05 (63.9%)
(22.4%), 227.01 (15.7%), 196.01 58.35; H, 3.13; N, 6.16.
3042.74 (aromatic C-H str),
2941.42 (methyl C-H str),
3.88 (s, 3H, OCH3), 7.23–7.31 (d, 401.01 (24.1%) [M+], 368.04
4H, Ar-H), 7.61–7.82 (m, 5H, Ar- (15.6%), 351.01 (31.2%), 320.03 C, 65.83; H, 3.78; N, 10.50.
Anal. calcd. for C22H15SN3O3:
1625.74 (aromatic C=C str), H), 7.95 (s,1H, Ar-H), 8.17–8.28 (72.3%), 248.02 (30.7%), 212.03 Found: C, 65.79; H, 3.79; N,
1274.96 (Ar-O-CH3 str)
(d, 2H, Ar-H)
(20.5%), 182.01 (27.4%), 133.06 10.46.
(100%), 110.07 (38.8%), 91.03
(33.4%)
3025.45 (aromatic C-H str),
2925.43 (methyl C-H str),
1.74 (s, 3H, CH3), 3.76 (s, 3H,
OCH3), 7.13–7.21 (d, 2H, Ar-H), (21.7%), 400.04 (25.1%), 382.06 C, 66.48; H, 4.11; N, 10.14.
417.02 (17.3%) [M + 2]+, 415.01 Anal. calcd. for C23H17SN3O:
1616.37 (aromatic C=C str), 7.43–7.50 (d, 2H, Ar-H), 7.64– (18.3%), 328.03 (53.2%), 256.03 Found: C, 66.45; H, 4.15; N,
1289.34 (Ar-O-CH3 str) 7.71 (d, 2H, Ar-H), 7.89–7.96 (28.8%), 194.05 (32.4%), 134.08 10.21.
(d, 2H, Ar-H), 8.12 (s, 1H, Ar-H) (100%), 109.07 (37.1%), 89.05
(34.6%)
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Arch. Pharm. Chem. Life Sci. 2010, 343, 353–359
Antibacterial Activity of Imidazo(2,1-b)-benzothiazoles
357
Table 3. In-vitro antibacterial activity of 2,3-diaryl-substituted imidazo(2,1-b)-benzothiazoles (13a, b, d, f, g–j, l, m, and o) against
selected strains (MIC in lg/mL)*.
Compd.
R1
R2
R9
R99
Gram-positive organisms
Gram-negative organisms
Staphylococcus Bacillus
Escherichia
coli
Pseudomonas
aeruginosa
aureus
subtilis
13a
13b
13d
13f
13g
13h
13i
13j
13l
7-Cl
7-F
7-NO2
7-F
7-Cl
6-NO2
7-F
7-Cl
7-NO2
7-NO2
6-NO2
–
8-Cl
8-Cl
8-H
8-H
8-H
8-H
8-H
8-H
8-H
8-H
8-H
–
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
Br
64
32
>128
32
0.5
2
32
0.25
32
128
8
0.5
2
>128
>128
0.5
2
32
0.5
64
>128
2
0.25
1
>128
>128
0.5
1
>128
0.5
>128
>128
4
0.25
0.5
16
0.25
32
64
2
0.25
4
0.5
Br
OCH3
CH3
CH3
–
13m
13o
Ampicillin
OCH3
OCH3
–
1
2
0.5
0.5
0.5
mental analysis and spectral data (IR, 1H-NMR, and Mass), activity against all evaluated organisms. Especially com-
which are summarized in Tables 1 and 2, respectively.
pounds 13d (MIC = 0.25 to 2 lg/mL), 13h (MIC = 0.25 to 0.5
lg/mL), and 13m (MIC = 0.25 to 1 lg/mL) showed high
antibacterial activity while compounds 13f (MIC = 0.5 to
Antibacterial activity
All the newly synthesized compounds 13a–o were eval- 2 lg/mL), 13l (MIC = 2 to 8 lg/mL), and 13o (MIC = 1 to 4
uated for their in-vitro antibacterial activity against two lg/mL) showed respectable antibacterial activity. A brief
Gram-positive bacterial strains namely, Staphylococcus investigation of the structure-activity relationship (SAR)
aureus (ATCC-25923) and Bacillus subtilis (ATCC 6633) and revealed that the compounds with a nitro (-NO2) or a halo
two Gram-negative bacterial strains namely, Escherichia group (especially fluoro) at position C-6 and C-7 of the
coli (ATCC-25922) and Pseudomonas aeruginosa (ATCC- imidazo(2,1-b)-benzothiazole nucleus contributed to a
27853) using the conventional agar-dilution method [20]. better antibacterial activity. Further, the presence of a
Ampicillin was used as the reference standard. The methoxy (-OCH3) group on the phenyl ring of either C-2
results of the in-vitro antibacterial activity screening of or C-3 of the imidazo(2,1-b)benzothiazole nucleus influ-
the novel series of 2,3-diaryl-substituted imidazo(2,1-b) enced the antibacterial activity. It is interesting to note
benzothiazoles (13a, b, d, f, g–j, l, m, and o) are summar- that the introduction of a bromo group to the aromatic
ized in Table 3. Among the series tested, three com- ring (compounds 13i and 13j), resulted in compounds
pounds (13d, 13h, and 13m) exhibited excellent antibac- with a poor antibacterial activity. However, the replace-
terial activity against both Gram-positive and Gram-nega- ment of the bromo by a methyl group (-CH3), as it is
tive bacteria while compounds 13f, 13i, 13l, and 13o observed in compounds 13m–o, retained the antibacte-
showed moderate to good antibacterial activity against rial activity. Hence, compounds 13d, 13h, and 13m have
the tested organisms. However, all other compounds in exhibited excellent in-vitro antibacterial activity against
the series were found to have less or poor activity against all the test organisms and have emerged as active anti-
both Gram-positive and Gram-negative bacteria as com- bacterial agents.
pared to the standard. Minimum inhibitory concentra-
tion (MIC) was recorded as the lowest concentration of a
compound that inhibits the growth of the tested micro-
organisms. In comparing the MIC values with the stand-
Conclusion
ard ampicillin (MIC = 0.5 lg/mL), compounds 13d, 13h, In the present paper, we report the synthesis, spectral
and 13m exhibit the most potent in-vitro antibacterial studies, and in-vitro antibacterial activity of a new series of
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358
M. Palkar et al.
Arch. Pharm. Chem. Life Sci. 2010, 343, 353–359
solution was stirred for an additional 2 h at 08C and, then, at
room temperature for 10 h. Then, it was allowed to stand over-
night during which period an orange-colored precipitate settled
at the bottom; water (6 mL) was added quickly and the slurry
was heated at 858C on a steam bath and filtered hot. The orange
residue was placed in a reaction flask and treated with 10 mL of
glacial acetic acid, heated again to 858C and was filtered hot.
The combined filtrates were cooled and neutralized with con-
centrated ammonia solution to pH 6, when a dark yellow precip-
itate was collected. Recrystallized from benzene (twice) after
treatment with charcoal gave the colorless plates of 2-amino-6,7-
dichloro-benzothiazole 1 while pale yellow-colored plates were
obtained for 2-amino-6-fluoro-7-chloro-benzothiazole 2.
novel 2,3-diaryl-substituted imidazo(2,1-b)-benzothiazole
derivatives 13a–o. These novel heterocyclic compounds
were prepared by cyclo-dehydration reaction between the
various substituted 2-aminobenzothiazole derivatives 1–8
and various substituted a-bromo-1-[49-substituted] phenyl-
2-[499-substituted] phenyl-1-ethanones 9–12inthepresence
of anhydrous acetonitrile and methylcellosolve, under
theinfluence of atrace quantity ofphosphorus pentoxide.
In general, the results of the in-vitro antibacterial activity
are also encouraging, as out of eleven compounds tested,
compounds 13d, 13h, and 13m exhibited antibacterial
activities, which are comparable or more potent regard-
ing their activity than the reference drug. The MIC values
of these novel compounds evidenced that the presence of
a nitro group at position C-6 or C-7 of the imidazo(2,1-b)-
benzothiazole nucleus gave rise to a better antibacterial
potency. Possible improvements in the antibacterial activ-
ity can be further achieved by slight modifications in the
ring substituents and/or extensive additional structural
activity investigations.
General procedure for the preparation of 2-amino-6-
substituted benzothiazole 3–7 [17]
The appropriately substituted aniline (0.1 mol) and potassium
thiocyanate (0.2 mol) were dissolved in 150 mL of glacial acetic
acid, cooled in ice, and stirred mechanically while a solution of
bromine (0.1 mol) in acetic acid (25 mL) was slowly added drop
by drop. External cooling was applied throughout the process to
keep the temperature below 108C and the stirring was contin-
ued for thirty minutes after all of the bromine had been added.
The precipitate of imino-benzothiazole hydrobromide was
removed by filtration with a pump, dissolved in warm water,
and the base was precipitated with alkali. The residue was recrys-
tallized from alcohol or ligroin to yield the derivatives of 2-
amino-6-substituted benzothiazole 3–7.
Experimental
Chemistry
All research chemicals were purchased from Sigma-Aldrich (St.
Louis, MO, USA) or Lancaster Co. (Ward Hill, MA, USA) and were
used as such for the reactions. Solvents except for those with lab-
oratory reagent grade were dried and purified according to the
literature, when necessary. Reactions were monitored by thin
layer chromatography (TLC) on pre-coated silica gel plates from
E. Merck and Co. (Darmstadt, Germany).
Melting points of the synthesized compounds were deter-
mined in a Thermonik (Mumbai, India) melting point apparatus.
IR spectra were recorded on a Thermo Nicolet IR200 FT-IR Spec-
trometer (Nicolet, Madison WI, USA) by using KBr pellets. The 1H-
NMR were recorded on Bruker AVANCE II 400 MHz (Bruker,
Rheinstetten/Karlsruhe, Germany) using DMSO-d6 as solvent.
Chemical shifts are reported in d [ppm] units with respect to
TMS as internal standard. Mass spectra were recorded on Micro-
mass Q-Tof Micro LC/MS/MS (Waters, Milford, MA, USA) under
electron impact at 70 eV. The elemental analyses (C, H, N) of the
compounds were performed on a CHN Elemental Analyser (Per-
kin Elmer 2400, Waltham, MA, USA). Results of the elemental
analyses were within € 0.3% of the theoretical values. The purity
of compounds was examined by TLC on silica gel plate using n-
hexane and ethyl acetate (6:4) as a mobile phase and iodine
vapor as visualizing agent.
General procedure for the preparation of 2-amino-5-nitro-
benzothiazole 8 [18]
A solution of 2,4-dinitrochlorobenzene (0.05 mol) and thiourea
(0.2 mol) in pyridine (50 mL) was boiled with stirring, under a
reflux condenser for 3 h. After cooling, the mixture was thor-
oughly stirred with 500 mL of water and the solid was filtered
off with suction, washed with water and dried.
General procedure for the synthesis of 1-[49-substituted]
phenyl-2-[499-substituted] phenyl-1-ethanones [15]
To a mixture of substituted phenyl acetic acid (0.0073 mol), sub-
stituted aromatic hydrocarbon (0.0088 mol), and 88–93% ortho-
phosphoric acid (0.0088 mol) trifluoroaceic anhydride (0.029
mol) was added rapidly with vigorous stirring at 258C. The mix-
ture turned into a dark-colored solution with vigorous exother-
mic reaction. The reaction mixture was stirred for 1 min at the
same temperature and poured into ice-cold water (50 mL) with
stirring. Then, it was washed with cold hexane (2610 mL) to
obtain the title compounds which were used for the next step.
General procedure for the synthesis of a-bromo-1-[49-
substituted] phenyl-2-[4”-substituted] phenyl-1-ethanones
9–12
General procedure for the preparation of 2-amino-6,7-
disubstituted benzothiazoles 1 and 2 [16]
To a solution of 1-[49-substituted] phenyl-2-[499-substituted] phe-
nyl-1-ethanone (0.2 mol) in chloroform (30 mL) kept at 508C, bro-
mine (0.22 mol) was added dropwise with stirring. After being
stirred at 508C for 0.5 h, the mixture was washed successively
with aqueous 10% sodium thiosulphate solution and water. The
solvent was removed in vacuo to obtain the title compounds a-
bromo-1-[49-substituted] phenyl-2-[499-substituted] phenyl-1-etha-
nones either as sold mass/oil crystalline compounds.
Potassium thiocyanate (8 g, 0.08 mol) and of 3,4-disubstituted
aniline (0.01 mol) were added to a pre-cooked (to 58C) solution of
glacial acetic acid (20 mL). The mixture was placed in a freezing
mixture of ice and salt and was mechanically stirred, while 1.6
mL of bromine in 6 mL of glacial acetic acid was added from a
dropping funnel at such a rate that the temperature did not rise
beyond 08C. After all the bromine had been added (105 min), the
i 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2010, 343, 353–359
Antibacterial Activity of Imidazo(2,1-b)-benzothiazoles
359
Y. S. Agasimundin, Professor, K.L.E. University's College of Pharmacy,
Hubli, for his encouragement. The authors are grateful to the Director,
SAIF, Punjab University, for providing the spectral data. The authors
also express their sincere gratitude to the Chief Executive, BioGenics,
Hubli, for providing the antibacterial activity profile.
General procedure for the synthesis of 2,3-diaryl-
substituted imidazo(2,1-b) benzothiazoles 13a–o [19]
The various substituted 2-aminobenzothizole (1–8, 0.03 mol)
and the appropriate a-bromo-1-[49-substituted] phenyl-2-[499-sub-
stituted] phenyl-1-ethanone (9–12, 0.029 mol) were added in 150
mL of anhydrous acetonitrile and the mixture was heated to 65–
758C for 1 h with constant stirring. After the reaction was fin-
ished, the reaction mixture was cooled, the crystals formed were
recovered by filtration, washed with acetonitrile, and dried to
provide the crystals of 2-imino-3-[1-[49-substituted] phenyl-2-[499-
The authors have declared no conflict of interest.
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phenyl-1-ethanone]-2,3-dihydrobenzo-thiazole
hydrobromide. Then, crystals of hydrobromide were refluxed
under heating in 75 mL of methylcellosolve. After 2–4 h, phos-
phorus pentoxide (0.015 mol) was added and the reflux was con-
tinued for another 2–6 h. Then, the reaction mixture was cooled
to about 508C. 30 mL of 5% aqueous ammonia was added to the
reaction mixture, the crystals formed were recovered by filtra-
tion and recrystallized from ethanol to provide the various 2,3-
diaryl substituted imidazo(2,1-b)benzothiazoles 13a–o.
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