Synthesis and antibacterial activity of some 5-guanylhydrazone/thiocyanato-6-arylimidazo[2,1-b]-1,3,4-thiadiazole-2-sulfon amide derivatives

Article abstract of DOI:10.1016/S0223-5234(00)00166-5

6-Arylimidazo[2,1-b]-1,3,4-thiadiazole-2-sulfonamides 3 on Vilsmeier-Haak reaction produced 5-formyl-6-arylimidazo[2,1-b]-1,3,4-thiadiazole-2-[N-(dimethylaminomethino)]s ulfonamides 4, while 3 on treatment with potassium thiocyanate in the presence of bro

Full text of DOI:10.1016/S0223-5234(00)00166-5

Eur. J. Med. Chem. 35 (2000) 853−857
© 2000 Éditions scientifiques et médicales Elsevier SAS. All rights reserved
S0223523400001665/FLA
Preliminary communication
Synthesis and antibacterial activity of some 5-guanylhydrazone/thiocyanato-6-
arylimidazo[2,1-b]-1,3,4-thiadiazole-2-sulfonamide derivatives¥
Andanappa K. Gadad*, Chanabasappa S. Mahajanshetti, Sudarshan Nimbalkar, Anandkumar
Raichurkar
Department of Medicinal Chemistry, College of Pharmacy, J. N. Medical College Campus, Belgaum – 590 010, India
Received 30 September 1999; revised 10 March 2000; accepted 17 March 2000
Abstract – 6-Arylimidazo[2,1-b]-1,3,4-thiadiazole-2-sulfonamides 3 on Vilsmeier-Haak reaction produced 5-formyl-6-arylimidazo[2,1-b]-
1,3,4-thiadiazole-2-[N-(dimethylaminomethino)]sulfonamides 4, while 3 on treatment with potassium thiocyanate in the presence of bromine
in acetic acid produced 5-thiocyanato-2-sulfonamides 6. Interaction of 4 with aminoguanidine hydrochloride in ethanol produced the
corresponding 5-guanylhydrazone derivatives 5. Compounds 5 and 6 showed a high degree of antibacterial activity against both Escherichia
coli and Staphylococcus aureus comparable to that of sulfamethoxazole and Norfloxacin. However, they were found to show moderate activity
against Salmonella typhi, Pseudomonas aeruginosa and Pneumococci. © 2000 Éditions scientifiques et médicales Elsevier SAS
5-guanylhydrazone / thiocyanatoimidazo[2,1-b]-1,3,4-thiadiazoles-2-sulfonamides / synthesis / antibacterial activity
1. Introduction
phylococcus aureus, and moderate activity against Sal-
monella typhi, Pseudomonas aeruginosa and Pneumo-
cocci.
The development of sulfonamides is a fascinating and
informative area in medicinal chemistry, highlighting the
role of skillful planning and serendipity in drug research.
Sulfonamide derivatives are widely used in various con-
ditions including gastrointestinal and urinary tract infec-
tions. They are preferred due to the ease of administra-
tion, wide spectrum of antimicrobial activity, non-
interference with the host defense mechanism and relative
freedom from problems of superinfection. Andreani et al.
[1] reported that some imidazo[2,1-b]thiazoles are more
active than levamisole.
In view of the above and in continuation of our
research [2, 3] on fused imidazo[2,1-b]-1,3,4-thiadiazoles,
we report here the synthesis and antibacterial activity of
some 5-guanylhydrazone/thiocyanato-6-arylimidazo[2,1-
b]-1,3,4-thiadiazole-2-sulfonamide derivatives 5 and 6
(figure 1). Both 5 and 6 showed promising activity during
antibacterial screening against Escherichia coli and Sta-
2. Chemistry
The title compounds were prepared using a synthetic
method closely related to the general procedure that we
normally employed to obtain bicyclic imidazo[2,1-b]-
1,3,4-thiadiazole derivatives [4]. In the present case the
condensation of 1 and 2 involved attack of an electrophile
α-bromoketone on the more basic endo nitrogen (3-N) of
2-amino-1,3,4-thiadiazole–5-sulfonamide 1 followed by
dehydrocyclisation of the intermediate 3A in boiling
anhydrous ethanol to yield 6-arylimidazo[2,1-b]-1,3,4-
thiadiazole-2-sulfonamides 3. The products 3 were sub-
jected to Vilsmeier-Haack reaction which involved attack
of chloroimmonium ion at 5-position to give 5-formyl
derivatives 4. During this reaction, the dimethylforma-
mide also reacted with the NH2 function of the
2-sulfonamido group converting it to N-(dimethyl-
aminomethino)sulfonamide group. Reaction of 4 with
aminoguanidine hydrochloride gave 5-guanylhydrazones
5 which belonged to the E configuration (figure 1). A
* Correspondence and reprints: akgadad@usa.net
¥Dedicated to Dr F.V. Manvi, Principal, College of Pharmacy,
Belgaum for his contribution to the profession of pharmacy.

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A.K. Gadad et al. / Eur. J. Med. Chem. 35 (2000) 853–857
made by the UV, IR, 1H-NMR, 13C-NMR and mass
spectral data. In particular, it must be pointed out that the
1
correct interpretation of the IR and H-NMR spectra of
the 5-thiocyanato-6-phenyl derivative 6a gave firm basis
of the structural assignments to all other compounds of
the series, whereas mass spectral data obtained by using
FAB technique and 1H-NMR were the basis for
5-guanylhydrazones 5 (tables I and II).
5-H of 3 generally appeared as a singlet between δ
8.9–9.2 ppm in 1H-NMR, whereas this singlet disap-
peared in the case of 5-formyl derivatives 4. Formyl
proton of 4 appeared around δ 10 ppm. Such observation
was first reported by O’Daly et al. [5] in the case of
5-formylimidazo[2,1-b]thiazole derivatives.
1H-NMR of 5 showed consistent peaks: particularly
the attribution of peaks at δ 12.1 (guanyl NH), 8.55
(5-CH=N), δ 8.40 (–SO2N=CH) and 7.75–7.50 (aryl
protons) and 3.25, 3.00 for –N(CH3)2 are correct (table I).
Compound 5d showed an additional signal for Ar–CH3 at
δ 2.30 and 5f showed 6-(3-coumarinyl) protons as a
singlet at δ 8.60 and a multiplet at 8.00–7.30 ppm. The
singlets at δ 8.55 and δ 8.40 indicated that these
compounds are single pure geometrical isomers. On the
basis of reported nuclear overhauser enhancement differ-
ence spectroscopic experiments [6–8], it was inferred that
CH=N– and SO2–N=CH– of 5 belonged to E-isomer
structure (figure 1).
Figure 1.
reaction of 3 with KSCN in the presence of bromine in
acetic acid produced 5-thiocyanato derivatives 6. The
correct structural assignments to these products were
We noticed that electron impact mass spectra of 5a–c
did not show the molecular ion peaks at 70 eV. However,
Table I. UV, IR and 1H-NMR spectral data of 5-guanylhydrazone-6-arylimidazo[2,1-b]-1,3,4-thiadiazole-2-[N-(dimethylamino-
methino)]sulfonamides 5a–d and 5f.
Compound
Ethanol λmax (nm)
IR (KBr): cm–1
1H-NMR (δ ppm) in DMSO-d6
Aryl
–N(CH3)2
=N–NH–
–CH=N-SO2
5–CH=N
5a
290, 248, 226
3 412 (b), 1 683,
1 640, 1 319, 1 146,
1 134, 1 078, 911, 850,
670
3 443 (b), 1 677,
1 634, 1 498, 1 405,
1 313, 1 152, 1 084,
917, 846
3 412 (b), 1 677,
1 634, 1 492, 1 424,
1 319, 1 152, 985, 924,
850
12.10 s
12.10 s
12.20 s
8.40 s
8.50 s
8.55 s
8.55 s
7.75–7.50 m 3.25 s; 3.00 s
7.75–7.50 d 3.25 s; 3.00 s
7.75–7.60 d 3.25 s; 3.00 s
5b
5c
289, 257, 225
288, 264, 225
8.40 s
8.40 s
5d
5f
294, 248, 226
349, 292, 225
3 425 (b), 1 678,
1 641, 1 418, 1 326,
1 147, 1 091, 918, 850
3 425 (b), 1 727,
1 678, 1 647, 1 486,
1 425, 1 313, 1 153,
1 128, 1 036, 918, 850
12.10 s
12.10 s
8.40 s
8.40 s
8.55 s
8.55 s
7.70–7.30 d; 3.25 s; 3.00 s
2.30 (ArCH3)
s
8.60 s;
3.25 s; 3.00 s
8.00–7.30 m

A.K. Gadad et al. / Eur. J. Med. Chem. 35 (2000) 853–857
Table II. IR and H-NMR spectral data of 5-thiocyanato-6-arylimidazo[2,1-b]-1,3,4-thiadiazole-2-sulfonamides 6a–e.
855
1
Compound
IR (KBr) cm–1
1H-NMR (δ ppm) in DMSO-d6
NH2
SCN
–SO2NH2
Aryl
6a
6b
6c
6d
6e
3 375, 3 264
3 345, 3 172
3 320, 3 240
3 363, 3 197
3 329, 3 290
2 165
2 159
2 159
2 166
2 159
8.80 s
8.80 s
8.80 s
8.80 s
8.80 s
8.0–7.45 m
8.0–7.60 d
8.0–7.60 d
8.0–7.40 d, 2.13 (ArCH3) s
8.40–8.25 d
when a fast atomic bombardment technique was applied,
molecular ion peaks of 5a, 5b, 5c were observed at m/z
419, 453.5 and 498, respectively, confirming their struc-
tures. In all these cases, the fragmentation pattern was
similar and showed peaks at M+, 289, 165, 154, 136, 120,
107, 89, 77, 69, 55, 41 and 27.
can be considered as potential candidates for antibacterial
activity against both Gram-positive and Gram-negative
organisms.
4. Experimental protocols
Thiocyanation of 3a to 6a was clearly seen by the
appearance of a band around 2 165 cm–1 (SCN) in its IR
spectrum and absence of a 5-H singlet around 9.0 δ ppm
4.1. Chemistry
Thin layer chromatography by pre-coated silica gel
plates (Merck 60 F 254) was used to control the purity of
the products; all the compounds were designated as pure
when they showed a single spot after elution with
chloroform/methanol mixture (95:5). Detection of com-
ponents was made by UV light and/or treatment with
iodine vapours. Melting points were determined by open
capillary method and are uncorrected. Elemental analysis,
indicated by the symbols of the elements, were within ±
0.4% of the theoretical values. Commercially available
pure solvents and chemicals were used throughout the
work.
1
in H-NMR spectrum. Structure of 6a was further sup-
ported by MS showing molecular ion peak (m/z) at 337
and 13C-NMR showing signals at δ 102, 110, 148, 152,
166 (C-2, C-5, C-6, C-7a, SCN) and carbons of Ph group
at 127–132.5, respectively. Similarly, the structures of
remaining compounds 6b–d were confirmed by their IR
1
and H-NMR spectra (table II).
3. Results and discussion
Compounds 5 and 6 showed significant antibacterial
activity against E. coli and S. aureus, while they were
found to show moderate activity against S. typhi,
P. aeruginosa and Pneumococci. The starting compounds
3a–f were found to possess lesser activity (table III). The
most active compounds were 5b, 5c, 6b, 6c, and 6e
against both E. coli and S. aureus, which were approxi-
mately equipotent in activity and comparable to that of
sulfamethoxazole and Norfloxacin at all concentrations.
Both the reference drugs exhibit antibacterial activity by
inhibiting dihydrofolate reductase and bacterial DNA
gyrase, respectively. The antibacterial activity exhibited
by 5b–5d against S. aureus was more than that against
E. coli. Compounds 6b, 6c and 6e showed superior
activity against S. aureus even at 50 µg concentration.
From the results, it is evident that the presence of a
5-guanylhydrozone and 5-thiocyanato group of 3 resulted
in producing good antibacterial activity. Particularly 6-p-
chlorophenyl, 6-p-bromophenyl and 6-p-nitrophenyl de-
rivatives showed increased activity. All these compounds
The UV spectra in ethanol were recorded on a Jasco V
530 spectrophotometer, IR spectra (KBr) were recorded
1
on Nicolet Impact-410 FT, 13C- and H-NMR spectra
were recorded from a solution in DMSO-d6 on a Varian
VXR 500 spectrometer: chemical shift values are re-
ported in δ units (ppm) relative to tetramethylsilane used
as internal standard. Mass spectra were recorded on a
JEOL MS-DX-303 spectrometer.
The starting 6-arylimidazo[2,1-b]-1,3,4-thiadiazole-2-
sulfonamides 3a–f and 5-formyl-6-arylimidazo[2,1-b]-
1,3,4-thiadiazole-2-[N-(dimethylaminomethino)]sulfona-
mides 4a–d and 4f were prepared following this laboratory
method [3, 9]. Compounds 3d and 4d are new com-
pounds.
6-p-Methylphenylimidazo[2,1-b]-1,3,4-thia-
diazole-2-sulfonamide 3d was obtained by the condensa-
tion of 2-amino-1,3,4-thiadiazole-5-sulfonamide with
p-methylphenacylbromide as yellow needles, 51% yield,
m.p. 240 °C (d). Anal. C11H10N4O2S2 (294); C, H, N.
5-Formyl-6-p-methylphenylimidazo[2,1-b]-1,3,4-thiadia-
zole-2-[N-(dimethylaminomethino)]-sulfonamide 4d was

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A.K. Gadad et al. / Eur. J. Med. Chem. 35 (2000) 853–857
Table III. In vitro antibacterial activity data of 3a–f*, 5a–d, 5f and 6a–e1.
Compound
Escherichia coli
zone of inhibition in mm
Staphylococcus aureus
zone of inhibition in mm
Salmonella typhi zone Pseudomonas aerugi- Pneumococci zone of
of inhibition in mm
nosa zone of inhibi- inhibition in mm
tion in mm
0.05 mL 0.1 mL
0.15 mL 0.05 mL 0.1 mL
0.15 mL 0.1 mL
0.15 mL 0.1 mL
0.15 mL 0.1 mL
0.15 mL
5a
5b
5c
5d
5f
6a
6b
6c
6d
6e
14
15
15
12
15
14
16
14
12
16
18
18
20
20
18
18
16
18
18
16
20
22
22
27
24
22
22
23
24
23
20
24
24
14
20
22
18
14
16
25
24
17
24
12
18
24
24
19
16
18
26
25
20
26
18
20
28
27
22
18
22
27
26
24
28
27
14
18
14
18
14
16
14
18
14
16
29
18
18
18
18
20
20
22
20
18
22
32
14
14
14
14
14
12
12
14
12
12
–
18
24
24
24
14
16
14
14
16
18
–
12
16
14
14
14
14
18
14
16
18
–
14
20
18
18
18
18
20
18
20
20
–
Sulfame-
thoxazole
Norfloxacin
30
30
30
30
30
30
36
40
20
27
37
42
1 A majority of the compounds showed the resistance against S. typhi, P. aeruginosa and Pneumococci at a concentration of 50 µg/mL, hence
these values are not included in the table. Control (DMF) did not show any activity. Cup diameter was 7 mm for 0.05 mL and 0.1 mL, and
10 mm for 0.15 mL. * Compounds 3a–f did not show activity against S. aureus and P. aeruginosa; however, they were moderately active
against E. coli, S. typhi and Pneumococci (16–22 mm).
prepared by treating 3d with freshly prepared Vilsmeier
reagent and recrystallised from ethanol as yellow needles,
83% yield, m.p. 222–225 °C. Anal. C15H15N5O3S2 (377);
C, H, N.
5-Guanylhydrazone-6-p-bromophenylimidazo[2,1-b]-
1,3,4-thiadiazole-2-[N-(dimethylaminomethino)]sulfona-
mide 5c was obtained in 65% yield starting from 4.42 g
of 5-formyl-6-p-bromophenylimidazo[2,1-b]-1,3,4-thia-
diazole-2-[N-(dimethylaminomethino)]sulfonamide 4c as
yellow flakes, m.p. 232–234 °C dec. Anal.
C15H16BrN9O2S2 (498); C, H, N.
4.2. 5-Guanylhydrazone-6-arylimidazo[2,1-b]-1,3,4-
thiadiazole-2-[N-
(dimethylaminomethino)]sulfonamides 5
5-Guanylhydrazone-6-p-methylphenylimidazo[2,1-b]-
1,3,4-thiadiazole-2-[N-(dimethylaminomethino)]sulfona-
mide 5d was obtained in 70% yield starting from 3.77 g
of 5-formyl-6-p-methylphenylimidazo[2,1-b]-1,3,4-thia-
diazole-2-[N-(dimethylaminomethino)]sulfonamide 4d as
yellow needles, m.p. 215–220 °C dec. Anal.
C16H19N9O2S2 (433); C, H, N.
5-Guanylhydrazone-6-(3-coumarinyl)imidazo[2,1-b]-
1,3,4-thiadiazole-2-[N-(dimethylaminomethino)]sulfona-
mide 5f was obtained in 68% yield starting from 4.31 g
of 5-formyl-6-(3-coumarinyl)imidazo[2,1-b]-1,3,4-thia-
diazole-2-[N-(dimethylaminomethino)]sulfonamide 4f as
brown flakes, m.p. 218–222 °C dec. Anal. C18H17N9O4S2
(487); C, H, N.
General method:
5-Formyl-6-phenylimidazo[2,1-b]-1,3,4-thiadiazole-2-
[N-(dimethylaminomethino)]sulfonamide 4a (3.63 g,
0.01 mol) was dissolved in 150 mL of ethanol and treated
with (0.01 mol) of aminoguanidine hydrochloride pre-
pared from treating the suspension of aminoguanidine
bicarbonate in ethanol with excess of 37% hydrochloric
acid. The reaction mixture was refluxed for 30 min and
the resulting precipitate was collected by filtration and
dried. The HCl salt thus obtained was suspended in ice
cold water and basified with aqueous ammonia solution.
The free base 5a thus formed was filtered, dried and
recrystallised from ethanol as yellow flakes in 70% yield,
m.p. 222–226 °C. Anal. C15H17N9O2S2 (419); C, H, N.
5-Guanylhydrazone-6-p-chlorophenylimidazo[2,1-b]-
1,3,4-thiadiazole-2-[N-(dimethylaminomethino)]sulfona-
mide 5b was obtained in 65% yield starting from 3.97 g
of 5-formyl-6-p-chlorophenylimidazo[2,1-b]-1,3,4-thia-
diazole-2-[N-(dimethylaminomethino)]sulfonamide 4b as
yellow needles, m.p. 228–232 °C dec. Anal.
C15H16ClN9O2S2 (453.5); C, H, N.
4.3. 5-Thiocyanato-6-arylimidazo-
[2,1-b]-1,3,4-thiadiazole-2-sulfonamides 6
General method:
To a mixture of 6-arylimidazo[2,1-b]-1,3,4-thiadiazole-
2-sulfonamide (0.01 mol) and potassium thiocyanate
(1.56 g, 0.016 mol) in glacial acetic acid (50 mL) was
added (at 0–5 °C) bromine (1.6 g, 0.01 mol) in glacial

A.K. Gadad et al. / Eur. J. Med. Chem. 35 (2000) 853–857
857
acetic acid (20 mL) dropwise with stirring. Then stirring
was continued for 30 min at 15–18 °C and then at room
temperature for 30 min. The reaction mixture was poured
into ice water. The precipitate that separated was filtered,
dried and recrystallised from ethanol. Compound 6a was
obtained in 70% yield starting from 2.8 g of 3a as pale
yellow needles, m.p. 232–234 °C. Anal. C11H7N5O2S3
(337); C, H, N.
5-Thiocyanato-6-p-chlorophenylimidazo[2,1-b]-1,3,4-
thiadiazole-2-sulfonamide 6b was obtained in 65% yield
starting from 3.14 g of 6-p-chlorophenylimidazo[2,1-b]-
1,3,4-thiadiazole-2-sulfonamide 3b as colourless needles,
m.p. 211–213 °C. Anal. C11H6ClN5O2S3 (371.5); C, H,
N.
Each test compound (5 mg) was dissolved in 5 mL of
dimethylformamide (1 000 µg/mL). Volumes of 0.05 mL,
0.1 mL and 0.15 mL of each compound were used for
testing.
The cups were made by scooping out agar medium
with a sterilised cork borer in a Petri dish which were
streaked with the organisms. The solution of each test
compound (0.05, 0.1 and 0.15 mL) were added separately
in the cups and Petri dishes were subsequently incubated
at 37 °C for 48 h. Sulfamethoxazole and Norfloxacin
were used as standard reference drugs and dimethylfor-
mamide as a control which did not reveal any inhibition.
Zone of inhibition produced by each compound was
measured in mm and the results are presented in table III.
5-Thiocyanato-6-p-bromophenylimidazo[2,1-b]-1,3,4-
thiadiazole-2-sulfonamide 6c was obtained in 60% yield
starting from 3.59 g of 6-p-bromophenylimidazo[2,1-b]-
1,3,4-thiadiazole-2-sulfonamide 3c as colourless needles,
m.p. 216–218 °C. Anal. C11H6BrN5O2S3 (416); C, H, N.
5-Thiocyanato-6-p-methylphenylimidazo[2,1-b]-1,3,4-
thiadiazole-2-sulfonamide 6d was obtained in 72% yield
starting from 2.94 g of 6-p-methylphenylimidazo[2,1-b]-
1,3,4-thiadiazole-2-sulfonamide 3d as pale yellow
needles, m.p. 220–222 °C. Anal. C12H9N5O2S3 (351); C,
H, N.
5-Thiocyanato-6-p-nitrophenylimidazo[2,1-b]-1,3,4-
thiadiazole-2-sulfonamide 6e was obtained in 75% yield
starting from 3.25 g of 6-p-nitrophenylimidazo[2,1-b]-
1,3,4-thiadiazole-2-sulfonamide 3e as yellow needles,
m.p. 250–255 °C dec. Anal. C11H6N6O4S3 (382); C, H,
N.
Acknowledgements
The authors wish to express their thanks to Dr S.G.
Karadesai, Department of Microbiology, J.N. Medical
College, Belgaum–10 for providing necessary support for
carrying out the antibacterial activities.
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