Synthesis and antibacterial activities of novel imidazo[2,1-b]-1,3,4- thiadiazoles

Article abstract of DOI:10.3390/molecules16075496

2-Amino-5-(2-aryl-2H-1,2,3-triazol-4-yl)-1,3,4-thiadiazoles 2-4 have been synthesized by the reaction of 2-aryl-2H-1,2,3-triazole-4-carboxylic acids 1 with thiosemicarbazide. Their reaction with phenacyl (ρ-substituted phenacyl) bromides led to formation

Full text of DOI:10.3390/molecules16075496

Molecules 2011, 16, 5496-5506; doi:10.3390/molecules16075496
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and Antibacterial Activities of Novel
Imidazo[2,1-b]-1,3,4-thiadiazoles
Kamal F. M. Atta *, Omaima O.M. Farahat, Alaa Z. A. Ahmed and Mohamed G. Marei
Chemistry Department, Faculty of Science, Alexandria University, Ibrahimia P.O. Box 426,
Alexandria 21321, Egypt
* Author to whom correspondence should be addressed; E-Mail: prof.kf_atta@yahoo.com;
Tel.: 002035917883; Fax: 002035932488.
Received: 18 March 2011; in revised form: 2 June 2011 / Accepted: 7 June 2011 /
Published: 28 June 2011
Abstract: 2-Amino-5-(2-aryl-2H-1,2,3-triazol-4-yl)-1,3,4-thiadiazoles 2-4 have been
synthesized by the reaction of 2-aryl-2H-1,2,3-triazole-4-carboxylic acids 1 with
thiosemicarbazide. Their reaction with phenacyl (p-substituted phenacyl) bromides led to
formation of the respective 6-aryl-2-(2-aryl-2H-1,2,3-triazol-4-yl)imidazo[2,1-b]-1,3,4-
thiadiazoles 5. Reactivity of the latter fused ring towards reaction with different
electrophilic reagents afforded the corresponding 5-substituted derivatives 6-8. The
structure of the above compounds was confirmed from their spectral characteristics. Some
of these compounds were found to possess slight to moderate activity against the
microorganisms Staphylococcus aureus, Candida albicans, Pseudomonas aeruginosa, and
Escherichia coli.
Keywords: 1,3,4-thiadiazole; imidazo[2,1-b]thiadiazole; electrophile; thiosemicarbazide;
phenacyl bromide; antimicrobial activity
1. Introduction
2-Amino-1,3,4-thiadiazole derivatives are well known as compounds of a wide range of anticancer
activity [1-4] that have been prepared from their respective aldehydes [5] or carboxylic acids [6]. They
appeared to be the most feasible route to fused imidazo[2,1-b]-1,3,4-thiadiazole rings [6-14] of
interesting potential applications [15,16]. Some of these compounds show anticancer [17],

5497
Molecules 2011, 16
antitubercular [18], antibacterial [19], antifungal [20], anticonvulsant analgesic [21], antisercetory [22]
and antiapoptotic [23] properties. Also, certain compounds incorporating the imidazo[2,1-b]-1,3,4-
thiadiazole moiety are used as anti-inflammatory [24], cardiotonic [25], diuretic [26] and herbicidal
[27] agents and are used in the manufacture of dyes [28-30]. With all this in mind, the present paper
focused on the synthesis of some new fused imidazo[2,1-b]-1,3,4-thiadiazole rings and testing their
reactivity towards electrophilic substitution reactions and against Staphylococcus aureus, Candida
albicans, Pseudomonas aeruginosa and Escherichia coli.
2. Results and Discussion
2-Aryl-2H-1,2,3-triazole-4-carboxylic acids 1 [31] were chosen as starting materials for these
studies. They were converted with thiosemicarbazide in the presence of POCl3 to the corresponding
2-amino-5-(2-aryl-2H-1,2,3-triazol-4-yl)-1,3,4-thiadiazoles 2-4 in good yields (Scheme 1).
Scheme 1. Synthesis and electrophilic substitution reactions of imidazo[2,1-b]-1,3,4-thiadiazoles.
a
b
c
d
e
f
g
h
i
X H H
H
Br Br Br Cl Cl l
Y H Br Cl H Br Cl H Br Cl
The structures of the above compounds were confirmed from their spectral data. Their IR spectra
showed two medium intensity bands at range 3282–3485 and 3165–3300 cm−1 due to the asymmetric
and symmetric NH stretching frequencies of the primary amino group [32,33].

5498
Molecules 2011, 16
Table 1. Infrared and 1H NMR spectral data of imidazo[2,1-b]-1,3,4-thiadiazoles (5-7).
IR (cm−1)
1H-NMR Chemical Shift (δ/ppm) *
Cpd.
No.
C=N
C=N
C=N
C=C
C-S-C
ArH
(m)
Imidazole proton Triazole proton
(thiadiazole ring) (imidazole ring) (triazole ring) (imidazole ring) (thiadiazole ring)
(s, 1H)
(s, 1H)
5a
5b
5c
5d
5e
5f
5g
5h
5i
6a
6b
6c
6d
6e
6f
6g
6h
6i
7a
7b
7c
7d
7e
7f
7g
7h
7i
1638
1635
1634
1629
1631
1626
1651
1649
1652
1640
1641
1637
1632
1632
1628
1645
1642
1641
1634
1640
1636
1642
1633
1633
1639
1640
1639
1594
1595
1594
1527
1555
1600
1601
1565
1599
1597
1594
1595
1549
1552
1545
1550
1568
1585
1595
1594
1596
1547
1565
1565
1545
1595
1598
1534
1532
1536
1540
1528
1529
1538
1533
1533
1545
1522
1524
1526
1522
1521
1510
1519
1522
1532
1527
1530
1522
1535
1521
1509
1555
1565
1490
1490
1490
1844
1488
1488
1486
1487
1485
1489
1487
1488
1436
1486
1686
1488
1487
1488
1488
1489
1489
1486
1485
1487
1488
1487
1486
690
669
669
690
669
669
690
671
670
662
669
669
686
669
669
686
672
672
663
668
669
685
671
671
685
669
670
7.33–8.14 (10H)
7.61–8.84 (9H)
8.07
7.50
8.33
8.46
7.42–8.11 (8H)
8.06
8.50
7.25–8.14 (10H)
7.44–8.15 (9H)
7.42–8.14 (9H)
7.35–8.06 (9H)
7.57–8.03 (8H)
7.42–8.04 (8H)
7.36–8.10 (9H)
7.49–8.09 (8H)
7.42–8.09 (8H)
7.37–8.15 (10H)
7.42–8.14 (9H)
7.43–8.14 (9H)
8.41
8.42
8.41
8.42
8.42
8.42
8.42
8.41
8.41
8.43
8.41
8.41
7.58–8.03 (8H)
7.43–8.03 (8H)
7.39–8.11 (9H)
7.49–8.09 (8H)
7.43–8.10 (8H)
8.41
8.42
8.42
8.41
8.41
*s = Singlet, m = multiplet.

5499
Molecules 2011, 16
Also, the 1H-NMR spectra revealed a singlet at δ 7.60–7.61 (2H) for exchangeable NH2 protons and
a singlet at δ 8.51–8.52 for the H-5 triazole proton. The structures were further confirmed from mass
spectral data (cf. Experimental). The reaction of 2-amino-5-(2-aryl-2H-1,2,3-triazol-4-yl)-1,3,4-
thiadiazoles 2-4 with phenacyl(p-substituted phenacyl) bromides in boiling dry ethanol led to the
formation of the new series of 6-aryl-2-(2-aryl-2H-1,2,3-triazol-4-yl)imidazo[2,1-b]-1,3,4-thiadiazoles
5a-i. The reaction proceeds via the formation of the iminothiadiazole intermediate, followed by
dehydrative cyclization to form the desired fused heterocycle [19]. The disappearance of the NH2
absorption bands in the IR spectra of 5 as well as the absence of the exchangeable singlets of this
1
group in their H-NMR spectra, in addition to the presence of singlets at δ 8.33–8.50 for triazole
protons, and a singlet at δ 7.50–8.07 for imidazole protons confirmed the structures (Table 1). It was
reported that [27-29] the electrophilic substitution reactions of imidazo[2,1-b]-1,3,4-thiadiazole take
place at position 5. Thus, in the present work, bromination of 5 with bromine as well as iodination with
1
iodine monochloride gave the respective 5-bromo (6a-i) and 5-iodo derivatives 7a-i. The H-NMR
spectra of both derivatives revealed the disappearance of H-5 singlet of imidazole ring and presence of
triazole proton as singlets at δ 8.41–8.43 (Table 1). The structure of the imidazothiadiazoles 5-7 was
further confirmed by studying their mass spectral data, where the possible fragmentation pathways
for all compounds gave rise to the bicyclic (I), 2-aryl-4-cyano-1,2,3-triazole (II). In addition to
2-acetylenic imidazo-thiadiazoles (III) (Figure 1). The relative intensity of the molecular ion peaks and
the most prominent peaks are listed in (Table 2).
Figure 1. The most prominent fragments of the mass spectra of imidazo[2,1-b]-1,3,4-thiadiazoles.
I
II
III
Table 2. Relative intensity of the molecular ion peaks and the most prominent peaks in the
mass spectra of imidazo[2,1-b]-1,3,4-thiadiazoles (5-7).
Cpd. No.
M
33
100,78
21
I
2
10
5
24
II
11
70
36
40
III
8
5
4
4
5a
5b
5g
5i
29
6a
6d
6f
69
7
8
100
57
40
34
100
8
18
12
7
6g
6i
22
5
100
35
29
34
19
1
7a
7e
7g
7i
100
39
46
73
22
44,46
18
18
2
57
1
16,15
100
36
14
18

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Molecules 2011, 16
Formylation of 5a with dimethylformamide in the presence of phosphorus oxychloride (Vilsmeier-
Haack reagent) gave the 5-formyl derivative 8 in excellent yield. Its IR spectrum showed a strong
absorption band at 1676 cm−1 characteristic of the entered carbonyl group and two weak absorption
bands at 2921 and 2885 cm−1 of formyl hydrogen. Also, the 1H-NMR spectrum revealed the absence of
the H-5 singlet of the imidazole ring and exhibited two singlets at δ 8.53 and 10.10 for the triazole and
formyl protons respectively.
Biological screening: antimicrobial activity tests
The antibacterial activities of compounds 2-8 were tested against the micro-organisms
Staphylococcus aureus (ATCC6538p), Candida albicans (ATCC2091), Pseudomonas aeruginosa
(ATCC9027) and Escherichia coli (ATCC8739). After incubation, the diameters of inhibition zones
around the wells were measured, to the nearest mm, in three different directions using a ruler and the
average diameter was recorded and compared to that of the control. From the data presented in Table 3 it
is clear that compounds 5d and 6h were moderately active against Escherischia coli, while 7b was also
moderately active but against Pseudomonas aeruginosa microorganisms. Generally, other derivatives
were slightly too moderately active against Candida albicans, Pseudomonas aeruginosa and
Escherischia coli. Finally, compounds 2–8 were found to be inactive against Staphylococcus aureus.
Table 3. Result of antimicrobial activity tests (agar diffusion method) of compounds (2–8).
Test microorganisms
S
C
Ps
E
Test compounds
Average inhibition zone diameter in mms
Imepenam
Ampicillin
Clotrimazole
30
30
-
-
-
30
-
-
26
-
-
40
18
18
18
18
18
18
18
18
18
18
19
18
19
18
18
18
18
18
18
18
2
3
4
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
22
22
22
22
22
22
22
22
22
22
22
23
22
23
22
23
22
22
22
22
17
16
16
17
18
16
20
16
18
16
18
16
17
16
17
17
16
17
17
20
5a
5b
5c
5d
5e
5f
5g
5h
5i
6a
6b
6c
6d
6e
6f
6g
6h
-
-
-
-

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Molecules 2011, 16
Table 3. Cont.
6i
7a
7b
7c
7d
7e
-
-
-
-
-
-
-
-
-
-
-
-
18
18
18
18
18
19
19
19
18
18
18
18
22
22
26
22
22
22
22
22
22
22
22
22
16
19
19
16
16
17
17
16
17
16
19
16
7f
7g
7h
7i
8
DMF
S: Staphylococcus aureus; C: Candida albicans; Ps: Pseudomonas aeruginosa;
E: Escherichia coli.
3. Experimental
3.1. General
Melting points were determined on a Kofler Block and are uncorrected. TLC was done on Merck
Kiesel gel 60-f 254 precoated plastic plates. Infrared spectra (IR) were measured with a Fourier
Transform Infrared 8400 spectrophotometer (BRUKER TENSOR 37) using potassium bromide
pellets. The 1H-NMR spectra were recorded on a JEOL JNM ECA 500 MHZ with tetramethylsilane as
internal standard. Mass spectra (MS) were recorded at 70 ev using GCMS-QP 1000EX mass
spectrometer. Microanalyses were performed by the Microanalytical Unit, Cairo University, Cairo.
2-Aryl-2H-1,2,3-triazole-4-carboxylic acids 1 were prepared from the respective D-glucose
arylosotriazoles as described earlier [31].
3.2. Synthesis of Compounds
3.2.1. 2-Amino-5-(2-aryl-2H-1,2,3-triazol-4-yl)-1,3,4-thiadiazoles (2-4)
2-Aryl-2H-1,2,3-triazole-4carboxylic acids (1, 0.1 mol) and thiosemicarbazide (9.1 g, 0.1 mol)
were refluxed gently in the presence of phosphorus oxychloride (30 mL) for 45 min. The reaction
mixture was cooled and quenched with cold water (90 mL). The resulting solution was refluxed for an
additional 6 hours. The separated solid was filtered and suspended in water and basified with
potassium hydroxide. The solid was filtered, washed with water, dried and crystallized from a
suitable solvent.
2-Amino-5-(2-phenyl-2H-1,2,3-triazol-4-yl)-1,3,4-thiadiazole (2). Yield (75%); m.p. 251–252 °C
(crystallization from ethanol); IR (cm−1): 3282, 3165 (NH2), 1637 (thiadiazole ring C=N), 1555
1
(triazole ring C=N) and 690 (thiadiazole ring C-S-C); H-NMR (DMSO-d6, δ, ppm): 7.42 (t, 1H,
aromatic-H), 7.55 (t, 2H, aromatic-H), 7.60 (s, 2H, exchangeable NH2), 7.98 (d, 2H, aromatic-H) and
8.51 (s, 1H, triazole-H); MS, m/z (%): 244 (100, M+), 188 (23, M+-C2H2N3), 161 (3, M+-C2H3N4),

5502
Molecules 2011, 16
145 (2, M+-C2HN3S), 105 (3, M+-C4H3N4S) and 91 (21, M+-C2H3N5S); Anal. Calc. for C10H8N6S
(244.28): C, 49.17; H, 3.30; N, 34.40%, found: C, 49.00; H, 3.45; N, 34.25%.
2-Amino-5-[2-(4-bromophenyl)-2H-1,2,3-triazol-4-yl]-1,3,4-thiadiazole (3). Yield (77%); m.p.
259–260 °C (crystallization from dioxane); IR (cm−1): 3485, 3300 (NH2), 1639 (thiadiazole ring C=N),
1597 (triazole ring C=N) and 660 (thiadiazole ring C-S-C); 1H-NMR (DMSO-d6 δ, ppm): 7.55 (d, 2H,
aromatic-H), 7.61 (s,2H, exchangeable NH2), 7.98 (d, 2H, aromatic-H) and 8.52 (s, 1H, triazole-H);
MS, m/z (%): 324 (8, M+ +2), 322 (5, M+), 266 (3, M+-CH2N3), 239 (1, M+-C2H3N4), 244 (100, M+
-Br+H), 188 (54, M+-CHBrN3), 184 (3, M+-C4H2N4S), 169 (4, M+-C4H3N5S),161 (1, M+-C2H2BrN4),
145 (1, M+-C2BrN3S), 133 (2, M+-C3BrN3S), 105 (4, M+-C4H2BrN4S) and 91 (9, M+-C2HBrN5S);
Anal. Calc. for C10H7BrN6S (323.17): C, 37.17; H, 2.18; N, 26.00%, found. C, 37.00; H, 2.60; N,
25.70%.
2-Amino-5-[2-(4-chlorophenyl)-2H-1,2,3-triazol-4-yl]-1,3,4-thiadiazole (4). Yield (65%); m.p.
269–270 °C (crystallization from dioxane); IR (cm−1): 3465, 3290 (NH2), 1626 (thiadiazole C=N),
1532 (triazole C=N) and 694 (thiadiazole C-S-C); Anal. Calc. for C10H7ClN6S (278.72): C, 43.09; H,
2.53; N, 30.15%, found. C, 43.12; H, 2.51; N, 30.17%.
3.2.2. 6-Aryl-2-(2-aryl-2H-1,2,3-triazol-4-yl)imidazo[2,1-b]-1,3,4-thiadiazoles 5a-i
A mixture of equimolar quantities of thiadiazoles 2-4 (0.01 mol) and phenacyl (p-substituted
phenacyl) bromides (0.01 mol) was refluxed in dry ethanol (50 mL) for 24 hours. The excess of
solvent was distilled off and the solid hydrobromide salt that separated out was collected by filtration,
suspended in water and neutralized by sodium carbonate to get free base 5a-i. The product was
1
filtered, washed with water, dried and crystallized from carbon tetrachloride. Their IR, H-NMR
spectra and analytical data are listed in Tables 1 and 4.
3.2.3. 6-Aryl-2-(2-aryl-2H-1,2,3-triazol-4-yl)-5-haloimidazo[2,1-b]-1,3,4-thiadiazoles 6a-i and 7a-i
A solution of bromine (iodine monochloride) (0.01 mol) in acetic acid (10 mL) was gradually
added to a suspension of 5a-i (0.01 mol) in acetic acid (10 mL) with stirring for one to eight days at
room temperature. The reaction mixture was poured onto ice cold water. The separated solid was
collected, washed with water, dried and crystallized from either chloroform or benzene in methanol
mixture. Their IR, 1H-NMR spectra and analytical data are listed in Tables 1 and 4.
Table 4. Analytical data of imidazo[2,1-b]-1,3,4-thiadiazoles (5-7).
Calcd. %
H
Found %
H N
Cpd.
No.
5a
5b
5c
Mp
(°C)
Yield
(%)
60
62
61
Formula
C
N
C
225–226
253–254
257–258
285–286
281–282
C18H12N6S
62.77 3.51 24.40 62.50 3.42 24.43
51.07 2.62 19.85 51.00 2.32 19.92
57.07 2.93 22.18 57.11 2.86 22.20
51.07 2.62 19.85 51.15 2.40 20.06
43.05 2.01 16.73 43.07 2.00 16.81
C18H11BrN6S
C18H11ClN6S
C18H11BrN6S
C18H10 Br2N6S
5d
5e
61
60

5503
Molecules 2011, 16
Table 4. Cont.
C18H10BrClN6S 47.23 2.20 18.36 47.31 2.12 18.02
C18H11ClN6S 57.07 2.93 22.18 57.10 2.92 22.21
C18H10BrClN6S 47.23 2.20 18.36 47.19 2.26 18.41
5f
5g
5h
5i
6a
6b
6c
6d
6e
6f
6g
6h
6i
7a
7b
7c
7d
7e
7f
276–277
279–280
267–268
271–272
221–222
261–262
255–256
265–266
246–247
248–249
257–258
259–260
237–238
270–271
251–252
251–252
273–274
251–252
243–244
285–286
255–256
253–254
66
58
55
58
80
80
80
82
76
80
80
80
80
85
83
82
85
80
85
82
84
80
C18H10 Cl2N6S
C18H11BrN6S
C18H10 Br2N6S
52.31 2.44 20.33 52.40 2.40 20.21
51.07 2.62 19.85 51.12 2.42 20.03
43.05 2.01 16.73 43.12 2.00 16.92
C18H10BrClN6S 47.23 2.20 18.36 47.21 2.15 18.38
C18H10 Br2N6S
C18H9 Br3N6S
43.05 2.01 16.73 43.05 2.01 16.73
37.21 1.56 14.46 37.22 1.81 14.51
C18H9Br2ClN6S 40.29 1.69 15.66 40.01 1.81 15.62
C18H10BrClN6S 47.23 2.20 18.36 47.12 2.25 18.39
C18H9Br2ClN6S
0.29 1.69 15.66 40.42 1.72 15.52
C18H9 BrCl2N6S 43.93 1.84 17.08 43.90 1.87 16.90
C18H11IN6S
45.97 2.36 17.87 45.82 2.39 17.85
39.37 1.84 15.30 39.40 1.90 15.21
42.83 2.00 16.65 42.90 2.03 16.82
39.37 1.84 15.30 39.21 1.61 15.42
34.42 1.44 13.38 34.50 1.49 13.42
C18H10BrIN6S
C18H10ClIN6S
C18H10BrIN6S
C18H9Br2IN6S
C18H9BrClIN6S 37.04 1.55 14.40 37.24 1.52 14.43
C18H10ClIN6S 42.83 2.00 16.65 42.72 1.95 16.62
C18H9BrClIN6S 37.04 1.55 14.40 36.92 1.61 14.41
C18H9Cl2IN6S 40.10 1.68 15.59 40.20 1.72 15.51
7g
7h
7i
3.2.4. 5-Formyl-6-phenyl-2-(2-phenyl-2H-1,2,3-triazol-4-yl)imidazo[2,1-b]-1,3,4-thiadiazole (8)
The Vilsmeir-Haack reagent was prepared by adding phosphorus oxychloride (3 mL) to dimethyl-
formamide (20 mL) at 0 °C with stirring. Then, compound 5a (3.44 g, 0.01 mol) was added to the
reagent and stirred at 0 °C for 30 min. The mixture was further stirred at room temperature for 2 hours
and then at 60 °C for an additional 2 hours. The reaction mixture was then poured onto sodium
carbonate solution and stirred at 90 °C for 2 hours. After cooling, the mixture was diluted with water
and extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous
sodium sulfate and the residue obtained after removal of the solvent was crystallized from chloroform/
methanol. Yield (80%); m.p. 184–185 °C; IR (cm−1): 2921, 2885 (formyl hydrogen), 1676 (CO), 1629
(thiadiazole C=N), 1589 (imidazole C=N), 1492 (triazole C=N), 1444 (imidazole C=C) and 664
1
(thiadiazole C-S-C); H-NMR (CDCl3, δ, ppm): 7.44 (t, 1H, aromatic-H), 7.54 (m, 5H, aromatic-H),
7.89 (d, 2H, aromatic-H), 8.15 (d, 2H, aromatic-H), 8.53 (s, 1H, triazole-H) and 10.1 (s, 1H, formyl-H);
Anal. Calc. for C19H12N6OS (372.40): C, 61.28; H, 3.25; N, 22.57%, found. C, 61.30; H, 3.30;
N, 22.57%.
3.3. Antibacterial Activity Tests
The antibacterial activity tests were performed according to agar diffusion method [34] using
ampicillin, imepenam and clotrimazole as the reference compounds. The Sterile cotton swabs were
separately dipped into each of the adjusted organism cultures and excess inoculum was removed by

5504
Molecules 2011, 16
pressing and rotating the swab firmly several times against the wall of the tube above the level of the
liquid. The swab was streaked all over the surface of the nutrient agar in three dimensions at an angle
of 60° to obtain an even distribution of the inoculum. The plates were then left to dry at room
temperature for few minutes. A sterile cork porer (8 mm in diameter) is used to make wells in the solid
nutrient agar plates, so that the distance between the edges of each two wells is not less than 24 mm.
Fill each well with 75 μL of the test compound and another well with same volume of DMF as a
vehicle control. Allow a period of free diffusion for 2 h, then incubated at 37 °C for 18–24 h.
4. Conclusions
In conclusion, formation of diverse 2-amino-5-substituted-1,3,4-thiadiazoles using carbohydrates
as precursors was successfully achieved, followed by their conversion into the novel target
imidazo[2,1-b]-1,3,4-thiadiazole fused heterocyles. The antibacterial activities of the synthesized
compounds were also examined.
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Sample Availability: Samples of the compounds (1-8) are available from the authors.
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