Synthesis and evaluation of antitubercular activity of imidazo[2,1-b][1,3, 4]thiadiazole derivatives

Bioorganic & Medicinal Chemistry 14 (2006) 3069–3080

Synthesis and evaluation of antitubercular activity

of imidazo[2,1-b][1,3,4]thiadiazole derivatives

Gundurao Kolavi,^aVinayak Hegde,^aImtiyaz ahmed Khazi^a,*and Pramod Gadad^b

^aDepartment of Chemistry, Karnatak University, Dharwad, India

^bK.L.E. Pharmacy college, Hubli, India

Received 11 November 2005; revised 10 December 2005; accepted 13 December 2005

Available online 6 January 2006

Abstract—AbstractA series of 2,6-disubstituted and 2,5,6-trisubstituted imidazo[2,1-b][1,3,4]thiadiazoles were synthesized, the struc-

tures of the compounds were elucidated and screened for antitubercular activity against Mycobacterium tuberculosis H₃₇Rv using the

BACTEC 460 radiometric system, antibacterial activity against Escherichia coli and Bacillus cirrhosis, and antifungal activity against

Aspergillus niger and Penicillium wortmanni. Among the tested compounds 2-(2-furyl)-6-phenylimidazo[2,1-b][1,3,4] thiadiazole-5-

carbaldehyde (6c) and (2-cyclohexyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methanol (7a) have shown the highest (100%)

inhibitory activity. Compounds 6a, 6b, 7c, and 8a exhibited moderate antitubercular activity with percentage inhibition 36, 30,

15, and 20, respectively, at a MIC of >6.25 lg/ml.

1. Introduction

cer^16–18activities. Recently, these derivatives have

attracted the interest of researchers as antituberculosis

agents. Some members of the imidazo[2,1-b][1,3,4]thia-

diazoles family displayed good activity against M.

tuberculosis H₃₇Rv.

Tuberculosis is one of the serious health problems with a

wide variety of manifestations caused by Mycobacterium

tuberculosis and as per the recent report it has been

estimated that approximately one-third of the world’s

population is infected with this microorganism. The

treatment of mycobacterial infections especially the

tuberculosis, has become an important problem due to

the emergence of monodrug and multidrug-resistant

strains of M. tuberculosis.¹Therefore, there is a need

for new drugs of new structural classes and with a novel

mechanism of action other than isoniazid (INH),

rifampicin (RIF), and pyridazinamide (PZA). In this

regard, since the last decade search for new antitubercu-

lar substances has ranked among the priority areas of

chemotherapeutic research.

The purpose of the present work was to explore and

develop the novel molecules with improved potential

for treating tuberculosis. In this paper, we report the de-

sign, synthesis, and antimycobacterial and antimicrobial

evaluation of various imidazo[2,1-b][1,3,4]thiadiazole

derivatives.

2. Chemistry

Synthesis of the basic nucleus imidazo[2,1-b][1,3,4]thia-

diazole is brought about by the condensation of 2-

amino-1,3,4-thiadiazole with a-bromoarylketone under

reﬂux in dry ethanol (Scheme 1). Mannich reaction of

imidazo[2,1-b][1,3,4]thiadiazole (2) with diﬀerent cyclic

secondary amines (morpholine, piperidine, and pyrrol-

idine) and formaldehyde in methanol with catalytic

amount of acetic acid yielded corresponding deriva-

tives 3, 4, and 5. Vilsmeier–Haack reaction of

imidazothiadiazole 2 in DMF and POCl₃provided

5-formyl derivative 6 (Scheme 2). The aldehyde func-

tional group has been utilized to synthesize corre-

sponding alcohols, nitriles, and thiazolidinone

During recent years, there have been intense investiga-

tions on thiadiazole and imidazo[2,1-b][1,3,4]thiadia-

zole compounds, many of which are known to

possess interesting biological properties such as antimi-

crobial,^2–6antitubercular,^7,8anti-inﬂammatory,^9–11

anticonvulsant,^12,13antihypertensive,^14,15and antican-

Keywords: Imidazo[2,1-b][1,3,4]thiadiazole; Mannich reaction;

Vilsmeier–Haack reaction; Antitubercular activity

*

.

Corresponding author. Tel.: +91 836 2215286; fax: +91 836

2771275; e-mail: dr_imk@yahoo.com

doi:10.1016/j.bmc.2005.12.020

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G. Kolavi et al. / Bioorg. Med. Chem. 14 (2006) 3069–3080

Scheme 1. Reagents and conditions: (a) dry ethanol, reﬂux, 12 h, Na₂CO₃; (b) morpholine, HCHO, AcOH, MeOH, reﬂux, 4 h; (c) piperidine,

HCHO, AcOH, MeOH, reﬂux, 4 h; (d) pyrrolidine, HCHO, AcOH, MeOH, reﬂux, 4 h.

derivatives. The reduction of aldehyde 6 by NaBH₄in

methanol at room temperature yielded the respective

carbinols 7 in good yields. The condensation of alde-

hyde 6 with hydroxylamine hydrochloride in pyridine

gave corresponding oxime 8, which on dehydration

with thionylchloride produced the nitrile 9 in good

yields. The aldehyde 6 when treated with aniline gave

the corresponding Schiﬀ bases, which on reﬂuxing

with thioglycolic acid in benzene underwent heterocyc-

lization to yield thiazolidinone derivatives 10.

the microplate Alamar blue assay (MABA).⁸Com-

pounds exhibiting ﬂuorescence were tested in the BAC-

TEC 460 radiometric system. Compounds eﬀecting

<90% inhibition in the primary screen were not evalu-

ated further. Compounds demonstrating at least 90%

inhibition were tested at lower concentrations by serial

dilution against M. tuberculosis H₃₇Rv to determine the

minimum inhibitory concentration (MIC) using

MABA. Compound 6c was selected for further screen-

ing, where it exhibited promising inhibitory activity of

42%. The MIC is deﬁned as the lowest concentration

eﬀecting a reduction in ﬂuorescence of 90% relative to

controls. Rifampicin was used as a reference drug. Bio-

logical signiﬁcance of all the derivatives was also estab-

lished by screening them against two bacterial strains

Bacillus cirrhosis and Escherichia coli and two fungal

species Aspergillus niger and Penicillium wortmannii

by the cup plate method at a concentration of

25–100 lg/mL using DMF as the solvent. Norﬂoxacin

and Greseofulvin were used as standards, respectively.

The activity data are given in the following tables

(Tables 1–4).

3. Biological activity

The in vitro antimycobacterial activity was assayed by

Tuberculosis Antimicrobial Acquisition and Coordinat-

ing Facility (TAACF), antitubercular drug discovery

program.

Primary screening was conducted at 6.25 lg/mL against

M. tuberculosis H₃₇Rv (ATCC 27294) in BACTEC

12B^19,20medium using a broth microdilution assay,^21,22

G. Kolavi et al. / Bioorg. Med. Chem. 14 (2006) 3069–3080

3071

Scheme 2. Reagents and conditions: (a) DMF/POCl₃, Na₂CO₃; (b) NaBH₄, MeOH, rt; (c) NH₂OHÆHCl, pyridine reﬂux; (d) SOCl₂, digest, 10 min;

(e) (i) PhNH₂, EtOH, reﬂux, (ii) thioglycolic acid, benzene, reﬂux.

Table 1. The in vitro antitubercular activity of compounds against

Mycobacterium tuberculosis H₃₇Rv

and presence of imidazole proton (C5-H) around d 7.90

1

in H NMR spectra. The H NMR spectra of the prod-

ucts 3, 4, and 5 showed the absence of imidazole proton

and a singlet was observed around d 4.00, which was as-

signed to methylene protons and the other aliphatic pro-

tons of the amine substituent resonated in the expected

region. For morpholine derivatives (3), two triplets were

observed. Formation of Mannich bases was further con-

ﬁrmed by their ¹³C NMR and mass spectra. IR spectra

of 6 displayed the sharp band for carbonyl stretching

frequency (m_C@O) around 1675 cm^À1and the singlet

due to C₅-imidazole proton was absent and a signal

for aldehyde proton was observed around d 10.00 in

R3

N

R1

N

S

N

R2

Compound R₁

R₂R₃

4-Morpholinyl >6.25

Cyclohexyl Br 4-Morpholinyl >6.25 (4)

4-Morpholinyl >6.25

Br 4-Morpholinyl >6.25

4-Morpholinyl >6.25

Br 4-Morpholinyl >6.25

MIC (lg/mL)

3a

3b

3c

3d

3e

3f

Cyclohexyl

H

2-Furyl

H

2-Furyl

2-Thienyl

Cyclohexyl

H

1

the H NMR spectrum, thus conﬁrming the formation

4a

4b

4c

4d

4e

4f

H

1-Piperidinyl

>6.25

of imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehydes (6a–

f). The products 7a–f showed the absence of carbonyl

stretching frequency m_C@Oand the presence of broad

band in the region 3200 cm^À1for m_O–Hin IR spectra.

The ¹H NMR showed the absence of signal due to alde-

hyde proton and the methylene protons resonated as

singlet around d 5.00 and –OH proton was observed

as broad singlet. In a few cases, the doublet–triplet

pattern was observed for –CH₂OH. The data conﬁrmed

the conversion of carbaldehydes 6 to imidazo[2,1-b]-

[1,3,4]thiadiazole-5-carbinols (7). The absence of m_C@O

band and the presence of m_O–Hband in the IR spectrum

of the product conﬁrmed the formation of oximes 8.

Cyclohexyl Br 1-Piperidinyl

2-Furyl

H

1-Piperidinyl

Br 1-Piperidinyl

1-Piperidinyl

Br 1-Piperidinyl

1-Pyrrolidinyl

2-Thienyl

Cyclohexyl

H

5a

5b

5c

5d

5e

5f

H

Cyclohexyl Br 1-Pyrrolidinyl

2-Furyl

H

1-Pyrrolidinyl

Br 1-Pyrrolidinyl

1-Pyrrolidinyl

Br 1-Pyrrolidinyl

2-Thienyl

H

Rifampicin (standard) 6.25 lg/mL (100% inhibition). The active

compounds and their activity is marked in bold letters.

1

Their H NMR spectra also conﬁrmed the aldoximes

4. Results and discussion

where the signal for aldehyde proton was absent, the

azomethine and the –OH proton (D₂O exchangeable)

resonated around d 8.50 and 9.60, respectively. The

product obtained after treatment of these aldoximes

The formation of imidazothiadiazole derivatives 2 was

conﬁrmed by the absence of m_N–Hband in the IR spectra

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G. Kolavi et al. / Bioorg. Med. Chem. 14 (2006) 3069–3080

Table 2. The in vitro antitubercular activity of compounds against Mycobacterium tuberculosis H₃₇Rv

R3

N

R1

R2

S

N

Compound

R₁

R₂

R₃

MIC (lg/mL)

2a

2b

2c

Cyclohexyl

2-Furyl

H

Br

H

Br

H

Br

H

Br

H

Br

H

Br

H

Br

H

Br

H

Br

H

>6.25

H

>6.25 (9)

>6.25

2d

2e

2-Furyl

H

2-Thienyl

Cyclohexyl

2-Furyl

H

2f

H

>6.25

6a

6b

6c

CHO

CH₂OH

>6.25 (36)

>6.25 (30)

>6.25 (100)

>6.25

6d

6e

2-Furyl

2-Thienyl

Cyclohexyl

2-Furyl

>6.25 (10)

>6.25

6f

7a

7b

7c

>6.25 (100)

>6.25 (13)

>6.25

7d

7e

2-Furyl

>6.25

2-Thienyl

Cyclohexyl

2-Furyl

7f

>6.25

8a

8b

8c

CH@NOH

CN

>6.25

2-Thienyl

Cyclohexyl

2-Furyl

9a

9b

9c

>6.25

CN

2-Thienyl

Cyclohexyl

2-Furyl

>6.25

10a

10b

10c

2(3-Phenyl-1,3-thiazolidin-4-one)

>6.25

2-Thienyl

Rifampicin (standard) 6.25 lg/mL (100% inhibition). The active compounds and their activity is marked in bold letters.

with thionylchloride exhibited the sharp band around

2200 cm^À1in the IR spectrum assigned for m_CNand

there was no band due to m_O–H. The H NMR of the

were reduced to the corresponding carbinols (7a–f).

In this series (2-cyclohexyl-6-phenylimidazo [2,1-

b][1,3,4]thiadiazol-5-yl)methanol (7a) showed highest

inhibition at the same concentration. It is interesting

to note that the derivatization of aldehydes (6a–f) to

oximes (8a–f), nitriles (9a–f), and thiazolidinones

(10a–c) resulted in compounds with minimized activ-

ity potentials. Similarly, the Mannich bases of imi-

dazothiadiazole at the 5th position derived from

various secondary cyclic amines failed to produce

any compound with improved antimycobacterial

activity. We have noticed that even among the most

active compounds (6a, 6c, and 7a) the 2-cyclohexyl/

furyl and 6-phenyl contributed more to the antitu-

bercular activity. The result of the antimycobacterial

activity is presented in Tables 1 and 2.

1

compound showed the absence of both –OH proton

and azomethine proton. This conﬁrmed, the products

obtained were the resultants of dehydrated aldoximes,

that is, nitriles (9). The compound 10 showed the car-

bonyl stretching frequency m_C@Oaround 1700 cm^À1

the H NMR of the same exhibited two singlets around

d 6.00 and 7.50, respectively. These data conﬁrmed the

presence of thiazolidinone ring at 5-position.

,

1

The synthesized compounds were evaluated for their

in vitro anti-tuberculosis activity against M. tubercu-

losis strain H₃₇Rv by using radiometric BACTEC

and broth dilution assays. The data of the antituber-

cular activity screening reveal that the compounds

2a–f having no substitution at position-5 did not

show any considerable activity, in spite of the

changes at the two variable at position-2 and posi-

tion-6. However, when a formyl group was intro-

duced at position-5 (compounds 6a–f), it resulted

in compounds having an enhanced antimycobacterial

activity. 2-(2-Furyl)-6-phenylimidazo[2,1-b][1,3,4]thia-

diazole-5-carbaldehyde 6c showed 100% inhibition

at a concentration of 6.25 lg/mL. Encouraging activ-

ity proﬁle was also found when the aldehydes (6a–f)

The antibacterial screenings (Table 3) revealed that

the Mannich bases are superior over imidazo[2,1-b]-

[1,3,4]thiadiazoles. Among these the pyrrollidine deriva-

tives were found to have more activity against E. coli

and 5e has shown complete inhibition of B. cirrhosis.

The morpholine derivative 3a and piperidinyl derivative

4a showed signiﬁcant activity against E. coli and B. cir-

rhosis. The aldehydes 6b and 6c showed good inhibition

of E. coli and B. cirrhosis, respectively, at a concentra-

tion of 100 lg/mL.

G. Kolavi et al. / Bioorg. Med. Chem. 14 (2006) 3069–3080

3073

Table 3. The in vitro antibacterial activity of compounds against Escherichia coli and Bacillus cirrhosis

Compound

Relative inhibition (%)

Escherichia coli

Bacillus cirrhosis

100 lg/mL

50 lg/mL

25 lg/mL

100 lg/mL

50 lg/mL

25 lg/mL

2a

2b

2c

2d

2e

2f

10

12

21

35

9

—

9

—

30

20

34

—

15

18

—

39

18

36

—

47

—

43

—

23

—

51

18

30

—

30

10

—

28

—

40

28

—

12

—

24

10

34

32

20

12

40

65

50

70

58

60

24

30

66

40

14

12

30

24

12

88

100

18

12

82

46

58

30

60

24

44

20

34

60

30

10

—

81

15

—

22

10

12

80

10

—

20

16

—

22

46

38

45

36

46

10

14

42

24

—

12

—

62

80

—

61

24

28

12

46

—

20

—

12

50

12

—

60

—

55

—

30

10

34

12

30

—

26

10

—

49

68

—

17

10

12

—

26

—

12

—

30

—

48

—

30

—

60

54

51

10

24

30

50

20

50

46

50

10

80

—

89

20

69

—

78

30

44

10

—

48

28

12

—

46

12

14

66

40

—

30

14

—

22

11

90

71

60

24

40

44

91

35

75

64

75

34

100

12

100

44

84

15

10

14

93

55

60

24

12

60

40

25

18

64

20

34

80

68

12

64

24

10

34

3a

3b

3c

3d

3e

3f

4a

4b

4c

4d

4e

4f

5a

5b

5c

5d

5e

5f

6a

6b

6c

6d

6e

6f

7a

7b

7c

7d

7e

7f

8a

8b

8c

9a

9b

9c

10a

10b

10c

Norﬂoxacin (standard) 100% inhibition at each concentration.

From the antifungal screening results it is clear that, the

Mannich bases 3c, 4a, and 5a, and 5a, 7c, and 7e dis-

played better antifungal activity against P. wortmannii

and A. niger, respectively. Compound 5a is found to

be the most potent antifungal agent against both the

fungal strains.

imidazo[2,1-b][1,3,4]thiadiazole derivatives, reported in

the present article, evidenced that many of the com-

pounds from the series have emerged as potent anti-

tubercular, antibacterial, and antifungal agents

endowed with moderate to good activity. The possi-

ble improvements in the activity can be further

achieved by slight modiﬁcations in the substituents

on the basic imidazo[2,1-b][1,3,4]thiadiazole nucleus.

Our ﬁndings will have impact on chemists and phar-

macists for further investigations in this ﬁeld in

search of potent antitubercular and antimicrobial

agents.

5. Conclusion

The preliminary in vitro antituberculosis screening,

antibacterial and antifungal screening results of novel

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G. Kolavi et al. / Bioorg. Med. Chem. 14 (2006) 3069–3080

Table 4. The in vitro antifungal activity of compounds against Penicillium wortmannii and Aspergillus niger

Compound

Relative inhibition (%)

Penicillium wortmannii

Aspergillus niger

100 lg/mL

50 lg/mL

25 lg/mL

100 lg/mL

50 lg/mL

25 lg/mL

2a

2b

2c

2d

2e

2f

26

20

78

56

10

12

10

64

78

50

32

44

91

24

40

12

30

14

100

32

22

12

78

12

—

22

38

60

22

10

34

26

68

24

66

12

10

12

20

24

40

14

68

60

46

12

—

45

30

—

30

52

30

—

36

78

10

15

—

20

—

85

12

10

—

42

—

15

38

—

20

10

42

10

52

—

10

24

—

46

38

20

—

25

20

—

12

24

20

—

14

60

—

12

—

57

—

20

—

20

—

26

—

30

—

20

12

—

24

18

54

22

10

—

30

—

20

71

10

—

18

44

—

10

—

80

12

—

30

—

10

20

—

41

—

3a

3b

3c

3d

3e

3f

30

44

91

30

10

40

78

18

20

25

20

18

100

34

14

4a

4b

4c

4d

4e

4f

5a

5b

5c

5d

5e

5f

46

20

—

22

20

—

12

8

20

—

10

—

10

—

51

14

49

—

25

—

22

—

6a

6b

6c

6d

6e

6f

7a

7b

7c

7d

7e

7f

28

22

75

46

75

12

10

24

—

10

—

20

8a

8b

8c

9a

9b

9c

10a

10b

10c

Greseofulvin (standard) 100% inhibition at each concentration.

6. Experimental

6.1. Preparation of 2-alkyl/aryl-6-arylimidazo[2,1-b]-

[1,3,4]thiadiazoles (2a–f): general method

Melting points were determined in open capillaries and

are uncorrected. The IR spectra were recorded on a Nic-

olet Impact 410 FT IR spectrophotometer using KBr pel-

A mixture of equimolar quantities of 2-amino-5-alkyl/

aryl-1,3,4-thiadiazoles 1a–c, (0.01 mol) and bromoacetyl

compound (0.01 mol) was reﬂuxed in dry ethanol for

8 h. The excess of solvent was distilled oﬀ and the solid

hydrobromide that separated was collected by ﬁltration,

suspended in water, and neutralized by aqueous sodium

carbonate solution to get free base (2). It was ﬁltered,

washed with water, dried, and recrystallized from suit-

1

lets. H and ¹³C NMR were recorded on a Bruker 300-

MHz FT NMR spectrometer in CDCl₃and DMSO-d₆

with TMS as internal standard. Mass spectra were record-

ed on a Quattro II Micromass Walter instrument (UK

Ltd.) by electron impact technique and elemental analysis

was carried out using Heraus CHN rapid analyzer.

G. Kolavi et al. / Bioorg. Med. Chem. 14 (2006) 3069–3080

3075

able solvent. (Compounds 2a, 2c, and 2e were prepared

as per the literature method.²³)

6.2.2. 6-(4-Bromophenyl)-2-cyclohexyl-5-(morpholin-4-ylm-

ethyl)imidazo[2,1-b][1,3,4]thiadiazole (3b). Yield 62%;

colorless solid (chloroform + hexane); mp 164–166 ꢁC;

¹H NMR (CDCl₃) d 1.31–2.16 (m, 10H, cyclohexyl),

2.53 (t, J = 4.5 Hz, 4H, C3, C5-H, morpholine), 3.01

(m, 1H, C1-H, cyclohexyl), 3.69 (t, J = 4.5 Hz, 4H, C2,

C6-H, morpholine) 3.84 (s, 2H, CH₂), 7.55 (d,

J = 8.7 Hz, 2H, C3, C5-H, phenyl), 7.84 (d, J = 8.7 Hz,

2H, C2, C6-H, phenyl); ¹³C NMR (CDCl₃) d 25.9 (C4,

cyclohexyl), 26.0 (C3, C5 cyclohexyl), 33.0 (C2, C6,

cyclohexyl), 41.6 (C1 cyclohexyl), 51.7 (CH₂), 53.3

(NCH₂morpholine), 67.3 (OCH₂morpholine), 120.3,

121.5, 129.4, 131.8, 134.1, 143.6, 143.8 and 170.1; Anal.

Calcd for C₂₁H₂₅BrN₄OS: C, 54.66; H, 5.46; N, 12.14.

Found: C, 54.58; H, 5.89; N, 12.72. Mass, m/z(%), 461

(25), 463 (25), 374 (100), 376 (100).

6.1.1. 6-(4-Bromophenyl)-2-cyclohexylimidazo[2,1-b][1,3,4]-

thiadiazole (2b). Yield 75%; colorless solid (ethanol); mp

1

188–190 ꢁC IR (KBr) m cm^À12928, 1623, 1580, 1457; H

NMR (CDCl₃) d 1.34–3.01 (m, 11H, cyclohexyl), 7.55

(d, J = 9 Hz, 2H, C3, C5-H, phenyl), 7.71

(d, J = 9 Hz, 2H, C2, C6-H), 7.90 (s, 1H, C5-H, imidaz-

ole); ¹³C NMR (CDCl₃) d 25.9 (C4, cyclohexyl), 26.0

(C3, C5, cyclohexyl), 33.0 (C2, C6, cyclohexyl), 41.7

(C1, cyclohexyl), 109.5, 123.1, 126.9, 132.1, 133.4,

145.2, 145.7 and 170.5; Anal. Calcd for C₁₆H₁₆BrN₃S:

C, 53.04; H, 4.45; N, 11.60. Found: C, 53.19; H, 4.61;

N, 11.93.

6.1.2. 6-(4-Bromophenyl)-2-(2-furyl)imidazo[2,1-b][1,3,4]-

thiadiazole (2d). Yield 42%; pale yellow solid (etha-

nol + DMF); mp 188–190 ꢁC; IR (KBr) m cm^À11593,

6.2.3. 2-(2-Furyl)-5-(morpholin-4-ylmethyl)-6-phenylimi-

dazo[2,1-b][1,3,4]thiadiazole (3c). Yield 63%; pale yellow

solid chloroform + hexane); mp 120–122 ꢁC; H NMR

1

1533, 1500; ¹H NMR (CDCl₃)

d

6.64 (dd,

J_H3H4= 3 Hz, J_H4H5= 3 Hz, 1H, C4-H, furan), 7.13

(d, J = 3 Hz, 1H, C3-H, furan), 7.57 (d, J = 9 Hz, 2H,

C3, C5-H, phenyl), 7.64 (d, J = 3 Hz, 1H, C5-H, furan),

7.71 (d, J = 9 Hz, 2H, C2, C6-H, phenyl), 8.03 (s, 1H,

C5-H, imidazole); Anal. Calcd for C₁₄H₈BrN₃OS: C,

48.57; H, 2.33; N, 12.14. Found C, 48.71; H, 2.48; N,

12.49.

(CDCl₃) d 2.54 (t, J = 4.5 Hz, 4H, C3, C5-H, morpho-

line), 3.68 (t, J = 4.5 Hz, 4H, C2, C6-H, morpholine),

3.90 (s, 2H, CH₂), 6.60 (dd, J_H3H4= 4.5 Hz,

J_H4H5= 3.3 Hz, 1H, C4-H, furan), 7.14 (d, J = 4.5 Hz,

1H, C3-H, furan), 7.50–7.94 (m, 6H, phenyl, C5-H, fur-

an). Anal. Calcd for C₁₉H₁₈N₄O₂S1: C, 62.28; H, 4.95;

N, 15.29. Found: C, 62.42; H, 5.16; N, 15.62.

6.1.3. 6-(4-Bromophenyl)-2-thien-2-ylimidazo[2,1-b][1,3,4]-

thiadiazole (2f). Yield 70%; light yellow solid (ethanol);

6.2.4. 6-(4-Bromophenyl)-2-(2-furyl)-5-(morpholin-4-ylm-

ethyl)imidazo[2,1-b][1,3,4]thiadiazole (3d). Yield 63%;

pale yellow crystalline solid (benzene + pet ether); mp

176–178 ꢁC; H NMR (CDCl₃) d 2.58 (t, 4.5 Hz, 4H,

C3, C5-H, morpholine), 3.72 (t, J = 4.5 Hz, 4H, C2,

C6-H, morpholine), 3.95 (s, 2H, CH₂), 6.63 (dd,

J_H3H4= 3.3 Hz, J_H4H5= 3.3 Hz, 1H, C4-H, furan),

7.14 (d, J = 3.3 Hz, 1H, C3-H, furan), 7.52 (d,

J = 9 Hz, 2H, C3, C5-H, phenyl), 7.63 (d, J = 3.3 Hz,

1H, C5-H, furan), 7.90 (d, J = 9 Hz, C2, C6-H, phenyl);

Anal. Calcd for C₁₉H₁₇BrN₄O₂S: C, 51.24; H, 3.85, N,

12.58. Found: C, 51.62; H, 3.91; N, 12.88.

1

mp 165–167 ꢁC; IR (KBr) m cm^À13015, 1605, 1543; H

1

NMR (CDCl₃) d 7.05 (dd, J_H3H4= 3 Hz, J_H4H5= 3 Hz,

1H, C4-H, thiophene), 7.07 (d, J = 3 Hz, 1H, C3-H, thio-

phene), 7.40 (d, J = 3 Hz, 1H, C5-H, thiophene), 7.67 (d,

J = 9 Hz, 2H, C3, C5-H, phenyl), 7.90 (d, J = 9 Hz, 2H,

C2, C6-H, phenyl), 8.03 (s, 1H, C5-H, imidazole); Anal.

Calcd for C₁₄H₈BrN₃S₂: C, 46.42; H, 2.23; N, 11.60.

Found: C, 46.87; H, 2.35; N, 11.86.

6.2. Preparation of 2-alkyl/aryl-5-(morpholin-4-ylmethyl)-6-

arylimidazo[2,1-b] [1,3,4]thiadiazoles (3a–f): general method

6.2.5. 5-(Morpholin-4-ylmethyl)-6-phenyl-2-thien-2-ylimi-

dazo[2,1-b][1,3,4] thiadiazole (3e). Yield 70%; colorless

needles (chloroform + hexane); mp 158–160 ꢁC; ¹H

NMR (CDCl₃) d 2.61 (t, J = 6 Hz, 4H, C3, C5-H, mor-

pholine), 3.73 (t, J = 6 Hz, 4H, C2, C6-H, morpholine),

3.97 (s, 2H, CH₂), 7.17 (dd, J = 3.6 Hz and 4.2 Hz, 1H,

C3-H, thiophene), 7.32–7.58 (m, 5H, phenyl, C3, C5-H

thiophene), 7.99 (m, 2H, C2, C6-H phenyl); ¹³C NMR

(CDCl₃) d 51.6 (CH₂), 53.4 (NCH₂morpholine), 67.4

(OCH₂morpholine), 120.7, 127.8, 127.9, 128.4, 128.9,

129.3, 130.0, 133.1, 134.4, 143.3, 145.4 and 155.5; Anal.

Calcd for C₁₉H₁₈N₄OS₂: C, 59.66; H, 4.74; N, 14.65.

Found: C, 59.98; H, 4.89; N, 15.03.

A mixture of 2-alkyl/aryl-6-arylimidazo[2,1-b][1,3,4]-

thiadiazole (0.005 mol), morpholine (0.52 g, 0.006

mol), formalin (1 mL), and acetic acid (1 mL) in metha-

nol (20 mL) was reﬂuxed for 8 h (monitored by TLC).

The solution was diluted with water, extracted with

chloroform (3· 30 mL), the combined chloroform ex-

tract was washed with water (3· 30 mL) and dried over

anhydrous sodium sulfate. The solution was evaporated

to dryness in vacuum and the residue was recrystallized

from appropriate solvent.

6.2.1. 2-Cyclohexyl-5-(morpholin-4-ylmethyl)-6-phenylimi-

dazo[2,1-b][1,3,4]thiadiazole (3a). Yield 75%; colorless nee-

1

dles (hexane); mp 104–106 ꢁC; H NMR (CDCl₃) d 1.31–

6.2.6. 6-(4-Bromophenyl)-5-(morpholin-4-ylmethyl)-2-thien-

2-ylimidazo[2,1-b][1,3,4]thiadiazole (3f). Yield 60%; pale

yellow solid (benzene + pet ether); mp 84–86 ꢁC; ¹H

NMR (CDCl₃) d 2.50 (t, 4H, J = 6 Hz, C3, C5-H, mor-

pholine), 3.71 (t, J = 6 Hz, 4H, C2, C6-H, morpholine),

4.14 (s, 2H, CH₂), 71.16 (dd, J_H3H4= 3.6 Hz,

J_H4H5= 3.6 Hz, C4-H, thiophene), 7.23 (d, J = 3.6 Hz,

1H, C3-H, thiophene), 7.57 (d, J = 3.6 Hz, C5-H, thio-

2.19 (m, 10H, cyclohexyl), 2.56 (t, J = 4.2 Hz, 4H, C3, C5-

H, morpholine), 3.05 (m, 1H, C1-H, cyclohexyl), 3.72 (t,

J = 3.9 Hz, 4H, C2, C6-H, morpholine), 3.91 (s, 2H,

CH₂), 7.30–7.47 (m, 3H, C3, C4, C5-H, phenyl), 7.98

(m, 2H, C2, C6-H, phenyl); Anal. Calcd for C₂₁H₂₆N₄OS:

C, 65.914; H, 6.85; N, 14.65. Found: C, 66.35; H, 6.78; N,

14.79. Mass (m/z) 376.

3076

G. Kolavi et al. / Bioorg. Med. Chem. 14 (2006) 3069–3080

phene), 7.71 (d, J = 9 Hz, 2H, C3, C5-H, phenyl), 7.89

(d, J = 9 Hz, 2H, C2, C6-H, phenyl); Anal. Calcd for

C₁₉H₁₇BrN₄OS₂: C, 49.46; H, 3.71; N, 12.14. Found:

C, 49.82; H, 3.76; N, 12.60.

6.3.5. 6-Phenyl-5-(piperidin-1-ylmethyl)-2-thien-2-ylimi-

dazo[2,1-b][1,3,4]thiadiazole (4e). Yield 60%; yellow

granules (chloroform + hexane); mp 144–146 ꢁC; ¹H

NMR (CDCl₃) d 1.44–1.61 (m, 6H, C3, C4, C5-H,

piperidine), 2.52 (m, 4H, C2, C6-H, piperidine), 3.92

(s, 2H, CH₂), 7.17 (dd, J = 3.6 Hz and 4.5 Hz, 1H, C4-

H, thiophene), 7.31–7.57 (m, 5H, C3, C4, C5-H phenyl,

C3, C5-H, thienyl), 8.04 (m, 2H, C2, C6-H, phenyl); ¹³C

NMR (CDCl₃) d 24.6 (C4, piperidine), 26.4 (C3, C5

piperidine), 51.9 (C2, C6 piperidine), 54.3 (CH₂),

125.4, 127.6, 128.0, 128.3, 129.8, 129.1, 129.1, 129.8,

133.3, 135.2, 145.1 and 155.1; Anal. Calcd for

C₂₀H₂₀N₄S₂: C, 63.13; H, 5.30; N, 14.72. Found: C,

63.38; H, 5.55; N, 15.31.

6.3. Preparation of 2-alkyl/aryl-6-aryl-5-(piperidin-1-

ylmethyl)imidazo[2,1-b][1,3,4]thiadiazoles (4a–f):

general method

Prepared by following the same procedure as for the

preparation of 14, piperidine was used as secondary

amine.

6.3.1. 2-Cyclohexyl-6-phenyl-5-(piperidin-1-ylmethyl)imi-

dazo[2,1-b][1,3,4] thiadiazole (4a). Yield 58%; colorless

1

granules (hexane); mp 100–102 ꢁC; H NMR (CDCl₃)

6.3.6. 6-(4-Bromophenyl)-5-(piperidin-1-ylmethyl)-2-thien-2-

ylimidazo[2,1-b][1,3,4]thiadiazole (4f). Yield 56%; pale yel-

d 1.27–3.08 (m, 21H, cyclohexyl, piperidinyl), 3.86 (s,

2H, CH₂), 7.31–7.46 (m, 3H, C3, C4, C5-H, phenyl),

7.98 (m, 2H, C2, C6-H, phenyl);¹³C NMR (CDCl₃) d

24.6 (C4, piperidine), 25.9 (C4, cyclohexyl), 26.0 (C3,

C5 cyclohexyl), 26.4 (C3, C5 piperidine), 33.1 (C2, C6

cyclohexyl), 41.7 (C1, cyclohexyl), 52.0 (CH₂), 54.3

(NCH₂, piperidine), 121.2, 127.3, 128.0, 128.7, 135.4,

143.5, 144.4 and 169.6; Anal. Calcd for C₂₂H₂₈N₄S: C,

69.44; H, 7.42; N, 14.72. Found: C, 69.82; H, 7.48; N,

14.91.

1

low granules (chloroform + hexane); mp 138–140 ꢁC; H

NMR (CDCl₃) d 1.27–1.57 (m, 6H, C3, C4, C5-H, piper-

idine), 2.49 (m, 4H, C2, C6-H, piperidine), 3.76 (s, 2H,

CH₂), 7.15 (dd, J_H3H4= 3.6 Hz, J_H4H5= 3.6 Hz, 1H, C4-

H, thiophene), 7.22 (d, J = 3.6 Hz, 1H, C3-H, thiophene),

7.58 (d, J = 3.6 Hz, 1H, C5-H, thiophene), 7.91 (d,

J = 8.4 Hz, 2H, C3, C5-H, phenyl), 7.96 (d, J = 8.4 Hz,

2H, C2, C6-H, phenyl); Anal. Calcd for C₂₀H₁₉BrN₄S₂:

C, 52.29; H, 4.17; N, 12.19. Found: C, 52.63; H, 4.21;

N, 12.73.

6.3.2. 6-(4-Bromophenyl)-2-cyclohexyl-(piperidin-1-ylmeth-

yl)imidazo[2,1-b][1,3,4]thiadiazole (4b). Yield 58%; pale yel-

low granules (benzene + pet ether); mp 138–140 ꢁC; H

6.4. Preparation of 6-aryl-2-alkyl/aryl-(pyrrolidin-1-yl-

methyl)imidazo[2,1-b][1,3,4]thiadiazoles (5a–f)

1

NMR (CDCl₃) d 1.26–2.47 (m, 20H, cyclohexyl, piperi-

dine), 3.02 (m, 1H, C1-H, cyclohexyl), 3.81 (s, 2H,

CH₂), 7.57 (d, J = 8.4 Hz, 2H, C3, C5-H, phenyl), 7.90

(d, J = 8.4 Hz, 2H, C2, C6-H, phenyl); ¹³C NMR

(CDCl₃) d 24.6 (C4, cyclohexyl), 25.9 (C4, piperidine),

26.0 (C3, C5, cyclohexyl), 26.3 (C2, C6 cyclohexyl),

33.1 (C3, C5 piperidine), 41.7 (C1, cyclohexyl), 52.0

(CH₂), 54.3 (C2, C6 piperidine), 121.4, 121.4, 129.6,

131.8, 134.3, 143.3, 143.6 and 169.9; Anal. Calcd for

C₂₂H₂₇BrN₄S: C, 57.51; H, 5.92; N, 12.19. Found: C,

57.82; H, 5.88; N, 12.53.

Prepared by following the same procedure as for the

preparation of 14, pyrrolidine was used as secondary

amine.

6.4.1. 2-Cyclohexyl-6-phenyl-5-(pyrrolidin-1-ylmethyl)imi-

dazo[2,1-b][1,3,4]thiadiazole (5a). Yield 59%; colorless crys-

talline solid (pet ether); mp 90–92 ꢁC; ¹H NMR (CDCl₃) d

1.27–3.34 (m, 19H, cyclohexyl, pyrrolidine), 4.04 (s, 2H,

CH₂), 7.31–7.46 (m, 3H, C3, C4, C5-H, phenyl), 7.91

(m, 2H, C2, C6-H, phenyl); Anal. Calcd for C₂₁H₂₆N₄S:

C, 68.82; H, 7.15; N, 15.29. Found: C, 68.65; H, 7.30;

N, 15.41.

6.3.3. 2-(2-Furyl)-6-phenyl-5-(piperidin-1-ylmethyl)imi-

dazo[2,1-b][1,3,4]thiadiazole (4c). Yield 67%; yellow

granules (benzene + pet ether); mp 128–130 ꢁC; ¹H

NMR (CDCl₃) d 1.24–1.53 (m, 6H, C3, C4, C5-H,

piperidine), 2.44 (m, 4H, C2, C6-H, piperidine), 3.78

(s, 2H, CH₂), 6.62 (dd, J_H3H4= 3 Hz, J_H4H5= 3 Hz,

1H, C4-H, furan), 7.14 (d, J = 3 Hz, 1H, C3-H, furan),

7.53–7.90 (m, 6H, phenyl, C5-H, furan); Anal. Calcd

for C₂₀H₂₀N₄OS: C, 65.91; H, 5.53; N, 15.37. Found:

C, 66.26; H, 5.55; N, 15.99.

6.4.2. 6-(4-Bromophenyl)-2-cyclohexyl-5-(pyrrolidin-1-yl-

methyl)imidazo[2,1-b][1,3,4]thiadiazole (5b). Yield 55%;

pale yellow solid (chloroform + pet ether); mp 128–

130 ꢁC; ¹H NMR (CDCl₃) d 1.29–3.35 (m, 19H, cyclohex-

yl, pyrrolidine), 3.89 (s, 2H, CH₂), 7.63 (d, J = 8.4 Hz, 2H,

C3, C5-H, phenyl), 7.88 (d, J = 8.4 Hz, 2H, C2, C6-H,

phenyl); Anal. Calcd for C₂₁H₂₅BrN₄: C, 56.63; H, 5.66;

N, 12.58. Found: C, 56.49; H, 5.51; N, 12.72.

6.3.4.

6-(4-Bromophenyl)-2-(2-furyl)-5-(piperidin-1-yl-

6.4.3.

2-(2-Furyl)-6-phenyl-5-(pyrrolidin-1-ylmethyl)imi-

methyl)imidazo[2,1-b][1,3,4]thiadiazole (4d). Yield 47%;

pale yellow granules (benzene + pet ether); mp 101–

103 ꢁC; ¹H NMR (CDCl₃) d 1.21–1.54 (m, 6H, C3,

C4, C5-H, piperidine), 2.41 (m, 4H, C2, C6-H, piperi-

dine), 3.81 (s, 2H, CH₂), 6.60 (dd, J_H3H4= 3 Hz,

J_H4H5= 3.3 Hz, 1H, C4-H, furan), 7.13 (d, J = 3 Hz,

1H, C3-H, furan), 7.51–7.88 (m, 5H, phenyl, C5-H, fur-

an); Anal. Calcd for C₂₀H₁₉BrN₄OS: C, 54.18; H, 4.32;

N, 12.64. Found C, 54.41; H, 4.21; N, 12.55.

dazo[2,1-b][1,3,4]thiadiazole (5c). Yield 60%; colorless

solid (benzene + pet ether); mp 110–112 ꢁC; ¹H NMR

(CDCl₃) d 2.13–2.60 (m, 4H, C3, C4-H, pyrrolidine),

3.29–3.46 (m, 4H, C2, C5-H, pyrrolidine), 3.98 (s, 2H,

CH₂), 6.69 (dd, J_H3H4= 3.3 Hz, J_H4H5= 4.2 Hz 1H, C4-

H, furan), 7.16 (d, J = 3.3 Hz, 1H, C3-H, furan), 7.50–

7.88 (m, 6H, phenyl, C5-H, furan); Anal. Calcd for

C₁₉H₁₈N₄OS: C, 65.12; H, 5.18; N, 15.99. Found: C,

65.61; H, 5.39; N, 16.60.

G. Kolavi et al. / Bioorg. Med. Chem. 14 (2006) 3069–3080

3077

6.4.4. 6-(4-Bromophenyl)-2-(2-furyl)-5-(pyrrolidin-1-yl-

methyl)imidazo[2,1-b][1,3,4]thiadiazole (5d). Yield 51%;

Yellow solid (chloroform); mp 150–152 ꢁC; H NMR

(CDCl₃) d 2.15–2.62 (m, 4H, C3, C4-H, pyrrolidine),

3.32–3.55 (m, 4H, C2, C5-H, pyrrolidine), 6.68 (dd,

J_H3H4= 3.3 Hz, J_H4H5= 3 Hz, 1H, C4-H, furan), 7.12

(d, J = 3.3 Hz, 1H, C3-H, furan), 7.50 (d, J = 9 Hz,

2H, C3, C5-H, phenyl), 7.61 (d, J = 3 Hz, 1H, C5-H,

furan), 7.92 (d, J = 9 Hz, C2, C6-H, phenyl); Anal.

Calcd for C₁₉H₁₇BrN₄OS: C, 53.15; H, 3.99; N, 13.05.

Found: C, 53.47; H, 4.26; N, 13.37.

2848, 1676, 1588; ¹H NMR (CDCl₃) d 1.30–3.15 (m, 11H,

cyclohexyl), 7.60 (d, J = 9 Hz, 2H, C3, C5-H, phenyl), 7.77

(d, J = 9 Hz, 2H, C2, C6-H, phenyl), 10.03 (s, 1H, alde-

hyde) Anal. Calcd for C₁₇H₁₆BrN₃OS: C, 52.31; H, 4.13;

N, 10.77. Found: C, 52.71; H, 4.27; N, 11.20.

1

6.5.3. 2-(2-Furyl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazole-

5-carbaldehyde (6c). Yield 76%; pale yellow solid (chloro-

form + hexane); mp 130–132 ꢁC; IR (KBr) m cm^À1, 2831,

1655, 1600, 1594; ¹H NMR (CDCl₃) d 6.68 (dd,

J_H3H4= 3 Hz, J_H4H5= 3 Hz, 1H, C4-H, furyl), 7.35 (d,

J = 3 Hz, 1H, C3-H, furyl), 7.52–7.92 (m, 6H, C5-H, furyl,

phenyl), 10.11 (s, 1H, aldehyde); Anal. Calcd for

C₁₅H₉N₃O₂S: C, 61.01; H, 3.07; N, 14.23. Found: C,

61.10; H, 3.12; N, 14.29.

6.4.5. 6-Phenyl-5-(pyrrolidin-1-ylmethyl)-2-thien-2-ylimi-

dazo[2,1-b][1,3,4]thiadiazole (5e). Yield 61%; colorless

solid (pet ether); mp 54–56 ꢁC; ¹H NMR (CDCl₃) d

2.22–2.66 (m, 4H, C3, C4-H, pyrrolidine), 3.28–3.47

(m, 4H, C2, C5-H, pyrrolidine), 4.10 (s, 2H, CH₂),

7.17 (dd, J = 3.6 Hz and 3.3 Hz, 1H, C4-H, thiophene),

7.30–7.86 (m, 7H, phenyl, C3, C5-H, thiophene); Anal.

Calcd for C₁₉H₁₈N₄S₂: C, 62.26; H, 4.95; N, 15.29.

Found: C, 62.45; H, 4.82; N, 15.76.

6.5.4. 6-(4-Bromophenyl)-2-(2-furyl)imidazo[2,1-b][1,3,4]-

thiadiazole-5-carbaldehyde (6d). Yield 63%; pale yellow sol-

id (chloroform); mp 172–174 ꢁC; IR (KBr) m cm^À12879,

1

1678, 1606; H NMR (CDCl₃) d 6.67 (dd, J_H3H4= 3 Hz,

J_H4H5= 3 Hz, 1H, C4-H, furyl), 7.31 (d, J = 3 Hz, 1H,

C3-H, furyl), 7.65 (d, J = 9 Hz, 2H, C3, C5-H, phenyl),

7.68 (d, J = 3 Hz, 1H, C5-H, furyl), 7.87 (d, J = 9 Hz,

2H, C2, C6-H, phenyl), 10.12 (s, 1H, aldehyde); Anal.

Calcd for, C₁₅H₈BrN₃O₂S: C, 48.14; H, 2.15, N, 11.23.

Found: C, 48.38; H, 2.26, N, 11.61.

6.4.6. 6-(4-Bromophenyl)-5-(pyrrolidin-1-ylmethyl)-2-thien-

2-ylimidazo[2,1-b][1,3,4]thiadiazole (5f). Yield 58%; Yellow

1

solid (chloroform + pet ether); mp 144–146 ꢁC; H NMR

(CDCl₃) d 2.18–2.63 (m, 4H, C3, C4-H, pyrrolidine), 3.33–

3.51 (m, 4H, C2, C5-H, pyrrolidine), 4.15 (s, 2H, CH₂),

7.17 (dd, J_H3H4= 3.6 Hz, J_H4H5= 3.6 Hz, 1H, C4-H, thio-

phene), 7.30 (d, J = 3.6 Hz, 1H, C3-H, thiophene), 7.57 (d,

J = 3.6 Hz, 1H, C5-H, thiophene), 7.69 (d, J = 8.4 Hz, 2H,

C3, C5-H, phenyl), 7.91 (d, J = 8.4 Hz, 2H, C2, C6-H, phen-

yl); Anal. Calcd for C₁₉H₁₇BrN₄S₂: C, 51.24; H, 3.85; N,

12.58. Found: C, 51.10; H, 3.71; N, 12.71.

6.5.5. 6-Phenyl-2-thien-2-ylimidazo[2,1-b][1,3,4]thiadia-

zole-5-carbaldehyde (6e). Yield 70%; colorless needles

(chloroform); mp 194–196 ꢁC; IR (KBr) m cm^À1

,

2850, 1650, 1550; ¹H NMR (CDCl₃) d 7.20 (dd,

J = 3 Hz and 3.9 Hz, 1H, C4-H, thienyl), 7.22–7.95

(m, 7H, C3, C5-H, thienyl and phenyl), 10.13 (s,

1H, aldehyde); Anal. Calcd for C₁₅H₉N₃OS₂: C,

57.86, H, 2.91, N, 13.49. Found: C, 58.02, H, 3.10,

N, 13.80.

6.5. Preparation of 2-alkyl/aryl-6-arylimidazo[2,1-b]-

[1,3,4]thiadiazole-5-carbaldehydes (6a–f)

Vilsmeier–Haack reagent was prepared by adding phos-

phoryl chloride (3 ml) in dimethylformamide (20 ml)

at 0 ꢁC with stirring. Then appropriately substituted

2-alkyl/aryl-6-arylimidazo[2,1-b][1,3,4]thiadiazole (2a–f,

0.01 mol) was added to the reagent and stirred at 0 ꢁC

for 30 min. The mixture was further stirred for 2 h at

room temperature and at 60 ꢁC for additional 2 h. The

reaction mixture was then poured in sodium carbonate

solution and stirred at 90 ꢁC for 2 h. After cooling, the

mixture was diluted with water, extracted with chloro-

form, and the collective extract was washed with water

and dried over anhydrous sodium sulfate. The residue

obtained after the removal of chloroform was recrystal-

lized from a suitable solvent to get the crystalline solid.

6.5.6. 6-(4-Bromophenyl)-2-thien-2-ylimidazo[2,1-b][1,3,4]-

thiadiazole-5-carbaldehyde (6f). Yield 72%; colorless prisms

(chloroform + hexane); mp 158–160 ꢁC; IR (KBr) m cm^À1

,

1

2856, 1673, 1565; H NMR (CDCl₃) d 7.18 (dd, J = 3 Hz

and 3.3 Hz, 1H, C4-H, thienyl), 7.25–7.98 (m, 6H, C3, C5-

H, thiophene and phenyl), 10.10 (s, 1H, aldehyde); Anal.

Calcd for C₁₅H₈BrN₃OS₂: C, 46.16; H, 2.07; N, 10.77.

Found: C, 46.45; H, 2.26; N, 11.14.

6.6. Preparation of (2-alkyl/aryl-6-arylimidazo[2,1-b][1,3,4]-

thiadiazol-5-yl) methanol (7a–f): general method

2-Alkyl/aryl-6-arylimidazo[2,1-b][1,3,4]thiadiazole-5-carb-

aldehyde (0.001 mol) was added in small portions to a

stirred and cooled solution of sodiumborohydride

(0.36 g, 0.001 mol) in dry methanol (20 ml). The mixture

was stirred at room temperature for 5 h (monitored by

TLC) and poured over ice water. The solid separated

was collected by ﬁltration, washed with cold methanol,

dried, and crystallized from benzene.

6.5.1. 2-Cyclohexyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazole-

5-carbaldehyde (6a). Yield 68%; colorless cubes (chloro-

form + benzene); mp 114–116 ꢁC; IR (KBr) m cm^À1

,

2851, 1674, 1597; ¹H NMR (CDCl₃) d 1.30–3.27 (m,

11H, cyclohexyl), 7.51–7.86 (m, 5H, ArH), 10.04 (s, 1H,

aldehyde); Anal. Calcd for C₁₇H₁₇N₃OS: C, 65.57; H,

5.50; N, 13.49. Found: C, 65.92; H, 5.67; N, 13.68.

6.6.1.

(2-Cyclohexyl-6-phenylimidazo[2,1-b][1,3,4]thia-

diazol-5-yl)methanol (7a). Yield 80%; colorless needles

(benzene); mp 176–178 ꢁC; IR (KBr) m cm^À1, 3201,

1603, 1557;¹H NMR (CDCl₃) d 1.25–2.12 (m, 10H,

cyclohexyl), 2.97 (m, 1H, C1-H, cyclohexyl), 3.18 (br s,

6.5.2. 6-(4-Bromophenyl)-2-cyclohexylimidazo[2,1-b][1,3,4]-

thiadiazole-5-carbaldehyde (6b). Yield 67%; colorless cubes

(chloroform + hexane); mp 144–146 ꢁC; IR (KBr) m cm^À1

,

3078

G. Kolavi et al. / Bioorg. Med. Chem. 14 (2006) 3069–3080

1H, OH, D₂O exchangeable), 5.03 (s, 2H, CH₂), 7.29–

7.79 (m, 5H, phenyl), ¹³C NMR (CDCl₃) d 25.8 (C4,

cyclohexyl), 26.0 (C3, C5, cyclohexyl), 33.1 (C2, C6,

cyclohexyl), 41.7 (C1, cyclohexyl), 54.4 (CH₂), 122.6,

127.8, 127.9, 129.0, 134.5, 144.3, 144.4 and 170.7; Anal.

Calcd for C₁₇H₁₉N₃OS: C, 65.15; H, 6.11, N, 13.41.

Found: C, 65.53; H, 6.22, N, 13.74. Mass, m/z (%),

314.03 (M + 1, 100%).

6.7. Preparation of 2-alkyl/aryl-6-arylimidazo[2,1-b]-

[1,3,4]thiadiazole-5-carbaldehydeoximes (8a–f): general

method

A mixture of 2-alkyl/aryl-6-arylimidazo[2,1-b][1,3,4]-

thiadiazol-5-carbaldehyde 3 (0.001 mol) and hydroxyl-

amine hydrochloride (0.83 g, 0.0012 mol) was reﬂuxed

in pyridine (10mL) for 6 h (monitored by TLC), the

cooled mixture was then poured over ice, and the precip-

itate was collected by ﬁltration, washed with water, aq

alcohol, dried, and recrystallized from appropriate sol-

vent to yield the corresponding aldoximes.

6.6.2. [6-(4-Bromophenyl)-2-cyclohexylimidazo[2,1-b][1,3,4]-

thiadiazol-5-yl] methanol (7b). Yield 76%; colorless needles

(chloroform + hexane); mp 190–192 ꢁC; IR (KBr) m cm^À1

,

1

3244, 1597, 1538; H NMR (CDCl₃) d 1.25–2.16 (m,10H,

cyclohexyl), 2.96 (m, 1H, C1-H, cyclohexyl), 3.01 (br s,

1H, OH, D₂O exchangeable), 4.99 (s, 2H, CH₂), 7.52 (d,

J = 8.4 Hz, 2H, C3, C5-H, phenyl), 7.77 (d, J = 8.4 Hz,

2H, C2, C6-H, phenyl); Anal. Calcd for C₁₇H₁₈BrN₃OS:

C, 52.05; H, 4.62; N, 10.71. Found: C, 52.29; H, 4.44; N,

11.32.

6.7.1. 2-Cyclohexyl-6-phenylimidazo[2,1-b][1,3,4]thiadia-

zole-5-carbaldehyde oxime (8a). Yield 83%; colorless crys-

talline solid(benzene + chloroform); mp 238–240 ꢁC; IR

1

(KBr) m cm^À13250, 1623, 1537; H NMR (CDCl₃) d

1.30–2.22 (m, 10H, cyclohexyl), 3.17 (m, 1H, C1-H, cyclo-

hexyl), 7.37–7.71 (m, 5H, phenyl), 8.46 (s, 1H, CH@N),

9.45 (s, b, 1H, OH, D₂O, exchangeable); Anal. Calcd for

C₁₇H₁₈N₄OS: C, 62.55; H, 5.56; N, 17.16. Found: C,

62.49; H, 5.48; N, 17.31. Mass, m/z (%), 327.03 (M+1,

100).

6.6.3. [2-(2-Furyl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-

yl]methanol (7c). Yield 85%; pale yellow granules (chloro-

form + hexane); mp 150–152 ꢁC; IR (KBr) m cm^À1, 3266,

1

1589; H NMR (CDCl₃) d 1.92 (br s, 1H, OH, D₂O

exchangeable), 5.11 (s, 2H, CH₂), 6.63 (dd, J_H3H4= 3 Hz,

J_H4H5= 3 Hz, 1H, C4-H, furyl), 7.14 (dd, J = 3 Hz, 1H,

C3-H, furan), 7.37 (m, 1H, C4-H, phenyl), 7.47 (m, 2H,

C3, C5-H, phenyl), 7.63 (d, J = 3 Hz, 1H, C5-H, furan),

7.83 (m 2H, C2, C6-H, phenyl); Anal. Calcd for

C₁₅H₁₁N₃O₂S: C, 60.59; H, 3.73; N, 14.13. Found: C,

60.95; H, 3.83; N, 14.79.

6.7.2. 6-(4-Bromophenyl)-2-cyclohexylimidazo[2,1-b][1,3,4]-

thiadiazole-5-carbaldehydeoxime (8b). Yield 82%; colorless

solid (ethanol); mp 202–204 ꢁC; IR (KBr) m cm^À13250,

1623, 1537; ¹H NMR (CDCl₃) d 1.30–3.15 (m, 11H, cyclo-

hexyl), 7.60 (d, J = 9 Hz, 2H, C3, C5-H, phenyl), 7.77 (d,

J = 9 Hz, 2H, C2, C6- H, phenyl), 8.63 (s, 1H, CH@N),

9.74 (br s, 1H, OH, D₂O exchange able); Anal. Calcd for

C₁₇H₁₇BrN₄OS: C, 50.38; H, 4.23; N, 13.82. Found: C,

50.75; H, 4.43; N, 13.97.

6.6.4. [6-(4-Bromophenyl)-2-(2-furyl)imidazo[2,1-b][1,3,4]-

thiadiazol-5-yl] methanol (7d). Yield 63%; pale yellow crys-

talline solid (benzene + pet ether); mp 192–194 ꢁC; IR

(KBr) m cm^À13321, 1602, 1543; ¹H NMR (CDCl₃) d 2.58

(br s, 1H, OH), 4.98(s, 2H, CH₂), 6.67(dd, J_H3H4= 3.3 Hz,

J_H4H5= 3 Hz, 1H, C4-H, furan), 7.12 (d, J = 3.3 Hz, 1H,

C3-H, furan), 7.49 (d, J = 9 Hz, 2H, C3, C5-H,

phenyl), 7.67 (d, J = 3 Hz, 1H, C5-H, furan), 7.88 (d,

J = 9 Hz, C2, C6-H, phenyl); Anal. Calcd for

C₁₅H₁₀BrN₃O₂S: C, 47.89; H, 2.68; N, 11.17. Found: C,

47.78; H, 2.77; N, 11.31.

6.7.3. 2-(2-Furyl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazole-

5-carbaldehydeoxime (8c). Yield 83%; pale yellow solid

(ethanol); mp 206–208 ꢁC; IR (KBr) m cm^À1, 2342,

1603, 1543; ¹H NMR (CDCl₃) d 6.66 (dd, J_H3H4

=

3.3 Hz, J_H4H5= 3 Hz, 1H, C4-H, furyl), 7.35 (d,

J = 3.3 Hz, 1H, C3-H, furyl), 7.52–7.92 (m, 6H, C5-H,

furyl, phenyl), 8.52 (s, 1H, CH@N), 9.83 (br s, 1H,

OH, D₂O exchangeable); Anal. Calcd for C₁₅H₁₀N₄O₂S:

C, 58.05; H, 3.25; N, 18.05. Found: C, 58.30; H, 3.32; N,

18.38.

6.6.5. (6-Phenyl-2-thien-2-ylimidazo[2,1-b][1,3,4]thia-

diazol-5-yl)methanol (7e). Yield 83%; colorless granules

6.7.4. 6-(4-Bromophenyl)-2-(2-furyl)imidazo[2,1-b][1,3,4]-

thiadiazole-5-carbaldehydeoxime (8d). Yield 77%; pale

yellow solid (ethanol); mp 212–214 ꢁC; IR (KBr) m

(benzene); mp 202–204 ꢁC; IR (KBr) m cm^À13242,

1

1605, 1546; H NMR (CDCl₃) d 2.30 (t, 1H, OH, D₂O

1

exchangeable), 5.14 (d, J = 5.7 Hz, 2H, CH₂), 7.18 (dd,

J = 3 Hz and 3.3 Hz, 1H, C4-H, thienyl), 7.38–7.85 (m,

7H, phenyl, C3, C5-H, thienyl); Anal. Calcd for

C₁₅H₁₁N₃OS₂: C, 57.49; H, 3.54; N, 13.41. Found: C,

57.86; H, 3.63; N, 13.55.

cm^À13301, 1597, 1533; H NMR (CDCl₃) d 6.68 (dd,

J_H3H4= 3.3 Hz, J_H4H5= 3 Hz, 1H, C4-H, furyl), 7.34

(d, J = 3.3 Hz, 1H, C3-H, furyl), 7.67 (d, J = 9 Hz,

2H, C3, C5-H, phenyl), 7.66 (d, J = 3 Hz, 1H, C5-H,

furyl), 7.85 (d, J = 8.7 Hz, 2H, C2, C6-H, phenyl),

8.43 (s, 1H, CH@N), 10.08 (br s, 1H, OH, D₂O

exchangeable); Anal. Calcd for C₁₅H₉BrN₄O₂S: C,

46.29; H, 2.33; N, 14.39. Found: C, 46.44; H, 2.21; N,

14.51.

6.6.6. [6-(4-Bromophenyl)-2-thien-2-ylimidazo[2,1-b][1,3,4]-

thiadiazol-5-yl] methanol (7f). Yield 71%; colorless granules

(benzene); mp 202–204 ꢁC; IR (KBr) m cm^À13312, 1621,

1539; ¹H NMR (CDCl₃) d 2.54 (br s, 1H, OH, D₂O

exchangeable), 5.08 (s, 2H, CH₂), 7.17 (dd, J = 3 Hz

and 3.3 Hz, 1H, C4-H, thienyl), 7.38–7.85 (m, 6H, phenyl

and C3, C5-H, thienyl); Anal. Calcd for C₁₅H₁₀BrN₃OS₂:

C, 45.92; H, 2.57; N, 10.71. Found: C, 46.32; H, 2.79; N,

11.11.

6.7.5. 6-Phenyl-2-thien-2-ylimidazo[2,1-b][1,3,4]thiadia-

zole-5-carbaldehydeoxime (8e). Yield 83%; colorless

crystalline solid (ethanol); mp 212–214 ꢁC; IR (KBr) m

1

cm^À13246, 1615, 1530; H NMR (CDCl₃) d 7.18 (dd,

J = 3.3 Hz and 3.3 Hz, 1H, C4-H, thienyl), 7.22–7.95

G. Kolavi et al. / Bioorg. Med. Chem. 14 (2006) 3069–3080

3079

(m, 7H, C3, C5-H, thienyl and phenyl), 8.47 (s, 1H,

CH@N), 9.65 (br s, 1H, OH, D₂O exchangeable); Anal.

Calcd for C₁₅H₁₀N₄OS₂: C, 55.20; H, 3.09; N, 17.17.

Found: C, 55.55; H, 3.38; N, 17.34.

6.8.5. 6-Phenyl-2-thien-2-ylimidazo[2,1-b][1,3,4]thiadia-

zole-5-carbonitrile (9e). Yield 73%; colorless solid (ben-

zene + chloroform); mp 166–168 ꢁC; IR (KBr) m cm^À1

2219, 1634, 1545; ¹H NMR (CDCl₃) d 7.17 (d,

J = 3 Hz and 4.2 Hz, 1H, C4-H, thienyl), 7.25–7.99 (m,

7H, C3, C5-H, thienyl and phenyl); Anal. Calcd for

C₁₅H₈N₄S₂: C, 58.42; H, 2.61; N, 18.17. Found: C,

58.68; H, 2.92; N, 18.45.

6.7.6. 6-(4-Bromophenyl)-2-thien-2-ylimidazo[2,1-b][1,3,4]-

thiadiazole-5-carbaldehydeoxime (8f). Yield 76%; colorless

granules (ethanol); mp 202–204 ꢁC; IR (KBr) m cm^À13229,

1618, 1526; ¹H NMR (CDCl₃) d, 7.15 (dd, J = 3.6 Hz and

3.3 Hz, 1H, C4-H, thienyl), 7.32–7.84 (m, 6H, ArH), 8.56

(s, 1H, CH@N), 9.34 (br s, 1H, OH, D₂O exchangeable);

Anal. Calcd for C₁₅H₉BrN₄OS₂: C, 44.45; H, 2.24; N,

13.82. Found: C, 44.34; H, 2.17; N, 13.93.

6.8.6. 6-(4-Bromophenyl)-2-thien-2-ylimidazo[2,1-b][1,3,4]-

thiadiazole-5-carbonitrile (9f). Yield 68%; pale yellow sol-

id (chloroform); mp 152–154 ꢁC; IR (KBr) m cm^À12222,

1632, 1544; ¹H NMR (CDCl₃) d 7.17 (dd, J = 3.3 Hz and

3.9 Hz, 1H, C4-H, thienyl), 7.22–7.96 (m, 6H, C3, C5-H,

thiophene, phenyl); Anal. Calcd for C₁₅H₇BrN₄S₂: C,

46.52; H, 1.82; N, 14.47. Found: C, 46.63; H, 1.98; N,

14.77.

6.8. Preparation of 2-alkyl/aryl-6-arylimidazo[2,1-b]-

[1,3,4]thiadiazole-5-carbonitriles (9a–f): general method

The 2-alkyl/aryl-6-arylimidazo[2,1-b][1,3,4]thiadiazole-

5-carbaldehydeoxime (0.001 mol) was suspended in

thionylchloride (7mL) and reﬂuxed for 5 min. Poured

over cold water, neutralized by sodium carbonate solu-

tion, the solid that separated was collected by ﬁltration

was washed repeatedly with water, dried, and recrystal-

lized from appropriate solvent.

6.9. Preparation of 2-(2-alkyl/aryl-6-phenylimidazo[2,1-b]-

[1,3,4]thiadiazol-5-yl)-3-phenyl-1,3-thiazolidin-4-ones

(10a–c): general method

2-Alkyl/aryl-6-phenylimidazo[2,1-b][1,3,4]thiadiazole-5-

carbaldehyde (0.01 mol) and aniline (1.1 g, 0.012 mol)

were reﬂuxed in rectiﬁed spirit (30mL) with catalytic

amount of acetic acid for 3 h. The solid that separated

was ﬁltered, washed with alcohol and dried. The crude

product was recrystallized from alcohol, the yellow col-

ored solid thus obtained (0.01 mol) was reﬂuxed with

thioglycolic acid (0.012 mol), in dry benzene (25 mL)

for 5 h. The colorless solid that separated was collected

by ﬁltration, dried, and recrystallized from appropriate

solvent.

6.8.1. 2-Cyclohexyl-6-phenylimidazo[2,1-b][1,3,4]thiadia-

zole-5-carbonitrile (9a). Yield 90%; colorless granules

(benzene); mp 145–147 ꢁC; IR (KBr) m cm^À12219, 1600;

¹H NMR (CDCl₃) d 1.45–1.91 (m, 10H, cyclohexyl),

3.12 (m, 1H, C1-H, cyclohexyl), 7.49–8.09 (m, 5H, phen-

yl); Anal. Calcd for C₁₇H₁₆N₄S: C, 66.21; H, 5.23; N,

18.17. Found: C, 66.30; H, 5.17; N, 18.54.

6.8.2. 6-(4-Bromophenyl)-2-cyclohexylimidazo[2,1-b][1,3,4]-

thiadiazole-5-carbonitrile (9b). Yield 81%; colorless granules

(benzene); mp 175–177 ꢁC; IR (KBr) m cm^À12223, 1608,

1546; ¹H NMR (CDCl₃) d 1.42–1.93 (m, 10H, cyclohexyl),

3.13 (m, 1H, C1-H, cyclohexyl); 7.62 (d, J = 9 Hz, 2H, C3,

C5-H, phenyl), 7.75 (d, J = 9 Hz, 2H, C2, C6-H, phenyl);

Anal. Calcd for C₁₇H₁₅BrN₄S: C, 52.72; H, 3.90; N, 14.47.

Found: C, 52.61; H, 3.71; N, 14.63.

6.9.1. 2-(2-Cyclohexyl-6-phenylimidazo[2,1-b][1,3,4]thia-

diazol-5-yl)-3-phenyl-1,3-thiazolidin-4-one (10a). Yield

66%; colorless granules (ethanol); mp 212–214 ꢁC; IR

(KBr) m cm^À12927, 1710, 1600, 1492; ¹H NMR

(DMSO-d₆) d 1.29–2.10 (m, 10H, cyclohexyl), 3.17 (m,

1H, C1-H, cyclohexyl), 5.90 (s, 2H, CH₂), 7.32–7.74

(m, 11H, Ar-H and CH, thiazolidinone); Anal. Calcd

for C₂₅H₂₄N₄OS₂: C, 65.19; H, 5.25; N, 12.16. Found:

C, 65.26; H, 5.39; N, 12.63.

6.8.3. 2-(2-Furyl)-6-phenylimidazo[2,1-b][1,3,4]thiadia-

zole-5-carbonitrile (9c). Yield 69%; pale yellow solid

(benzene); mp 206–208 ꢁC; IR (KBr) m cm^À1, 2215,

6.9.2. 2-[2-(2-Furyl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-

5-yl]-3-phenyl-1,3-thiazolidin-4-one (10b). Yield 64%;

pale yellow granules (ethanol); mp 218–220 ꢁC; IR (KBr)

1600, 1543; ¹H NMR (CDCl₃)

d

6.69 (dd,

J_H3H4= 3.3 Hz, J_H4H5= 3.3 Hz, 1H, C4-H, furyl), 7.29

(d, J = 3 Hz, 1H, C3-H, furyl), 7.48–7.98 (m, 6H, C5-

H, furyl, phenyl); Anal. Calcd for C₁₅H₈N₄OS: C,

61.63; H, 2.76; N, 19.17. Found: C, 61.55; H, 2.88; N,

19.31.

1

m cm^À11716, 1546, 1498, 1463; H NMR (DMSO-d₆)

d 5.95 (s, 2H, CH₂), 6.67 (dd, J = 3.9 Hz and 3 Hz,

1H, C4-H, furan), 7.26–7.94 (m, 13H, ArH and CH,

thiazolidinone); Anal. Calcd for C₂₃H₁₆N₄O₂S₂: C,

62.14; H, 3.63; N, 12.60. Found: C, 62.27; H, 3.55;

N, 12.88.

6.8.4. 6-(4-Bromophenyl)-2-(2-furyl)imidazo[2,1-b][1,3,4]-

thiadiazole-5-carbonitrile (9d). Yield 71%; pale yellow sol-

id (chloroform); mp 177–179 ꢁC; IR (KBr) m cm^À12220,

1605, 1546; ¹H NMR (CDCl₃) d 6.67 (dd, J_H3H4= 3.3 Hz,

J_H4H5= 3 Hz, 1H, C4-H, furyl), 7.32 (d, J = 3.3 Hz, 1H,

C3-H, furyl), 7.65 (d, J = 8.7 Hz, 2H, C3, C5-H, phenyl),

7.66 (d, J = 3 Hz, 1H, C5-H, furyl), 7.82 (d, J = 8.7 Hz,

2H, C2, C6-H, phenyl); Anal. Calcd for C₁₅H₇BrN₄OS:

C, 48.53; H, 1.90; N, 15.09. Found: C, 48.67; H, 2.01; N,

15.35.

6.9.3.3-Phenyl-2-(6-phenyl-2-thien-2-ylimidazo[2,1-b][1,3,4]-

thiadiazol-5-yl)-1,3-thiazolidin-4-one (10c). Yield 64%; pale

yellow granules (ethanol); mp 218–220 ꢁC; IR (KBr) m

1

cm^À11716, 1546, 1498, 1463; H NMR (DMSO-d₆) d,

5.95 (s, 2H, CH₂), 7.26–7.94 (m, 14H, ArH and CH, thiazo-

lidinone); Anal. Calcd for C₂₃H₁₆N₄OS₃: C, 59.98; H, 3.50;

N, 12.16. Found: C, 60.10; H, 3.87; N, 12.21%; Mass, m/z

(%), 460 (100).

3080

G. Kolavi et al. / Bioorg. Med. Chem. 14 (2006) 3069–3080

Bornemeier, D. A.; Dyer, R. D. J. Med. Chem. 1999, 42,

1161.

Acknowledgments

11. Labanauskas, L.; Kalcas, V.; Udrenaite, E.; Gaidelis, P.;

Brukstus, A.; Dauksas, A. Pharmazie 2001, 56, 617.

12. Chapleo, C. B.; Myers, M.; Myers, P. L.; Saville, J. F.;

Smith, A. C. B.; Stillings, M. R.; Terlloch, I. F.; Walter,

D. S.; Welbourn, A. P. J. Med. Chem. 1986, 29, 2273.

13. Chapleo, C. B.; Myers, P. L.; Smith, A. C.; Stillings, M.

R.; Tulloch, I. F.; Walter, D. S. J. Med. Chem. 1988, 31, 7.

14. Turner, S.; Myers, M.; Gadie, B.; Nelson, A. J.; Pape, R.;

Saville, J. F.; Doxey, J. C.; Berridge, T. L. J. Med. Chem.

1988, 31, 902.

The authors are thankful to Prof. C. S. Mahajanshetti

for his valuable suggestions. The authors are also grate-

ful to Tuberculosis Antimicrobial Acquisition and

Coordinating Facility (TAACF, NIAID, NIH, USA)

for anti-tuberculosis evaluations and Dr. Uday Mudda-

pur for antibacterial and antifungal screening.

References and notes

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Article Doi

Synthesis and evaluation of antitubercular activity of imidazo[2,1-b][1,3, 4]thiadiazole derivatives

DOI: 10.1016/j.bmc.2005.12.020

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