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Synthesis, Characterization and Antibacterial Evaluation of some Novel Benzimidazole Derivatives Containing 1,3,4-Thiadiazole Moiety.

Volume 33, Number 6

Muayed Ahmed Redayan1, Wassan Baqir Ali2 and Ahmed Mudhafar Mohammed2

1Department of Chemistry, College of education for pure sciences, Diyala University, Iraq.

2Department of Chemistry, College of Sciences, Diyala University, Iraq.

Corresponding Author E-mail: mredayan@gmail.com

DOI : http://dx.doi.org/10.13005/ojc/330656

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ABSTRACT:

A series of novel 5-amino-1,3,4-thiadiazole-2-thiol and 1,3,4-thiadiazole-2,5-dithiol  derivatives of benzimidazole were synthesized through nucleophilic substitution reaction of 5-substituted-2-(chloromethyl)-1H-benzimidazole, structures of the synthesized compounds were proved by spectral methods of analysis ( FT-IR, 1H and 13C NMR ). All the target compounds were screened for their antibacterial activity toward  gram-negative (E.coli, P. aeruginosa) and gram-positive (B. subtilis, S. aureus) bacteria, most of the synthesized derivatives  exhibited good to moderate  activity toward both  gram-positive (B. subtilis, S. aureus) and gram-negative (E.coli, P. aeruginosa) bacteria.

KEYWORDS:

Benzimidazole; Bis Benzimidazole; 1,3,4-Thiadiazole; Antibacterial Activity

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Redayan M. A, Ali W. B, Mohammed A. M. Synthesis, Characterization and Antibacterial Evaluation of some Novel Benzimidazole Derivatives Containing 1,3,4-Thiadiazole Moiety. Orient J Chem 2017;33(6).

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Redayan M. A, Ali W. B, Mohammed A. M. Synthesis, Characterization and Antibacterial Evaluation of some Novel Benzimidazole Derivatives Containing 1,3,4-Thiadiazole Moiety. Orient J Chem 2017;33(6). Available from: http://www.orientjchem.org/?p=40112

Introduction

The benzimidazole nucleus consider one of the most significant and important N-containing fused organic compounds in a large number  of synthetic pharmaceutical materials and natural products. [1, 2] Benzimidazole ring count a significant heterocyclic pharmacophore in the drug discovery, these compounds which carrying diverse substituents in the structure of benzimidazole are associated with a wide range of biological activities including: antifungal, [3, 4, 5]  anticancer, [6, 7, 8] anti-inflammatory, [9, 10]  antioxidant, [11, 12, 13] anti-bacterial, [14, 15, 16, 17] anti-viral, [18, 19] anticoagulant, [20] and anti-hypertensive properties . [21]

Despite of many attempts to develop and discover new structural type in the search for great and more effective antimicrobials, benzimidazoles still consider as one of the most versatile and significant type of compounds against microbes. [22, 23]

The benzimidazole containing compounds as a structural motif  have been widely used in medicinal chemistry and drugs development. Amongst the benzimidazole derivatives 2-chloromethyl benzimidazole show a considerable importance in biological chemistry, they are important intermediates in the synthesis of many biologically active compounds. [24]

Designing new compounds in order to deal with resistant bacteria has become one of the most significant and great  areas of antibacterial research today. Because the resistance of pathogenic bacteria toward common and available antimicrobial drugs is quickly becoming a major worldwide problem, so the discovery of new and potent antibacterial agent is more challenging and demanding for pharmacists and chemists nowadays. [25]

Materials and Methods

Melting points were determined using stuart smp3 apparatus and are uncorrected, FT-IR spectra were recorded on shimadzu FT-IR spectrophotometer, 1H and 13C –NMR spectra were recorded on brucker 300 MHz spectrophotometer  using (DMSO) as a solvent and  TMS as internal reference. The compounds were checked for their purity on silica gel TLC plates and the visualization of spots performed  by using UV light.

General Method for the Synthesis of 5-Substituted-2-(Chloromethyl)-1H-Benzimidazole 1(a-d)[15, 26, 27]

A mixture of  4-(un)substituted-o-phenylenediamine (0.05 mole) and chloroacetic acid (0.05 mole) was dissolved in ( 25 ml) 4N HCl and refluxed for 4hrs. The completion of the reaction was checked by using T.L.C ( mobile phase:ethyl acetate: hexane 2:1). The reaction mixture was allowed to cool down and neutralized with ammonium hydroxide solution, the precipitate appeared was dried and recrystallized from (methanol/water).

2-(chloromethyl)-1H-benzimidazole (1a)

yellow crystals, m.p: 147-150°C, IR (KBr, cm-1): N-Hstr (3133), aromtic C-Hstr ( 3050), aliphatic C-Hstr (2900, 2846), C=Nstr (1625), aromatic C=Cstr (1520, 1446), C-Clstr (640), Yield: 93%.

2-(chloromethyl)-5-methyl-1H-benzimidazole (1b)

Dark brown crystals, m.p:130-134°C, IR (KBr, cm-1): N-Hstr (3147), aromtic C-Hstr (3045), aliphatic C-Hstr(2919, 2850), C=Nstr (1622), aromatic C=Cstr (1522, 1447), C-Clstr(646), yield: 90%.

2-(chloromethyl)-1H– benzimidazole-5-carboxylic acid (1c)

Brown crystals, m.p: 290-293°C, IR (KBr, cm-1): N-Hstr (3379), OHstr (2600-3350), aromtic   C-Hstr ( 3040), aliphatic C-Hstr (2966, 2806), C=Ostr (1681), C=Nstr (1614), aromatic C=Cstr (1425-1573), C-Clst (675), yield: 88%.

2-(chloromethyl)-5-nitro-1H-benzimidazole (1d)

Dark yellow crystals, m.p:168-170°C, IR (KBr, cm-1): N-Hstr (3259), aromtic C-Hstr (3028), aliphatic C- Hstr (2980, 2800), C=Nstr (1624), C=Cstr (1446, 1471), NO2 str (1334, 1508), C-Clstr (690), yield: 85%.

Synthesis of 5-amino-1,3,4-thiadiazole-2-thiol (2)[28]

A mixture of (4 g, 0.04 mole) of thiosemicarbazide and (4.66g, 0.04 mole) of anhydrous Sodium carbonate were dissolved in 50 ml of absolute ethanol. (6.4 g, 0.08 mole) of carbon disulfide was then added to this solution. The resulting mixture was then refluxed for 11 hrs, subsequently the reaction mixture was allowed to cool down at R.T. Most of solvent was distilled off under reduced pressure and the residue was dissolved in 40 ml of distilled water and then carefully acidified with cold conc. Hydrochloric acid to give pale yellow precipitate. The product was then filtered and washed with cold water, then recrystallized from hot water, T.L.C (mobile phase: ethyl acetate: hexane 2:1 ). M.p: 232-234°C, IR (KBr, cm-1): N-Hstr (3399, 3279), S-Hstr (2529), C=Nstr (1601), C=Sstr (1363), C-Sstr (670), yield 83%.

General method for the Synthesis of compounds 3(a-d)[29]

5-amino-1,3,4-thiadiazole-2-thiol (2) (5 mmole) and fused sodium acetate (5 mmole) were added  To the solution of compound (3) (5 mmole) in absolute  ethanol (35 ml), the mixture was refluxed for 12 hrs, the reaction completion was checked by using T.L.C (mobile phase: ethyl acetate: hexane 2:1), then the reaction mixture was cooled and the precipitate was collected by filtration and dried.

5-[(1H-benzimidazol-2-ylmethyl)sulfanyl]-1,3,4-thiadiazol-2-amine (3a)

Yellow-brown crystals, m.p: 196-198°C, IR (KBr, cm-1): NH2 str (3252), aromtic C-Hstr (3085), aliphatic C-Hstr (2954, 2918), C=Nstr (1622), aromatic C=Cstr (1526, 1434), C-Sstr (671), yield 53%.

5-{[(5-methyl-1H-benzimidazol-2-yl)methyl]sulfanyl}-1,3,4-thiadiazol-2-amine (3b)

Brown crystals, m.p: >350°C, IR (KBr, cm-1): NH2 str (3342, 3264), N-Hstr (3133),  aromtic C-Hstr (3080), aliphatic C- Hstr (2972, 2918), C=Nstr (1610), aromatic C=Cstr (1556, 1449), C-Sstr (621), yield 47%.

2-{[(5-amino-1,3,4-thiadiazol-2-yl)sulfanyl]methyl}-1H-benzimidazole-5-carboxylic acid (3c)

Brown  crystals, m.p: 240 dec.°C, IR (KBr, cm-1): OHstr (2800-3550), NH2 str (3442, 3265), N-Hstr (3147), aromtic C-Hstr (3051), aliphatic C-Hstr (2941, 2864), C=Ostr (1697), C=Nstr (1616), aromatic C=Cstr (1571, 1512, 1421), C-Sstr (671). 1HNMR (DMSO-d6) δ ppm: 3.9 ( s, 2H, CH2), 4.4 ( s, 1H, N-H), 4.58 (s, 2H, NH2), 7.6 – 8.1 (m, 3H, Ar-H), 12.9 (s, 1H, OH),  yield 45%.

5-{[(5-nitro-1H-benzimidazol-2-yl)methyl]sulfanyl}-1,3,4-thiadiazol-2-amine (3d)

Light brown crystals, m.p: 214°C, IR (KBr, cm-1): NH2 str (3406, 3284), N-Hstr (3107), aromtic C-Hstr (3057),  aliphatic C-Hstr (2968, 2800), C=Nstr (1627), aromatic C=Cstr (1537, 1469), N02str (1338, 1514),  C-Sstr (640), 1HNMR (DMSO-d6) δ ppm:  3.37 (s, 1H, N-H),  4.3 (s, 2H, CH2), 7 ( s, 2H, NH2), 7.6-8.1 (m, 3H, Ar-H),  yield  90%.

Synthesis of 1,3,4-thiadiazole-2,5-dithiol (4)[30] 

 A mixture of carbon disulfide (0.04 mole, 30 ml) and hydrazine hydrate 80% (0.04 mole,10 ml) with pyridine (100 ml) was heated under reflux for 5 hours. Then excess solvent was distilled off and the solid obtained was separated by adding (50 ml ) of water and (10 ml) of hydrochloric acid. The precipitate was then filtered, dried and recrystallized from ethanol. T.L.C (mobile phase: ethyl acetate: hexane 2:1). Yellow crystals,  m.p:163-166°C, IR (KBr, cm-1): N-Hstr (3055), S-Hstr (2732), C=Nstr (1622), C=Sstr (1266), C-Sstr (677), yield  85%.

General method for the Synthesis of compounds 5(a-d) [29]

To the solution of compounds (1) (0.02mole ) in absolute ethanol(60 ml) the 1,3,4-thiadiazole-2,5-dithiol (4) (0.01 mole) and fused sodium acetate (0.02 mole) were added and the mixture was refluxed for 12 hrs, after completion of the reaction which was checked by T.L.C (mobile phase: ethyl acetate: hexane 2:1 ) the mixture was allowed to cool down and cooled in ice bath, the product was collected by filtration and dried.

2,2′-[1,3,4-thiadiazole-2,5-diylbis(sulfanediylmethanediyl)]bis(1H-benzimidazole) (5a)

Yellow-brown crystals, m.p: 218-220 dec.°C,  IR (KBr, cm-1): N- Hstr (3420), aromtic C-Hstr (3100),  aliphatic C-Hstr  (2978, 2930), C=Nstr (1622), aromatic C=Cstr (1526, 1437), C-Sstr (746), 1HNMR (DMSO-d6) δ ppm: 3.4 (s, 2H, CH2), 4.8 (s, 1H, N-H), 7.1-7.7 (m, 8H, Ar-H)  yield 47%.

2,2′-[1,3,4-thiadiazole-2,5-diylbis(sulfanediylmethanediyl)]bis(5-methyl-1H-benzimidazole)(5b)

Light brown crystals, m.p: >300°C, IR (KBr, cm-1): N- Hstr (3417), aromtic C-Hstr (3072),  aliphatic C-Hstr  (2976),  C=Nstr (1637), aromatic C=Cstr (1618, 1562), C-Sstr (619), yield 44%.

2,2′-[1,3,4-thiadiazole-2,5-diylbis(sulfanediylmethanediyl)]bis(1H-benzimidazole-5-carboxylic acid) (5c)

Light green. M.p: 284-285°C, IR (KBr, cm-1): N- Hstr (3431), OHstr (2500-3600), aromtic C-Hstr (3074),  aliphatic C-Hstr  (2974, 2889, 2804), C=Ostr (1699),  C=Nstr (1631), aromatic C=Cstr (1616, 1564), C-Sstr (769), 1HNMR (DMSO-d6) δ ppm: 5.09 (s, 2H, CH2), 5.3 (s, 1H, N-H), and  7.69-8.3 (m, 6H, Ar-H). 13CNMR (DMSO-d6) δ ppm: 29.5 (CH2), 114.3, 116.2, 124.5, 126.7, 134.1, 137.1(Ar-C), 152.1(C=N of  benzimidazole ), 164.3(C=N of thiadiazole , 167.2(C=O), yield 73%.

2,2′-[1,3,4-thiadiazole-2,5-diylbis(sulfanediylmethanediyl)]bis(5-nitro-1H-benzimidazole)(5d)

Light brown crystals, m.p: 165°C. IR (KBr, cm-1): N- Hstr (3419), aromtic C-Hstr (3099),  aliphatic C-Hstr  (2974, 2918), C=Nstr (1627), aromatic C=Cstr (1597, 1471 ), NO2str (1346, 1519), C-Sstr (738), 1HNMR (DMSO-d6) δ ppm: δ 3.6 (s, 1H, N-H), δ 5.0 (s,  2H, CH2), and δ 7.6-8.4 ( m, 6H, Ar-H ). 13CNMR (DMSO-d6) δ ppm: 31.0 (CH2),  104.7, 108, 116.1, 117.9, 118.2, 129.4 (Ar-C), 142.6 (C=N of benzimidazole), 164.5 (C=N of thiadiazole). Yield 78%.

Scheme 1: synthesis of benzimidazzole derivatives Scheme 1: synthesis of benzimidazzole derivatives



Click here to View scheme

 

Result and Discussion

The reaction sequence for various title compounds is summerized in (scheme 1). The starting material  5-substituted-2-(chloromethyl)-1H-benzimidazole 1(a-d) was synthesized according to a reported procedure through the reaction of  4-(un)substituted-o-phenylenediamine  with chloroacetic acid.[15, 26, 27] Structure of compounds 1(a-d) was confirmed by comparison of its physical and spectral data with the reported ones, [26, 27, 31]  nucleophilic substitution reaction  of compound 1(a-d) with 5-amino-1,3,4-thiadiazole-2-thiol (2) yielded 5-{[(5-substituted-1H-benzimidazol-2-yl)methyl]sulfanyl}-1,3,4-thiadiazol-2-amine 3(a-d) ( route I), the structure of compounds 3(a-d) was confirmed by its IR, 1H-NMR, the IR spectra of  the compound (3c) exhibited a broad band at (2800-3550 cm-1  for carboxylic OH ), (3442, 3265cm-1   for NH2), ( 3147 cm-1   for benzimidazole N-H), (1697 cm-1  for C=O) and band at (671 cm-1   for C-S ). 1HNMR spectra showed the following chemical shifts  at: δ 3.9 (s, 2H, CH2), δ 4.4  (s, 1H, N-H ), δ 4.58 (s, 2H, NH2), δ 7.6 – 8.1(m, 3H, Ar-H), and weak signal at δ 12.9 for  carboxylic OH, and the IR spectra of  the compound (3d) exhibited the following bands: (3406, 3284 cm-1)  for NH2, (3107 cm-1) for benzimidazole N-H, and two peaks at (1338, 1323 cm-1) corresponding for NO2 group. Whereas the 1HNMR spectra for this compound revealed the following peaks: δ 3.37 (s, 1H, N-H), δ 4.3 (s, 2H, CH2), δ 7 ( s, 2H, NH2), and multiplet signals at δ (7.6-8.1) corresponding for aromatic protons.

The ( route II ) also included nucleophilic substitution reaction of compound 1(a-d) with 1,3,4-thiadiazole-2,5-dithiol (4) yielded  2,2′-[1,3,4-thiadiazole-2,5-diylbis(sulfanediylmethanediyl)]bis(5-subsituted-1H-benzimidazole)  5(a-d), The structure of compounds 5(a-d) was confirmed by its IR, 1H-NMR and 13C-NMR, The IR spectra of  the compound (5c) showed a broad band at 2500-3600 cm-1  for carboxylic OH group, 3431 cm-1  for benzimidazole N-H, 1699 cm-1   for C=O group, 1631 cm-1  for C=N group, and band at 769 cm-1  for C-S group. Whereas the 1HNMR spectra exhibited  the following chemical shifts: δ 5.09 (s, 2H, CH2), δ  5.3 (s, 1H, N-H), and δ 7.69-8.3 (m, 6H, Ar-H). The signals in 13CNMR was appeared at around:  δ 29.5 accounted for the methylene group (-CH2-), signals at (114.3, 116.2, 124.5, 126.7, 134.1, 137.1) could be for benzene  ring, also 13CNMR spectra showed signal about 152.1 and 164.3 for (-C=N) of benzimidazole and  thiadiazole ring respectively, whereas signal at 167.2 accounted for (-C=O) group.

The IR spectra for the compound (5d) found have the following bands: 3419 cm-1 for N-H group , 1627 cm-1 for C=N group, and two bands observed at (1346, 1315 cm-1 ) accounted  for NO2 group. The 1HNMR spectra showed the chemical shifts: δ 3.6 (s, 1H, N-H), δ 5.0 (s, 2H, CH2), and peaks at δ 7.6-8.4 ( m, 6H, Ar-H ). 13CNMR spectra result for this compound  found in full agreement with its assigned structures. Beginning with signal appeared at about δ 31.0 corresponding for the methylene group (-CH2-), signals of benzene ring appeared at about δ (104.7, 108, 116.1, 117.9, 118.2, 129.4) whereas the chemical shifts at about 142.6 and 164.5 related to  benzimidazole and  thiadiazole (-C=N ) group respectively. The purity of the synthesized compounds was monitored by TLC. Physical properties  of the synthesized compounds are shown in Table 1.

Table 1: Physical properties of the compounds

Comp no.

R

m.p (oC)

M.wt(g/mole)

Mol.Formula

Color

Yield %

1a

H

147-150

166.61

C8H7ClN2

yellow

93%

1b

CH3

130-134

180.64

C9H9ClN2

dark brown

90%

1c

COOH

290-293

210.62

C9H7ClN2O2

brown

88%

1d

NO2

168-170

211.61

C8H6ClN3O2

dark yellow

85%

2

232-234

133.19

C2H3N3S2

pale yellow

83%

3a

H

196-198

263.34

C10H9N5S2

yellow-brown

53%

3b

CH3

>350

277.36

C11H11N5S2

brown

47%

3c

COOH

240 dec.

307.35

C11H9N5S2

brown

45%

3d

NO2

214

308.33

C10H8N6O2S2

light brown

90%

4

163-166

150.23

C2H2N2S3

yellow

85%

5a

H

218-220

410.53

C18H14N6S3

yellow-brown

47%

5b

CH3

>300

438.59

C20H18N6S3

light brown

44%

5c

COOH

284-285

498.55

C20H14N6O4S3

light green

73%

5d

NO2

165

500.53

C18H12N8O4S3

light brown

78 %

 

dec. : decomposed

Antibacterial Evaluation

Some of the newly synthesized compounds were tested for their in-vitro  antibacterial activities against gram-negative including (Pseudomonas aeruginosa, Esherichia coli) and  gram-positive including (Staphylococcus aureus, bacillus subtilis) bacteria by disc diffusion  method, the concentration of the compounds  used were (10 mg/ml and 100 mg/ml ). Inhibition zones were measured  in millimeters and compared with (Ampicillin and ciprofloxacin)  as a standard antibiotics references. The results are illustrated in ( Table 2) which demonstrates  that most of  compounds tested for their antibacterial activity exhibited good to moderate activities. Amongst all compounds tested (3a, 3c, 3d, 5c) showed good to moderate  activity against all types of bacteria used.

Table 2: antibacterial activity of the synthesized compounds

Comp no. Concentration(mg / ml)

Zone of inhibition ( in  mm)

Gram-positive

Gram-negative

S. aureus

B. subtilis

P. aeruginosa

E. coli

3a

 10

12

18

12

24
100

14

17

–

25

3b

 10

–

–

–

–
100

11

12

–

–

3c

 10

–

–

12

12
100

22

23

18

19

3d

 10

12

19

11

22
100

12

18

–

20

5a

 10

–

15

–

12
100

–

–

–

–

5b

 10

–

14

–

–
100

12

15

–

–

5c

 10

11

13

12

14
100

30

30

15

22

5d

 10

–

11

–

15
100

–

–

–

–
Ampicillin

22

23

–

10
ciprofloxacin

19

23

29

–
DMSO solvent

0

0

0

0

 

Conclusion

Bnzimidazole derivatives containing 5-amino-1,3,4-thiadiazole-2-thiol and 1,3,4-thiadiazole-2,5-dithiol were synthesized by nucleophilic substitution reaction of   5-substituted-2-(chloromethyl)-1H-benzimidazole. The pharmacological study was performed  to determine the effects of substituent on the antibacterial activity, most of the derivatives showed good to moderate activity toward gram-negative  (E.coli, P. aeruginosa) and gram-positive (B. subtilis, S. aureus) bacteria.

Acknowledgment

Authors are thankful to Chemistry department, college of education for pure sciences, Diyala university and also Chemistry department, Sciences college, Diyala university for their help and support.

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