Synthesis, Characterization and Antibacterial activity of Disulfide and Sulfone Compounds Derivatives from Benzimidazole

 

Muayedahmed Redayan^1*, Ali Hussein ali¹, Zainabalaa Monem¹

¹Department of Chemistry, College of Education for Pure Sciences, Diyala University, Diyala, Iraq

 

ABSTRACT:

This study aimed to prepare a series of disulfide and sulfone compounds derivatives from benzimidazole. The target compounds were prepared by three steps: First step comprise synthesis of 2-mercaptobenzimidazole derivatives from reaction of 4- (un)substituted-o-pheneylenediamine with carbon disulfide, In the second step: Alkylation of the 2-mercaptobenzimidazole derivatives with different alkyl halides to obtain thioether compounds. Final step: include oxidation of 2-mercaptobenzimidazole derivatives to yielded disulfide compounds while oxidation of thioether compounds gave sulfone derivatives by using hydrogen peroxide as oxidizing agent. The chemical structures of all synthesized compounds were confirmed by FT-IR and some by ¹H and ¹³C-NMR.Some selected compounds were tested in vitro for their antibacterial activity by disc diffusion method against two types of Gram-positive bacteria namely (Staphylococcous aureus, Bacillus subtilis) and Gram-negative bacteria namely (Pseudomonas aeruginosa, Escherichia coli). The results displayed that most of the prepared compounds have a good antibacterial activity when compared with the standard antibiotic ampicillin and ciprofloxacin.

 

 

 

1. INTRODUCTION:

The general method which described by Van allan and Deacon have been used to synthesis a number of benzimidazole 2-thione [1]. 2-mercaptobenzimidazole compound undergo to tautamersim form because contain a hydrogen atom attached to nitrogen in the 1-position. The thiol and thione forms as shown below [2].

 

 

 

Thiol Form                                         Thione form

 

Benzimidazole compound system can be considered a Master Key as it is an important core in many compounds acting at various targets to show diverse pharmacological properties. Though every one of the seven positions in the benzimidazole nucleus can be substituted with a different chemical groups, but the majority of the biologically active benzimidazole based compounds carry functional groups at 1, 2 and/or 5(or 6) positions. Therefore, the compounds may be mono-, di- or tri-substituted derivatives of the benzimidazole nucleus[3]. Benzimidazole compounds have various biological and medical activities for example antibacterial[4-6], antimicrobial[7], antitumor[8], anti-inflammatory[9] antihypertensive[10],Anti-HIV[11], anticancer[12]properties.

 

2. EXPERIMENTAL PART:

2.1 General:

Melting points were taken in an electrically heated using Stuart SMP³ instrument and are uncorrected. FT-IR spectra were recorded on (Shimadzu FT-IR- 8400S spectrophotometer at the Chemistry Department/ College of Education for Pure Science/ University of Diyala) by using KBr disc(v,cm^-1). The ¹H and ¹³C-NMR spectra were recorded on (Bruker 400MHz at the Jordan University for science and technology /Jordan) by using tetramethylsilane (TMS) as an internal standard and DMSO-d₆ as solvent. The purity of the compounds was checked by TLC on silica gel plates using ultraviolet lamp(365nm and 254nm).

 

2.2 General procedure for synthesis of compounds 1a and 1b[13]:

A mixture (10.8gm,0.1mole) of 4-un-substituted-o-phenylenediamine, (5.65g, 0.1mol) of potassium hydroxide and (7.67g, 0.1mol) of carbon disulfide CS₂ were dissolved in (100 ml of Ethanol and 15ml of water) The resulting mixture was heated under reflux for 3 hours, after the reflux, add (1-1.5mg) of activated charcoal with caution and then clamp the mixture for 10 min. Activated charcoal was removed by filtration and the solution was heated to (60-70^oC) after that add 100ml of water. Acid using diluted acetic acid with stirring. The product is separated as white crystals and the mixture is placed in a snow bath for three hours to complete the crystallization and the deposit is collected on buchner funnel and drying in 24 hours at 40°C.

 

1H-benzo[d]imidazole-2-thiol (1a):

Off White, yield 60%,m.p: 299 – 301°C, IRν_max (KBr/cm^-1):N-H benzimidazole (3155), aromatic C-H (3033), S-H (2571), Imidazole C=N (1633), aromatic C=C (1521, 1442). ¹H –NMR (400 MHZ, DMSO – d₆) δ : 3.13 (1H, s, N-H), 1.80 (1H, s, S-H), 7.51-7.75 (4H, m, Ar – H) as shown in figure 1. ¹³C –NMR (400 MHZ, DMSO) δ :168.04 (C=N imidazole), 109.39-132.22 (aromatic carbon).

 

 

Fig. 1: 1H-NMR spectrum of compound 1a.

 

 

Fig. 2: ¹H-NMR spectrum of compound 1b.

5-methyl-1H-benzo[d]imidazole-2-thiol (1b):Brown, yield 62%, m.p : 286 – 288°C, IRν_max (KBr/cm^-1): N-H benzimidazole (3190), S-H (2573), aromatic C-H(3090), aliphatic C-H (2983, 2879), imidazole C=N (1625), aromatic C=C (1500-1441). ¹H –NMR (400 MHZ, DMSO – d₆) δ : 3.03 (3H, d, CH₃), 1.93 (1H, S-H), 3.19 (1H, s, N-H benzimidazole), 7.61-7.87 (3H, m, Ar – H) as shown in figure 2.¹³C–NMR (400 MHZ, DMSO) δ: 20.86 (CH₃), 167.76 (C=N imidazole), 109.06-132.66 (aromatic carbon).

 

2.3 General procedure for synthesis of thioether of 2-mercaptobenzimidazole 2(a-f)[14].

(8.4 g, 0.05 mol) of 2-mercaptobenzimidazole was dissolved in absolute ethanol (15 ml) with different alkyl halides (0.05 mol) and sodium hydroxide (2.0 g, 0.05 mole) in round flask (50 ml) and reflux condenser. The mixture was refluxed for (4-7 hours) and filtered directly to get rid of the precipitated salt the filtered sample was cooled and recrystallized from ethanol and water. Table (1) shows the physical properties of the prepared compounds.

 

2-(butylthio)-1H-benzo[d]imidazole (2a):beige, yield 88%, m.p: 245-247 °C,. IRν_max (KBr/cm^-1):N-H benzimidazole (3150), aromatic C-H (3047), aliphatic C-H (2954, 2870), Imidazole C=N (1622), aromatic C=C (1498,1406), C-S (675).

 

2-(hexylthio)-1H-benzo[d]imidazole (2b):light brown, yield 75%, m.p: 266-268°C, IRν_max (KBr/cm^-1) : N-H benzimidazole (3185), aromatic C-H (3087), aliphatic C-H (2954, 2856), Imidazole C=N (1620), aromatic C=C (1508,1401), C-S (695).       

 

2-(octylthio)-1H-benzo[d]imidazole (2c) :beige, yield 77%, m.p: 277-279°C,. IRν_max (KBr/cm^-1) : N-H benzimidazole (3175), aromatic C-H (3039), aliphatic C-H (2954, 2852), Imidazole C=N (1618), aromatic C=C (1508,1404), C-S (617).       

 

2-(butylthio)-5-methyl-1H-benzo[d]imidazole (2d) :dark brown, yield 83%, m.p: 287-289 °C,. IRν_max (KBr/cm^-1) : N-H benzimidazole (3180), aromatic C-H (3047), aliphatic C-H (2954, 2870), Imidazole C=N (1617), aromatic C=C (1498,1433), C-S (675).       

 

2-(hexylthio)-5-methyl-1H-benzo[d]imidazole (2e):light brown, yield 81%, m.p: 296-298°C,. IRν_max (KBr/cm^-1) : N-H benzimidazole (3180), aromatic C-H (3045), aliphatic C-H (2953, 2856), Imidazole C=N (1627), aromatic C=C (1521,1392), C-S (669).           

 

5-methyl-2-(octylthio)-1H-benzo[d]imidazole (2f):brown, yield 77%, m.p: 293-295°C,. IRν_max (KBr/cm^-1) : N-H benzimidazole (3124), aromatic C-H (3093), aliphatic C-H (2956, 2854), Imidazole C=N (1618), aromatic C=C (1521,1396), C-S (665).         

2.3 General procedure for synthesis of Disulfide and Sulfone compounds 3(a-f)and(1a,1b)[15].

Thiole or thioether compounds (1.0 g, 0.006 mole) was added to ethanol (10 ml) in round flask (50 ml) hydrogen peroxide (5 ml, 30%) was added drop wise to mixture with continuous stirring for (1-2 hours) at room temperature. The precipitated was filtered and washed by distil water and dried. Table (1) shows the physical properties of the prepared compounds.    

 

2-(butylsulfonyl)-1H-benzo[d]imidazole (3a):light pink, yield 81%, m.p: 295-297 °C, IRν_max (KBr/cm^-1): N-H benzimidazole (3182), aromatic C-H (3047), aliphatic C-H (2954, 2929), Imidazole C=N (1610), aromatic C=C (1498,1394), Sulfone S=O (1363,1269), C-S (617).

 

2-(hexylsulfonyl)-1H-benzo[d]imidazole (3b):light green, yield 76%,m.p: 312-314 °C, IRν_max (KBr/cm^-1): N-H benzimidazole (3385), aromatic C-H (3047), aliphatic C-H (2854, 2974), Imidazole C=N (1622), aromatic C=C (1458,1521), Sulfone S=O (1361,1269), C-S (615).

 

2-(octylsulfonyl)-1H-benzo[d]imidazole (3c):light beige, yield 74%, m.p: 316-318 °C, IRν_max (KBr/cm^-1): N-H benzimidazole (3132), aromatic C-H (3047), aliphatic C-H (2924, 2852), Imidazole C=N (1620), aromatic C=C (1508,1404), Sulfone S=O (1361,1269), C-S (617).

 

2-(butylsulfonyl)-5-methyl-1H-benzo[d]imidazole (3d) :

dark brown, yield 86%, m.p: 325-326°C, IRν_max (KBr/cm^-1): N-H benzimidazole (3135), aromatic C-H (3087), aliphatic C-H (2954, 2868), Imidazole C=N (1624), aromatic C=C (1521,1396), Sulfone S=O (1336,1274), C-S (600).

 

2-(hexylsulfonyl)-5-methyl-1H-benzo[d]imidazole (3e):dark brown, yield 88%, m.p: 334-336 °C, IRν_max (KBr/cm^-1): N-H benzimidazole (3136), aromatic C-H (3042), aliphatic C-H (2928, 2855), Imidazole C=N (1624), aromatic C=C (1501,1403), Sulfone S=O (1394,1274), C-S (599).

 

5-methyl-2-(octylsulfonyl)-1H-benzo[d]imidazole (3f):brown, yield 73%, m.p: 340-342 °C, IRν_max (KBr/cm^-1): N-H benzimidazole (3133), aromatic C-H (3081), aliphatic C-H (2950, 2861), Imidazole C=N (1623), aromatic C=C (1520,1395), Sulfone S=O (1335,1284), C-S (610).

 

1,2-bis(1H-benzo[d]imidazol-2-yl)disulfane(4a):white, yield 71%, m.p: 314-316 °C, IRν_max (KBr/cm^-1): N-H benzimidazole (3188), aromatic C-H (3057), aliphatic C-H (2954, 2874), Imidazole C=N (1621), aromatic C=C (1508,1421), S-S (555), C-S (609).

 

 

Scheme 1: The proposed mechanism steps of formation of the 2-mercptobenzimidazole derivatives (1a and 1b)

 

 

1,2-bis(5-methyl-1H-benzo[d]imidazol-2-yl)disulfane(4b):brown, yield 84%, m.p: 319-321°C, IRν_max (KBr/cm^-1): N-H benzimidazole (3130), aromatic C-H (3049), aliphatic C-H (2944, 2854), Imidazole C=N (1620), aromatic C=C (1504,1421), S-S (565), C-S (610).

 

The present study comprise three reactions: the first reaction, 2-mercptobenzimidazole derivatives (1a and 1b) were synthesized according to the reaction of 4-(un)substituted-o-phenylenediamine with carbon disulfide in the presence of potassium hydroxide in absolute ethanol as shown in the following proposed mechanism reaction (Scheme 1).

 

3. RESULTS AND DISCUSSION

The structure of the prepared compounds (1a and 1b) was established on the basis of ¹H-¹³C-NMR and IR spectroscopy. In all cases TLC of the product showed the presence of one single spot referring to only one product. The IR spectra of compounds (1a and 1b) exhibited absorption bands, at (3155 and 3190cm^-1) which attributed to the NH imidazole group respectively. While the bands at (2571cm^-1) and (2573cm^-1) are attributed to S-H stretching frequency respectively. The IR spectra of compounds (1a and 1b) exhibited absorption bands at (1633 and 1625cm^-1) which assigned to C=N stretching frequency respectively. In ¹H-NMR spectra of compounds (1a and 1b) exhibited two different signals at (δ 3.13 and 5.58 ppm) which assigned to NH imidazole protons respectively. And signals at (1.24 ppm and 2.03ppm) for (S-H) group respectively. The ¹³C-NMR spectra of compounds (1a and 1b) exhibited signals at(δ 167.76 and 195.07 ppm) which attributed to the group (C=N) respectively. and signals at range(132-109.39ppm) and (132.66-109.06ppm) which attributed to the aromatic carbon respectively. In the second reaction, Compounds 1a and 1b was alkylation with different alkyl halides in the presence of NaOH and EtOH to give thioether compounds 2(a-f). The structure of compounds 2(a-f) was confirmed by FT-IR, The IR spectra of prepared compounds exhibited broad absorption band at (3185-3124)cm^-1 was attributed to the NH imidazole group. The IR spectra of synthesized compounds showed disappeared absorption bands at (2571cm^-1) and(2573cm^-1) which attributed to S-H stretching frequency of compounds 1a and 1b respectively which indicate the success of the alkylation reaction. Also, appeared the absorption bands at (2956-2954cm^-1) and (2870-2852cm^-1) which assigned to C-H aliphatic stretching frequency indicated the occurs the alkylation reaction. In third reaction, compounds 1a,1b and 2(a-f) oxidative by using hydrogen peroxide as oxidizing agent with stirring at room temperature to obtain disulfide and sulfone compounds 3(a-f) and (4a,4b). The structure of compounds 3(a-d)and (4a,4b) was confirmed by FT-IR, The IR spectra of compounds 3(a-d)exhibited tow absorption band at (1394-1361cm^-1) and (1284-1269cm^-1) cm^-1 was attributed to the asymmetrical and symmetrical stretching frequency of (S=O) group. While the IR spectra of compounds (4a,4b) exhibited bands at (555cm^-1) and (565cm^-1) which assigned to stretching frequency of (S-S) group indicated the formation of disulfide compounds. The reaction proceeds according to the Scheme 2.

 

 

Scheme 2 : Synthetic route of synthesized compounds

 

Table 1.Physical properties of the compounds.

 

Table 2. Antibacterial activity of synthesized compounds

 

 

4. ANTIBACTERIAL ACTIVITY:

The disk diffusion method was used to screened antibacterial activities of the some compounds synthesized herein against different strains of Gram-positive bacteria namely (Staphylococcus aureus, Bacillus subtilis) and Gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli) The compounds were tested at concentration of (10 mg /ml and 100 mg /ml). The zone of inhibition was measured in millimeters and was compared with reference standard antibiotic namely ampicillin and ciprofloxacin. The test compounds were dissolved in DMSO to obtain solution of different concentration. The results of antibacterial activity of the synthesized compounds are listed in (table 2) which demonstrate that most of compounds displayed significant activities when compared with the standard antibiotic ampicillin and ciprofloxacin. The antibacterial activities of the test compounds are shown briefly below.           

1- The compounds (1a, 2a,3a,3c, 4a) showed high activity against B.subtilis bacteria.

2- The compounds (2f,3a,3c,4a) showed high activity against E. coli bacteria.

3- The compounds (2f,3c,4a) showed high activity against P. aeruginosa bacteria.

4- The compounds (2c,3a,3f,4a,4b) showed good activity against S.aureus bacteria.

 

CONCLUSION:

A new series of benzimidazole derivatives containing disulifed and sulfone groups were prepared. Result of present study aimed to prepared of sulifide and sulfone derivatives. Some of the newly synthesized compounds exhibit importance antibacterial activity.            

 

ACKNOWLEDGMENT:

The authors express their thanks and appreciation to Department of Chemistry, Collage of Education for pure sciences, Diyala University for their support and assistance.

 

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Received on 12.10.2018          Modified on 17.11.2018

Accepted on 18.12.2018        © RJPT All right reserved