Synthesis and Antibacterial activity of some newer Benzimidazole derivatives

 

Pooja Kumari*, Umakant, Gyanendra Sharma

Department of Pharmaceutical Chemistry, Rajiv Academy for Pharmacy, N.H. #2, Mathura Delhi Road,

P.O. chhatikara, Mathura, Uttar Pradesh (INDIA) 281001

 

ABSTRACT:

A series of some newer benzimidazole derivatives were synthesized and evaluated for their anti-bacterial activity. Some of new benzimidazole derivatives are derived from the parent compound. The result shows all the compounds have low micromoler minimal inhibitory concentration (MIC) gives a good antibacterial activity against Gram-positive or Gram-negative bacteria.  Benzimidazole is the heterocyclic compound formed from benzene ring and five-member ring containing nitrogen and its derivatives are wide interest because of their diverse biological activity and clinical applications.

 

 

INTRODUCTION:

Since the benzimidazole is used as in medicinal chemistry and shows different physiological action like antifungal, Antibacterial, Antiviral, Analgesic, Anti-spasmodic & also shows Antimicrobial, Anticancer, Anticonvulsant, Antiarrhythmic, Antioxidant, Antiulcer, Cysticidal, Anti-folate, Antihypertensive, Nematicidal and many other benzimidazole is a coupling of 2-nitroanline, phenylenediamine. Various reagents such as nitrobenzene, Benzaquinone, Sodium metasulphite, Iodine, potassium iodide, P-toluenesulphonic acid and even air can be used for this purpose the show selective neuropeptides YY1 receptor antagonist. (1,2)

 

Benzimidazole is slightly white or being solid (3), melting at 172ºC, boils at 360ºC (4) it is soluble in ethanol and slightly soluble in water.

 

While many strategies are available for benzimidazole synthesis, there are two general methods for the synthesis 2-substituted benzimidazole. One is the coupling of phenylenediamine and carboxylic acid acidoser. There are different types of heterocyclic system which may be monocyclic or bi-cyclic fused ring or bridge with carbocyclic or similer or different heterocyclic atoms at different positions. (5) Commonly present hetro atoms with carbon are nitrogen, oxygen and sulpher. In 1943, Goodman and Nancy hart was very first time published a paper about pharmacological properties of benzimidazole (6). And in 1944 Woolley publish different properties and there action benzimidazole and purines (7)

 

MATERIALS AND METHODS:

All reaction were carried out in well-dried clean container by using reflux condenser reaction, to synthesis the reaction 1(o-phenyl di amine), 2 (glycolic acid) or 3 (dimethyl formamide) by using these type of chemicals, that are synthesized by the help of TLC using silica gel or coated plated were spot the product on the TLC plate or the solvent used for TLC are n-hexane or ethyl acetate, 

 

Scheme for preparation of new benzimidazole derivatives:

 

Compound (1A) 1H benzo[d]imidazole-2-yl) methanol (1A):

O-phenyldiamine bv (0.02mmol, 2.16gm) was reflux with glycolic acid (0.02mmole, 1.52gm) with the presence of DMF (dimethyl formamide 100ml) at 90^OC for 24 hours monitories the reaction by TLC time to time completion the reaction by diluted with ice or water. The reaction mixture was cooled allowed to stand for a while and the product was precipitated out. By the help of filteration. & after solid was precipitate out recrystalized with water or ethanol.(8)

 

Compound (1B) 5-nitro-1-H-benzo[d]imidazole-2-yl) methanol (2A):

 After completion the first step of synthesis 5.5ml of concentrate nitric acid was placed in three necked flask and equal quantity of concentrated sulphuric acid was slowly. The mixture was kept in ice      cold water then compound was formed (1.5gm) was missed in portion during 2.5 hours under room temperature. After stirred continuously for 2.5 hours 15 minute and then the reaction mixture was poured slowly over crushed ice with stirring. The precipitate product was filtered out and washed with cold water. The final product of step 2 was formed. (9)

 

Compound (1C) 5-nitro-1H[d]imidazole-2-carbaldehyde (3A):

 For the further synthesis 1, compound 2 (1mol) was dissolve in dry CH₂Cl_{2 (}25ml) was stirred briefly. Activated magnese dioxide (7.3mol) was added, stirred at room temperature for 4 h. another portion of activated magnese dioxide (5.9mol) was added and stirred at room temperature for 0.5h. after completion of the reaction, as monitored by TLC, the reaction mixture was filtered through celite and washed with ethyl acetate, concentrated and purified by isocratic flash chromatography (petroleum ether; ethyl acetate 9.5 0.5 v/v) on silica gel to afford pure compound either 70% yield. (10)

 

Compound (1D) 1-(3-chloro-5-iodobenzyl)-1H-benzo[d]imidazole-2-carbaldehyde:

After completion the 3 step of reaction the final step of the reaction will be started for the reaction 3 compound will be added slowly to NaH  (0.02mol, 4.79gm) or dry DMF (0.02 mol, 14.61 gm) for 12 hours the reaction was monitersied by TLC. Ppt out(11)

 

Newly synthesized derivative:

5-nitro-1-(perbromobenzyl)-1H-benzo[d]imidazole-2-carbaldehyde (4A):

 

 

 

IR(KBr)v:-

3205 (1^oamine.), 3319 (2^oamine.), 2785(CHO str.), 2980 (Aliphatic C-H str.), 1530 (Aromatic C=H str.) 3069 (Aromatic C-H str.), 2880 (H-C-H str.), 1672 (C=N str.),  1556 (C=C str.), 4830 (Aromatic C-N str.), 555 ( Br str.), 1631 (N=O str.) ¹HNMR (DMSO-d₆) δ 4.94 (s, 1H, CH₃), 6.272-6.790 (d, 1H, C-H) 9.652 (s, 1H, CHO), 7.119-7.331 (t, 3H, CH), 7.461-7.594 (T, 3H CH)

 

1-(2, 3, 4-triiodibenzyl)-5-nitro-1H-benzo[d]imidazole-2-carbaldehyde (4B)

 

 (4B)

IR (KBr) v:

3600 (N-H 1^oamine.), 3348 ( 2^oamine.), 2671 (CHO str.), 1592 (Aromatic C=H str.), 3087 (Aromatic C-H str.), 500 ( C-I str.), 2920 (Aliphatic H-C-H str.), 3667 (Aromatic C-N str.), 1631 (Aromatic C=N str.), 1514 Aromatic (C=C str.), 812 (Aromatic C-C str.), 1670 (aryl N=O), ¹HNMR (DMSO-d₆) δ 4.991 (s, 1H, CH₃), 6.672-6.707 (d, 1H, C-H) 7.133-7.785 (d, 2H, C-H), 7.616-7.667 (d, 2H, CH), 7.932-7.964 (d, 2H CH)

 

1-(3-bromo-5-chlorobenzyl)5-nitro-1H-benzo[d]imidazole-2-carbaldehyde (4c):

 (4C)

IR(KBr)v:

7300 (1^oamine str.), 3326 (2^oamine str.), 2834 (CHO str.)  3018 (Aromatic C-H str.), 500 (Aliphatic Cl str.), 563 (Br str.), 1694 (Aromatic C=N str.), 1540 (Aromatic C=C str.), 833 (Aromatic C-N str.), 1613 (Aromatic C=N str.), 1851 (Aryl C=N str.)  ¹HNMR (DMSO-d₆) δ 4.992 (s, 1H, CH₃)7.146-7.464 (d, 2H, C-H) 7.280-7.378 (d, 2H, C-H), 7.471-7.398-7.118 (t, 3H, CH), 49.608 (s, 1H CHO).

 

3-(3-bromo-5-nitrobenzyl)-1H-benzo[d]imidazole-2-carbaldehyde (4D)

 (4D)

IR (KBr) v:

3338 (2^oamine N-H str.), 3018 (Aromatic C-H str.), 2820 (CHO str.), 1687 (Aromatic C=N str.), 1564 (Aromatic CC str.), 913 (Aromatic C-N str.), 517 (aliphatic halogen Br-H str.), 1740 (N-O str.), 880 (Aromatic C-N str.) 3780 (1^oamine N=H str.), 1851 (Aryl N=C str.)¹HNMR (DMSO-d₆) δ 3.601 (s, 1H, CH₃)7.057-7.172 (d, 2H, C-H) 7.480-7.923 (d, 2H, C-H), 7.378-8.314 (t, 3H, CH), 9.668 (s, 1H CHO).

 

1-(3-phenoxybenzyl)-5nitro-1H-benzo[d]imidazole-2-carbaldehyde (4e):

(4e)

IR (KBr)v:

3312 (N-H str. (2^oamine)), 2840 (Aliphatic C-H str.), 3440 (1^oamine), 1100 (C-O-C str.), 3010 (aromatic C-H str.) 2690 (CHO str.), 1634 (Aromatic C­=C str.), 903 (Aromatic C-N str.), 1630 (Aromatic C=N str.), 1883 (Aryl C=N str.)¹HNMR (DMSO-d₆) δ 4.962 (s, 1H, CH₃), 6.694-6.891 (d, 2H, C-H) 7.133-7.385-7.594 (t, 3H, C-H), 7.467-7.544-7.470-7.662 (d,d, 8H, CH), 9.668 (s, 1H CHO).

 

5-nitro-1-phenoxy-1H-benzo[d]imidazole-2-carbaldehyde (4F):

 

(4f)

 

IR (KBr)v:

3495.18 (N-H str. (2^oamine)), 3345.51 (Aliphatic C-H str.), 3440 (1^oamine), 2855.61 (C-O-C str.), 3205.85 (aromatic C-H str.) 1581.84 (CHO str.), 2090.44 (Aromatic C­=C str.), 2889.83 (Aromatic C-N str.), 1679.54 (Aromatic C=N str.), 1602.74 (C=C str), 952.77 ( aromatic C-N str.),1873 (Aryl N=O),¹HNMR (DMSO-d₆) δ 6.789 (s, 1H, CH₃)7.801-8075 (d, 2H, C-H) 7.8.002-8.492 (d, 2H, C-H), 7.638-8.025-8.331 (t, 3H, CH), 9.653 (s, 1H CHO).

 

RESULT AND DISCUSSION:

Synthesis and characterization of benzimidazole:

All the compound were synthesized by the previously mentioned route in materials and methods and synthesized compound were periodically checked by TLC by using n-hexan and ethyl acetate in the ratio of 1:3, Rf values of the compounds were determined. Synthesized compound derivatives were characterized by different spectral methods using 1HNMR, IR & MASS SPECTROSCOPY.

 

Antibacterial activity:

Using the technique of disc diffusion, the freshly synthesized integrated derivatives were tested for antibiotic activity in vitro. The freshly synthesized derivative's antibacterial activity was all working against pathogenic bacterial strains S. Aureus, B.subtilis and E, coli, P. aeruginosa (gram-ve). Antibiotic zone reader evaluated the inhibition area.

 

The outcome uncovered that the recently combined mixes 4a, 4d, and 4c, indicated great antibacterial movement with 10.13, 11.66, 11.59mm zone of restraint individually against B, subtilis when given at fixation 50 µg/ml-1 though under indistinguishable conditions standard medication ciprofloxacin demonstrated 16.46 mm zone of hindrance compound 4b, 4c, 4f indicated moderate antibacterial action with 9.84, 8.84, 8.91mm zone of restraint separately against S. aureus Compound when given at convergence of 50µg/ml-1 under indistinguishable conditions standard medication ciprofloxacin demonstrated 4a, 4c, 4d indicated great antibacterial movement with 15.21, 14.21, 13.96 indicated moderate antibacterial movement with 4b, 4e, 4f indicate moderate antibacrerial action with 9.46, 10.64, 10.54mm zone of restraint individually against S. aureus Compound when given at when given at fixation 50µg/ml-1 though under indistinguishable conditions standard medication ciprofloxacin demonstrated 19.98 mm zone.

 

The outcome uncovered that recently incorporated antibacterial action against gram negative becteria mixes 4a, 4f, 4c indicated great antibacterial movement with 18.32, 16.64, 17.44 mm zone of hindrance separately against E. coli, when given at focus 50µg/ml-1 while under indistinguishable conditions standard medication ciprofloxacin demonstrated 23.065mm zone of inhition compound 4b, 4d, 4e indicated moderate movement with 12.63, 12.54, 13.23 and zone of hindrance  separately against P.aureginosa compound when given at focus 50 µg/ml-1 under indistinguishable conditions standard medication ciprofloxacin demonstrate 4c, 4f, 4a, 4e indicated greate antibacterial movement with 16.48, 16.33, 14.60, 14.54mm zone of hinderence separately greate antibacterial movement, the moderate antibacterial action with 4b, 4d indicated with 13.31, 13.98mm zone of restrain individually against P.aureginosa zone of restraint Compound when given at when given at fixation 50µg/ml-1 though under indistinguishable conditions standard medication ciprofloxacin demonstrated 24.62mm zone.

 

CONCLUSION:

In conclusion we have found a new products of 1H-benzo[d]imidazole derivatives containing 5-nitro-1-(perbromobenzyl)-1H-benzo[d]imidazole-2-carbaldehyde (4a), 1-(2,3,4-triiodibenzyl)-5-nitro-1H-benzo[d]imidazole-2-carbaldehyde (4b), 1-(3-bromo-5-chlorobenzyl)-5-nitro-1H-benzo-carbaldehyde (4c), 3-(3-bromo-5-nitrobenzyl)1H-benzo[d]imidazole-2-carbaldehyde (4d), 1-(3-phenoxybenzyl)-5-nitro-1H-benzo[d]imidazole-2-carbaldehyde (4e), 5-nitro-1-phenoxy-1H-benzo[d]imidazole-2-carbaldehyde (4f) the result should be creative or inventive for further investigation which represents an element of originality or difference in the SAR of benzimidazole derivatives. The newly derivative products are showed high antibiotic activity against both gram-ve bacterias or gram+ve bacterias. All the database were performed by exhausted database.  

 

ACKNOWLEDGMENT:

The author is thankful to principal of Rajiv academy for pharmacy, Mathura for provided the all facilities in college which necessary for the work.

 

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Accepted on 21.10.2019           © RJPT All right reserved

Research J. Pharm. and Tech 2020; 13(6):2597-2600.