Synthesis and Pharmacological Evaluation of Some New 2-Phenyl benzimidazoles Derivatives and their Schiff ’ s Bases

Some new 2phenyl benzimidazole derivatives were synthesised by cyclocondensation with appropriate reagents. The compounds synthesised were identified by H NMR, FAB Mass and FT-IR spectroscopic techniques. All compounds studied in this work were screened for their in vitro antimicrobial activities against the standard strains: Staphylococcus aureus ATCC 25923, ATCC 441 and Bacillus subtilis ATCC6633 as gram positive, Escherichia coli ATCC 11775 and Pseudomonas aeruginosa ATCC 10145 as gram negative bacteria. Some of the compounds inhibited the growth of grampositive bacteria (B. subtilis and S. aureus) at MIC values between 25 and 200 mg/mL. Some of the compounds exhibit antimicrobial activity against gram negative bacteria (E. coli and P. Aeruginosa) MIC values between 25 and 200 mg/mL.


Introduction
Benzimidazoles are very useful intermediates/subunits for the development of molecules of pharmaceutical or biological interest.Substituted benzimidazole derivatives have found applications in diverse therapeutic areas including anti ulcers, anti hypertensives, anti virals, antifungals, anticancers and antihistaminics to name just a few [1][2][3] .The widespread interest in benzimidazole containing structures has prompted extensive studies for their synthesis.There are two general methods for the synthesis of 2-substituted benzimidazoles.One is the coupling of phenylenediamines and carboxylic acids 4 or their derivatives (nitriles, imidates, or ortho esters) 5 , which often requires strong acidic conditions and sometimes combines with very high temperatures (i.e., PPA, 180 0 C) or the use of microwave irradiation 6 .The other way involves a two-step procedure that includes the oxidative cyclo-dehydrogenation of aniline Schiff's bases, which are often generated in situ from the condensation of phenylenediamines and aldehydes.Various oxidative reagents such as nitrobenzene (high-boiling point oxidant/solvent) 7 , 1,4-benzoquinone 8 , DDQ 9 , tetracyanoethylene 10 , benzofuroxan 11 , MnO 2 12 , Pb(OAc) 4 , Oxone, NaHSO 3 and Na 2 S 2 O 5 have been employed.Partially due to the availability of a vast number of aldehydes, the later method has been extensively used.
The compounds with the structure of -C= N-(azomethine group) are known as Schiff bases, which are usually synthesized from the condensation of primary amines and active carbonyl groups.Schiff bases important class of compounds in medicinal and pharmaceutical field.They show biological properties include antibacterial, antifungal antitumor, analgesic and anti-inflammatory activity.Presence of -C=N-and other functional groups forms more stable complexes compared to Schiff bases having only -C=N-coordinating moiety 12 .

Experimental
Melting points were determined with an electrothermal melting point apparatus and are uncorrected.Commercially available reagent grade chemicals were used as received.All reactions were followed by TLC, with detection by UV light and/or spraying a 20% KMnO 4 aq.solution column chromatography was performed on silica gel (60-120 mesh, E. Merck).IR spectra were recorded as thin films or in chloroform solution with a Shimadzu (4000-450 cm -1 ) FTIR spectrophotometer. 1 H NMR spectra were recorded on a Brucker AV400 in CDCl 3 .Chemical shift values are reported in ppm relative to SiMe 4 as internal reference, unless otherwise stated; s (singlet), d (doublet), t (triplet), m (multiplet); J in hertz.FAB mass spectra were performed using a mass Spectrometer Jeol SX-102 and ESI mass spectra with Quattro II (Micromass).

Preparation of 2-(4-aminophenyl) benzmidazole (YS-B, IV) and Schiff bases (V)
In another sequence of reactions, o-phenylenediamine was condensed with p-amino benzoic acid in poly phosphoric acid at 190-195 0 C for 4 hours.The reaction mixture was poured into crushed ice.The product was filtered, washed, dried, and recrystalized.The product 2-(4-aminophenyl) benzimidazole (YS-B, IV) was then treated with various aromatic aldehydes to obtain the Schiff bases compounds (V).

Results and Discussion
The antibacterial activity of all of the compounds against S. aureus and B. subtilis as gram positive and E. coli and P. aeruginosa as gram negative bacteria showed lower potencies than the control drug ampicillin.Some of the compounds (YS-1, YS-2, YS-5, YS-6 and YS-8) showed good activity with a MIC value of 25 µg/mL against P. aeruginosa, which was comparable to ampicillin.Compound YS-2 and YS-10 exhibited significant activity against B. subtilis with a 25 µg/mL.As a result of antimicrobial activity, substitution of amine function to anilide at the 2-phenyl moiety of benzimidazole ring increases the activity against B.subtilis.It was also observed that the presence of N=CH-group (azomethine) increase the potencies of the synthesized.

Conclusion
The present work has demonstrated the use of a simple cyclocondensation method for the synthesis of 2-(2-amino phenyl) benzimidazole and 2-(4-amino phenyl) benzimidazole.This method was able to give reasonably good and clean yields.Ten derivatives were prepared and biologically evaluated for antibacterial activity.The basic N=C group believed to enhance antimicrobial activity.Nevertheless, some of the compounds were found to possess good antimicrobial activity.Therefore they may be used as lead compounds for further development.