SYNTHESIS, CHARACTERIZATION, ANTIMICROBIAL, ANALGESIC AND ANTI INFLAMMATORY ACTIVITY OF NOVEL MANNICH BASES OF BENZIMIDAZOLE DERIVATIVES

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(1)World Journal of Pharmaceutical Research Abhay et al.. World Journal of Pharmaceutical Research SJIF Impact Factor 5.045. Volume 3, Issue 4, 517-528.. Research Article. ISSN 2277 – 7105. SYNTHESIS, CHARACTERIZATION, ANTIMICROBIAL, ANALGESIC AND ANTI-INFLAMMATORY ACTIVITY OF NOVEL MANNICH BASES OF BENZIMIDAZOLE DERIVATIVES Abhay Kumar Verma*1, Rashmi kumari1, Arun Kumar Singh (Sr.)1 , B.Nagaraju2, Mukesh Chandra Sharma3 *1 2. Department of Chemistry, Magadh University, Bodh Gaya, Gaya, Bihar, India.. School of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, VELS University, Chennai, Tamilnadu, India.. 3. Spectrum Institute of Pharmaceutical Sciences and Research, Greater Noida, U.P., India ABSTRACT. Article Received on 12 March 2014,. A new series of novel Mannich bases of benzimidazole were synthesized by condensation of substituted secondary amines and. Revised on 05 April 2014, Accepted on 28 April 2014. aldehyde in ethanol. These compounds were identified on the basis of melting point range, Rf values, elemental analysis, UV, IR and 1H. *Correspondence for. NMR spectral analysis. The compounds were evaluated for. Author Abhay Kumar Verma. antimicrobial,. analgesic. and. anti-inflammatory. activities.. Department of Chemistry,. compounds exhibited significant to moderate biological activity.. All. Magadh University, Bodh. Keywords: Mannich base, Benzimidazole, Antimicrobial, Analgesic,. Gaya, Gaya, Bihar, India.. Anti-inflammtory. INTRODUCTION The benzimidazole is an important pharmacophore in modern drug discovery. Literature review reveals that Manich bases of benzimidazole derivatives exhibits diverse pharmacological. activities. like,. antimicrobial[1],. analgesic[2],. anti-inflammatory[3],. anthelmintic[4], antiviral[5] as well as antitumor[6], etc. In addition benzimidazoles are very important intermediates in organic reactions. Research in this area is still unexplored and is directed towards the synthesis of compounds with enhanced biological activity. Based on the above observation it is worthwhile to prepare newer novel Mannich bases of benzimidazoles with enhanced biological activity.. www.wjpr.net. Vol 3, Issue 4, 2014.. 517.

(2) Abhay et al.. World Journal of Pharmaceutical Research. MATERIALS AND METHODS All the chemicals procured from Central Drug House (P.) Ltd, New Delhi. The melting points were determined in open glass capillaries and were uncorrected. Thin Layer Chromatography using silica gel G (E. Merck) plates were used to access the reaction and purity of synthesized compounds. Satisfactory C, H, N analysis were obtained for all the compounds on a Carlo Erba EA 1108 elemental analyzer. The λmax of synthesized compounds were scanned on UVvisible spectrophotometer - Shimadzu 1200. The IR spectra were recorded on Bruker FTIR system in KBr pellets and noted the absorption levels (cm-1) were listed.1H NMR spectra were run on JEOL GSX 400 NMR at 300 MHz in DMSO-d6 as solvent and TMS as an internal standard. The Mass spectra were recorded on JEOL GC mate spectrometer. Scheme-1 Synthesis of benzimidazole (Compound1) O-Phenylenediamine (1.08 g, 10.0 mmol) was placed in a 100 ml flask and it was added 0.7 g (0.52ml, 13.6 mmol) of 85% formic acid. The mixture was heated on a water bath for 2 hr at 100 0C, cooled and 10%NaOH solution was added slowly with constant rotation of the flask, until the mixture was just alkaline to litmus. Crude benzimidazole was filtered off at the pump, washed with ice cooled water. The crude product was dissolved in boiling water, discoloring carbon was added to it, and the mixture was digested for 15 minutes. Filtered rapidly at the pump through a preheated buckner funnel, the filtered was cooled to about 10 0. C, the product was filtered off, washed with cold water and dried to give pure benzimidazole. (compound 1). The yield of benzimidazole was found to be 88% and the m.p. was 1710C.The completion of reaction was confirmed by TLC .The solvent system used was Petroleum ether : Methanol (3:2). General procedure for the synthesis of Mannich bases of benzimidazole derivatives (Compound 1a-1d) To a solution containing benzimidazole (compound 1a) (1.18g,10 mmol), in 20 ml of ethanol, 0.50g (10 mmol) of secondary amine and 0.28 ml(10 mmol) of formaldehyde were added with constant stirring for 1 hr. the reaction mixture was reflux for 3 hr .On ice cooling the product formed was filtered, dried in vacuum and recrystallized with ethanol.. The. completion of reaction was confirmed by TLC .The solvent system used was Petroleum ether : Methanol (3:2).. www.wjpr.net. Vol 3, Issue 4, 2014.. 518.

(3) Abhay et al.. World Journal of Pharmaceutical Research. NH2. NH2. o-Phenylenediamine. Formic acid 10% NaOH. H N. N. Benzimidazole (1) Secondary amines. Secondary amines. Formaldehyde. Di-n methyl amine. Ethanol. Di ethyl amine Di butyl amine. R. H2. N. C. Compound 1a-R&R' =CH3. Di cyclohexyl amine R'. N. Compound 1b-R&R' =C2H5 N. Compound 1c-R&R'= C4H9 Compound 1d-R&R'= C6H11. Compound 1a-d. Scheme-1 Scheme-2 General procedure for the synthesis of Mannich bases of benzimidazole derivatives (Compound 1e-1h) To a solution containing benzimidazole(compound 1) (1.18g,10 mmol), in 20 ml of ethanol, 1.40g(10 mmol) of aromatic aldehyde and 1.37g(10 mmol) of 4-aminobenzoic acid were added with constant stirring for 1 hr. the reaction mixture was reflux for 10 hr .On ice cooling the product formed was filtered, dried in vacuum and recrystallized with ethanol. The completion of reaction was confirmed by TLC .The solvent system used was Ethyl acetate : Hexane (2:5). NH2. NH2. o-Phenylenediamine Formic acid 10%NaOH H N. N. Benzimidazole (1). p-Aminobenzoic acid Aromatic aldehyde Ethenol. Aromatic aldehyde R'. p-Chlorobenzaldehyde p-Dimethyl amino benzaldehyde HN. Compound1e-R' = Cl. CH. Compound 1f-R' = (CH3)N. N. Compound 1g-R' = OH Compound 1h-R' = OCH3. p-hydroxy benzaldehyde p-methoxy benzaldehyde. COOH. N. Compound 1e-h. Scheme-2. www.wjpr.net. Vol 3, Issue 4, 2014.. 519.

(4) Abhay et al.. World Journal of Pharmaceutical Research. Scheme-3 Synthesis of 2-methylbenzimidazole (compound-2) Mixture of o-phenylenediamine(1.08 g, 10.0 mmol), 6.67 ml of water,0.58 ml (10.0 mmol) of glacial acetic acid was heated together under the reflux for 45 min. The cooled reaction mixture was made distinctly basic by the gradual addition of conc. ammonia solution. The precipitate product was collected and recrystallized from 10% aqueous ethanol to give 2methylbenzimidazole (compound 2). The yield of 2-methyl benzimidazole was found to be 72% and the m.p. was 1750C.The completion of reaction was confirmed by TLC .The solvent system used was Petroleum ether : Ethanol (3:4). General procedure for the synthesis of Mannich bases of benzimidazole derivatives (Compound 2a-2b) To a solution containing 2-methyl benzimidazole (compound 2) (1.33g,10 mmol), in 20 ml of ethanol, 0.57ml(10 mmol) of secondary amine and 0.28 ml(10 mmol) of formaldehyde were added with constant stirring for 1 hr. the reaction mixture was reflux for 3 hr .On ice cooling the product formed was filtered, dried in vacuum and recrystallized with ethanol. The completion of reaction was confirmed by TLC .The solvent system used was Petroleum ether: Methanol (3:2). NH2. NH2. o-Phenylenediamine Glacial acetic acid Ammonia solution Water H N CH3 N. 2-Methylbenzimidazole (2) Secondary amines Formaldehyde Ethanol H2 C. Secondary amines. R. Di- methyl amine Di-ethyl amine. N R'. -. N. Compound 2a-R&R' =CH3. CH3. Compound 2b-R&R' =C2H5. N. Compound 2a-b. Scheme-3. www.wjpr.net. Vol 3, Issue 4, 2014.. 520.

(5) Abhay et al.. World Journal of Pharmaceutical Research. Antibacterial activity [7] All the compounds were screened in- vitro for their antibacterial activity against Staphylococcus aureus, Bacilllus subtilis, Solmonella typhi, Escherichia coli by cup- plate method at 100µg/ml concentration using Ciprofloxacin as standard and DMSO as solvent control. After 24 hr of incubation at 370C, the MIC was measured. Antifungal activity[8] All the compounds were screened in- vitro for their antifungal activity against Candida albicans and Aspergillus niger by cup- plate method at 100µg/ml concentration using Ketokonazole as standard and DMSO as solvent control. After 24-48 hr of incubation at 370C, the MIC was measured. Analgesic activity[9] All the compounds were screened for Analgesic activity in- vivo by Tail-flick method using Analgesiometer. Wistar albino mice of either sex (20-30g) in the groups of six animals each were selected by random sampling technique. Paracetamol at a dose level of 100 mg/kg was administered as a reference drug for comparison. The test compounds at dose level of 100 mg/kg were administered orally intragastric tube. The animals were held in position by a suitable restrained with the tail extending out and the tail (up to 5cm) was then dipped in a beaker of water maintained at 55±5°c. The time in seconds taken to withdraw the tail clearly out of the water was taken as the reaction time. The reading was recorded at 30,60,120 and 180 min. after administration of compounds. A cut off point of 10sec. was observed to prevent the tail damage. Anti-Inflammatory activity[10] All the compounds were screened for anti-inflammatory activity in- vivo by carrageenan induced rat hind paw oedema method using Plethysmograph. Albino rats of either sex weighing between 150-200 g were divided into eight groups of six animals The 1st group served as control and received the vehicle (saline) only. 2nd group of animals were treated with standard drug Aspirin (100 mg/kg).The animals of the other groups (3, 4, 5, 6, 7&8) were treated with calculated doses of synthesized Derivatives. A mark was made on both the hind paws just below the tibio-tarsal joint. So that every time the paw could constant paw volume. After 30 min. of drug treatment and inflammation of induced in the left hind paw by injecting 0.1 ml of carrageen 1% solution in the sub planter region of all the animals. The paw volume was measured at 30, 60, 120 and 180 mins after the carrageen challenging. www.wjpr.net. Vol 3, Issue 4, 2014.. 521.

(6) Abhay et al.. World Journal of Pharmaceutical Research. The mean difference in initial paw volume and subsequent reading was noted and percentage inhibition of oedema was calculated using the formula. Percentage inhibition = 100(1-Vt/Vc) Where, Vt = represent oedema volume in test RESULTS AND DISCUSSION The melting points of all synthesized compounds were found in open capillary tubes and readings were uncorrected. Mol. Formula, Mol. Wt., melting point, % yield and elemental analysis were determined and the results were tabulated in the Table -1. The lambda maxes of the compounds were measured by Shimadzu 1200 UV spectrophotometer. The results of the UV spectra were given in under the spectral detail heading. The IR spectra of the compounds were done in a Bruker infra-red spectrophotometer (ν max cm-1) by using KBr discs. The results of IR spectra were given in spectral detail heading which showed absorption bands for aromatic C-H,N-H,C-N,C=N,C=O,OH,C-Cl, and O-CH3 groups. The 1H NMR spectra of the synthesized compounds were recorded on JEOL GSX 400 spectrometer using TMS as internal standard (chemical shifts in δ, ppm) and DMSO as the solvent. The results of the 1H NMR spectra given under spectral detail heading showed that the numbers of hydrogen atoms present in all the synthesized compounds were exact when compared to the number of hydrogen atoms in the expected compounds. The Mass spectra of the all the synthesized compounds were done on a JEOL GC mate spectrometer. The results presented in the spectral heading showed that the molecular mass of the synthesized compounds was nearer to the molecular mass of the expected compounds. The spectral details of the synthesized compounds N, N-Dimethylaminomethyl-1H-benzimidazole (compound-1a): UV λmax (DMSO): 243 nm; IR (KBr) νmax : 1512 (C =C, Ar), 3147(C-H, Ar), 2850 (C-H,s), 1359 (C-H, b), 935 (C-C, Ring), 1359 (C-N, s), 1614 (C=N, s), 3439 (C-N, 30amine); 1H NMR(DMSO- d6) δ: 7.26 (ArH, m), 2.27 (-CH3, m), 2.40 (-CH2, m); LC-MS: m/z 190.26 (M+). N,N-Diethylaminomethyl-1H-benzimidazole(compound-1b): UV λmax (DMSO): 239 nm; IR (KBr) νmax : 1587 (C =C, Ar), 3109(C-H, Ar), 2856 (C-H,s), 1361 (C-H, b), 1028 (C-C,. www.wjpr.net. Vol 3, Issue 4, 2014.. 522.

(7) Abhay et al.. World Journal of Pharmaceutical Research. Ring), 1361 (C-N, s), 1614 (C=N, s), 3344 (C-N, 30amine); 1H NMR(DMSO- d6) δ: 7.26 (ArH, m), 3.63 (-CH3, m), 2.40 (-CH2 ,m); LC-MS: m/z 228.30 (M+). N,N-Dibutylaminomethyl-1H-benzimidazole(compound-1c): UV λmax (DMSO): 231 nm; IR (KBr) νmax : 1587 (C =C, Ar), 3362 (C-H, Ar), 3362 (C-H,s), 1350 (C-H, b), 1072 (C-C, Ring), 1350 (C-N, s), 1770 (C=N, s), 3441 (C-N, 30amine); 1H NMR(DMSO- d6) δ: 7.26 (ArH, m), 1.33 (-CH3, m), 2.36 (-CH2 ,m); LC-MS: m/z 274.42 (M+). N-Dicyclohexylaminomethyl-1H-benzimidazole(compound-1d): UV λmax (DMSO): 279 nm; IR (KBr) νmax : 1552 (C =C, Ar), 2854 (C-H, Ar), 2854 (C-H,s), 1458 (C-H, b), 1188 (CC, Ring), 1334 (C-N, s), 1678 (C=N, s), 2521 (C-N, 30amine); 1H NMR(DMSO- d6) δ: 7.26 (Ar-H, m), 2.05 (-CH3, m), 2.36 (-CH2, m); LC-MS: m/z 326.5 (M+). 4-[1H-Benzimidazole-yl-(p-chlorobenzal) methyl-amino]benzoic acid (compound-1e): UV λmax (DMSO): 281 nm; IR (KBr) νmax : 1589 (C =C, Ar), 3240 (C-H, Ar), 3284 (C-H,s), 1350 (C-H, b), 1091 (C-C, Ring), 1301 (C-N, s), 1770 (C=N, s), 3308 (C-N, 30amine), 678 (C-Cl, s), 2360 (COOH,s), 1770(C=O, s); 1H NMR(DMSO- d6) δ: 7.26 (Ar-H, m), 2.36 (CH2, m), 4.00 (-NH, d), 11(OH, COOH, s); LC-MS: m/z 453.00 (M+). 4-[1H-Benzimidazole-yl(p-dimethylaminobenzal)methyl-amino]. benzoic. acid. (compound-1f): UV λmax (DMSO): 279 nm; IR (KBr) νmax : 1591 (C =C, Ar), 3252 (C-H, Ar), 3259 (C-H,s), 1410 (C-H, b), 945 (C-C, Ring), 1352 (C-N, s), 1681 (C=N, s), 3429 (CN, 30amine), 2360 (COOH,s), 1681 (C=O, s); 1H NMR(DMSO- d6) δ: 7.26 (Ar-H, m), 0.86 (CH3,m) 2.36, 2.00 (-NH, d), 11(OH, COOH, s); LC-MS: m/z 446.58. (M+). 4-[1H-Benzimidazole-yl-(p-hydroxybenzal) methyl-amino]benzoic acid (compound-1g): UV λmax (DMSO): 278 nm; IR (KBr) νmax : 1609 (C =C, Ar), 3217 (C-H, Ar), 3196 (C-H,s), 1384 (C-H, b), 941 (C-C, Ring), 1348 (C-N, s), 1665 (C=N, s), 3390 (C-N, 30amine),3639(OH, s), 2804 (COOH,s), 1635 (C=O, s); 1H NMR(DMSO- d6) δ: 7.26 (Ar-H, m), 6.67(-CH2, m), 4.00 (-NH, d), 11(OH, COOH, s), 5.00 (OH, Ar, s); LC-MS: m/z 434.58 (M+). 4-[1H-Benzimidazole-yl-(p-methoxybenzal) methyl-amino] benzoic acid (compound-1h): UV λmax (DMSO): 279 nm; IR (KBr) νmax : 1512 (C =C, Ar), 3394 (C-H, Ar), 3394 (C-H,s), 1458 (C-H, b), 996 (C-C, Ring), 1350 (C-N, s), 1600 (C=N, s), 3454 (C-N, 30amine), 2350. www.wjpr.net. Vol 3, Issue 4, 2014.. 523.

(8) Abhay et al.. World Journal of Pharmaceutical Research. (COOH,s), 1688 (C=O, s), 1253(OCH3, s); 1H NMR(DMSO- d6) δ: 7.26 (Ar-H, m), 6.67(CH2, m), 4.00 (-NH, d), 11(OH, COOH, s), 6.65 (-OCH3, s); LC-MS: m/z 448.68 (M+). N,N-Dmethylaminomethyl-2-methyl-benzimidazole(compound-2a): UV λmax (DMSO): 293 nm; IR (KBr) νmax : 1593 (C =C, Ar), 3424 (C-H, Ar), 2943 (C-H,s), 1454 (C-H, b), 1197 (C-C, Ring), 1373 (C-N, s), 1643 (C=N, s), 3456 (C-N, 30amine); 1H NMR(DMSO- d6) δ: 7.26 (Ar-H, m), 0.86 (-CH3, m), 4.72 (-CH2, m); LC-MS: m/z 204.29 (M+). N,N-Diethylaminomethyl-2-methyl-bezimidazole(compound-2b): UV λmax (DMSO): 241 nm; IR (KBr) νmax : 1597 (C =C, Ar), 3221 (C-H, Ar), 3267 (C-H,s), 1481 (C-H, b), 1080 (CC, Ring), 1307 (C-N, s), 1757 (C=N, s), 3412 (C-N, 30amine); 1H NMR(DMSO- d6) δ: 7.26 (Ar-H, m), 3.36 (-CH3, m), 2.40 (-CH2, m); LC-MS: m/z 232.34 (M+). Table: 1-Elemental analysis Com poud. Mol. formula. % Yield. Mol. wt.. M.P. (0C). 1a 1b 1c 1d 1e 1f 1g 1h 2a 2b. C11H16N3 C13H20N3 C17H28N3 C21H32N3 C26H31ClN3O2 C27H34N4O2 C26H32N3O3 C27H34N3O3 C12H18N3 C14H22N3. 76 81 73 72 71 73 75 83 75 76. 190.26 218.32 274.42 326.5 453 446.58 434.58 448.68 204.29 232.34. 139-141 143-145 146-148 127-129 175-178 190-191 195-197 158-160 140-142 154-156. Elemental analysis of compound (%found) C H N O Cl 69.44 8.48 22.09 71.52 9.23 19.25 74.40 10.28 15.31 77.25 9.88 12.87 68.94 6.90 9.28 7.06 7.83 72.62 7.67 12.55 7.17 71.86 7.42 9.67 11.05 72.29 7.64 9.37 10.70 70.55 8.88 20.57 72.37 9.54 18.09 -. Table: 2-Antibacterial activity Compound. Concentration (µg/ml). 1a 1b 1c 1d 1e 1f 1g 1h 2a 2b Standard. 100 100 100 100 100 100 100 100 100 100 100. www.wjpr.net. Zone of inhibition (mm) Gram positive Gram negative B.subtilis S .aureus E. coli S. typhi 10 8 3 8 11 10 10 4 10 10 4 12 8 8 10 12 12 12 14 11 13 12 8 13 12 12 13 14 13 10 10 12 10 8 11 8 8 8 9 10 24 22 21 22. Vol 3, Issue 4, 2014.. 524.

(9) Abhay et al.. World Journal of Pharmaceutical Research. (Ciproflox acin) Control (DMSO). -. -. -. -. -. Table: 3-Antifungal activity Compound 1a 1b 1c 1d 1e 1f 1g 1h 2a 2b Standard (Ketoconazole) Control(DMSO). Concentration (µg/ml) 100 100 100 100 100 100 100 100 100 100. Zone of inhibition (mm) Candida albicans Aspergillus niger 7 8 6 9 10 10 9 8 10 11 11 10 9 9 8 8 8 9 8 8. 100. 23. 22. -. -. -. Table: 4- Analgesic activity Compound. Dose mg/ml 100 100 100 100 100 100 100 100 100 100 100. Reaction time in seconds (Mean± Sem), 30 Min 1Hr 2 Hr 3 Hr 2.23±0.11 3.73±0.20* 5.63±0.11** 5.73±0.20** 2.66±0.10 4.44±0.21** 5.33±0.21** 5.46±0.33** 2.56±0.11 3.43±0.33* 3.63±0.11* 5.56±0.22** 2.83±0.30 5.06±0.37** 6.73±0.11** 7.0±0.20** 3.32±0.11* 5.4±0.11** 6.00±0.11** 7.06±0.20** 3.06±0.30* 6.0±0.36** 7.0±0.30** 7.40±0.32** 3.12±0.25 5.136±0.33** 6.15±0.22** 7.33±0.33** 3.23±0.11* 5.23±0.32** 6.23±0.33** 7.06±0.20** 2.4±0.12 3.13±0.20* 5.53±0.11** 5.26±0.23** 2.23±0.11 3.63±0.20* 4.53±0.11** 5.73±0.20** 3.4±0.33** 5.32±0.21** 7.15±0.29** 7.82±0.30**. (%) Activity 26.01 28.05 11.01 33.25 40.10 36.61 39.05 37.03 14.16 19.25 41.03. 1a 1b 1c 1d 1e 1f 1g 1h 2a 2b Paracetamol Control 100 2.15±0.16 2.32±0.21 2.56±0.21 2.72±0.72 6 (CMC) n= 6 animals in each group, Significance level: ** p< 0.01, *p< 0.05 as compared with the respective control.. www.wjpr.net. Vol 3, Issue 4, 2014.. 525.

(10) Abhay et al.. World Journal of Pharmaceutical Research. Table:5-Anti-Inflammatory activity Compound. Dose mg/ml 100 100 100 100 100 100 100 100 100 100 100. Paw volume in ml( Mean± Sem) 30 Min 1Hr 2 Hr 3 Hr 1.00± 0.01 0.96 ± 0.01 0.93 ± 0.01* 0.89 ± 0.02* 1.01 ± 0.02 0.94 ± 0.01 0.95 ± 0.02* 0.91 ± 0.02* 1.00 ± 0.01 0.93 ± 0.01* 0.92 ± 0.01* 0.91 ± 0.01* 0.92± 0.01** 0.90 ± 0.01** 0.82 ± 0.01** 0.75 ±0.01** 0.93 ± 0.01* 0.91 ± 0.02** 0.83 ± 0.01** 0.80 ±0.02** 0.92 ± 0.01* 0.92 ± 0.01** 0.83 ± 0.01** 0.78 ±0.01** 0.89± 0.01** 0.91 ± 0.01** 0.81 ± 0.01** 0.77 ±0.01** 0.91 ± 0.02* 0.89 ± 0.01** 0.84 ± 0.01** 0.77 ±0.01** 1.00 ± 0.02 0.96 ± 0.01 0.93 ± 0.02* 0.92 ± 0.01* 1.00 ± 0.01 0.95 ± 0.01 0.94 ± 0.01 0.90 ± 0.01 0.88± 0.01** 0.87 ± 0.01** 0.78 ± 0.01** 0.68 ±0.01**. (%) Inhibition 13.18 9.46 14.51 21,16 22.36 19.68 23.90 21.31 15.37 13.86 30. 1a 1b 1c 1d 1e 1f 1g 1h 2a 2b Aspirin Control 100 1.02 ± 0.01 1.06 ± 0.02 1.01 ± 0.01 0.99 ± 0.01 5 (CMC) n= 6 animals in each group, Significance level: ** p< 0.01, *p< 0.05 as compared with the respective control.. For all ten compounds antibacterial activity was determined using standard Ciprofloxacin, results were tabulated in table-2. All the compounds showed significant inhibitory activity against the microbes with the 100µg/ml which produces 100% inhibition against the microorganism. Depending on the functional group present in the aromatic ring, different MIC values were obtained. Out of the synthesized compounds 1f, 1g and 1h shows excellent antibacterial activity. The compounds substituted with methoxy and hydroxyl group (1g, 1h) showed higher antibacterial activity compared to others, For all ten compounds antifungal activity was determined using standard Ketokonazole, results were tabulated in table-3. Out of ten compounds, compound 1c,1e and 1f showed good antifungal activity than others. The synthesized compounds were screened for their analgesic activity .The results were tabulated in table 4. All the compounds showed good analgesic activity. Out of all the synthesized compounds 1d, 1e, 1f and 1h showed good analgesic activity. The synthesized compounds were screened for their anti-inflammatory activity. The results were tabulated in table 5. All the compounds showed near about good anti-inflammatory activity. Out of all the synthesized compounds 1d,1e,1f,1g and 1h showed good antiinflammatory activity.. www.wjpr.net. Vol 3, Issue 4, 2014.. 526.

(11) Abhay et al.. World Journal of Pharmaceutical Research. CONCLUSION The research work was oriented towards the finding of newer Mannich bases of Benzimidazole derivatives with Antimicrobial, Analgesic and Anti-inflammatory activities. The different Substituted Mannich bases of Benzimidazole derivatives were synthesized using ethanol, formaldehyde and secondary amines. All synthesized compounds showed very good biological activities against previously reported Mannich bases of Benzimidazole derivatives. ACKNOWLEDGEMENT The authors are thankful to Magadh University, Bodh Gaya, Bihar, India for providing research facilities and encouragement and to our friends those who helped us to complete this research. REFERENCES 1. Khadar A. M. A., Gowda Janardhana, Kalluraya Balakrishna, Kumar Suchetha Nalilu, Microwave assisted synthesis of 1,3,4-oxadiazoles carrying benzimidazole moiety and their antimicrobial properties, Indian Journal of Chemistry, 2010,49:1130-1134. 2. Khan S. A., Nandan A. Mahmood, 2-substituted benzimidazoles as anti-inflammatory and analgesic agents. Indian Journal of Heterocyclic Chemistry, 1997,7:55-58 3. V. Gunasekaran, J.T. Leonard, O.S. Rajesh, L. Jeyaseel, Synthesis, anti-inflammatory and antibacterial activities of substituted phenyl benzimidazole , Asian Journal of chemistry, 2007, 19(1):116-120. 4. Murthi Yogesh, Arora Rashmi, Pathak Devendar, Synthesis, characterization and in vivo anthelmintic activity of some novel N-Mannich bases of benzimidazoles, Journal of Indian Chemical Society, 2010,87:627-631. 5. Pandey V. K., Gupta V. D., Tiwari D.N., 1, 2-disubstituted benzimidazole as potential antiviral agents. Indian Journal of Heterocyclic Chemistry, 2005, 14:217-220. 6. Hranjec Marijana, Pavlovic Gordana, Marjanovic Marko, Kralj Marijeta, KarminskiZamola, Grac, Benzimidazole derivatives related to 2,3-acrylonitriles, benzimidazol [1,2]quinolines and fluorenes: Synthesis, antitumor evaluation invitro and crystal structure determination, ChemInform,2010,41:230-234. 7. Kokare C.R., Antimicrobial screening, Pharmaceutical Microbiology ‘Experiments and Techniques’, 2005, 1:50-55.. www.wjpr.net. Vol 3, Issue 4, 2014.. 527.

(12) Abhay et al.. World Journal of Pharmaceutical Research. 8. Kokare C.R., Antimicrobial screening, Pharmaceutical Microbiology ‘Experiments and Techniques’, 2005, 1:55-59. 9. Kulkarni S. K., Screening of analgesic and anti-inflammatory activity, Handbook of experimental pharmacology, 2009, 3:123-126. 10. Kulkarni S. K., Screening of analgesic and anti-inflammatory activity, Handbook of experimental pharmacology, 2009, 3:126-128.. www.wjpr.net. Vol 3, Issue 4, 2014.. 528.

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