Sreerama, Rajasekhar (2012) Synthesis, Characterization and Biological Evaluation of Some Novel NMannich Bases of Benzimidazole Derivatives. Masters thesis, Adhiparasakthi College of Pharmacy, Melmaruvathur.
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Abstract
In the present research, we decided to synthesize 2-substituted benzimidazole derivatives by conventional method. Further the study will extended to introduce sulphanilamide and piperazine group substitution on N-1 position of 2-substituted benzimidazole by Mannich reaction and to screen the newly synthesized compounds for their antibacterial and antifungal activity. Plan of the work: To synthesize 2-substituted benzimidazole derivatives and their corresponding N- mannich bases. To determine the physical properties such as percentage yield, melting point, Rf value, colour, solubility and nature of all the synthesized compounds (SR1 – SR9). To determine and characterize the spectral data such as UV spectroscopy, FT-IR, 1H NMR and Mass spectra of all the synthesized compounds (SR1 – SR9). To evaluate the biological activity such as antibacterial and antifungal activity of synthesized compounds (SR4 – SR9). The current interest in the development of new antimicrobial chemotherapy has been the mainstay of medicinal intervention against infectious diseases caused by various pathogens. A matter of concern in the treatment of microbial infections is the limited number of efficacious antimicrobial drugs. There is a real perceived need for the discovery of new compounds that are endowed with antimicrobial activities, possibly acting through mechanism of action, to which many clinically relevant pathogens are now resistant (Uday Kalidhar., 2011). In order to expand the group of benzimidazole derivatives, we synthesized several new benzimidazole ring containing N-mannich bases. It has been observed that the presence of two (or) more heterocyclic moieties fused or linked enhance the biological profile of drug molecules by many folds. The appropriate carboxylic acids were reacted with O-phenylene diamine to give the corresponding 2-substituted benzimidazole in good to excellent yields by Phillip’s reaction. Then, a series of six novel mannich bases of 2-alkyl substituted benzimidazole derivatives were synthesized using mannich reaction by reaction with amines (primary and secondary) and formaldehyde. The purity of the synthesized compounds was checked by performing Thin Layer Chromatography (TLC) and determining melting points. We reported our results from a study of replacing the N-1 hydrogen of novel benzimidazole derivatives with different types of substitutions like sulphanilamide and piperazine to form N-methyl substituted benzimidazole derivatives by mannich reaction. The structure of the synthesized compounds were elucidated by physical and spectral (UV, IR, 1H NMR and Mass) analysis. The NH band (3164-3385 cm-1) and NH proton signal (δ 4.80 – 5.0 ppm) of 2-substituted benzimidazole in IR and 1H NMR spectrum respectively in the synthesized compounds (SR1–SR3), confirmed the formation of benzimidazole nucleus. In SR1, 1H NMR spectrum showed a singlet for 3 protons at δ 2.42 confirmed the substitution of methyl group at C2 of benzimidazole nucleus. In SR2, gave quartet peak for 2 protons at δ 2.59 and a triplet peak for 3 protons at δ 1.27 indicated the presence of ethyl group at C2 of benzimidazole. In SR3, a two triplet peak for 5 protons at δ 2.55 and δ 0.96 and a multiplet peak for 2 protons at δ 1.66 indicated the presence of propyl group at C2 of benzimidazole. The IR spectrum of each N-mannich bases of SR4 to SR6 showed the characteristic IR absorption bands in the region of 3376-3385 cm-1, 3263-3289 cm-1 and 1312-1320 cm-1 due to the presence of primary amino, secondary amino and SO2 stretching of sulphonamide moiety. The structural confirmation of each N-mannich bases of SR4 to SR6 was further made using 1H NMR spectra. It showed signals at δ, ppm: 6.06 - 6.18 (2H, s, -CH2 proton), 4.57 – 4.60 (2H, s, SO2NH2 proton) and 5.76 – 5.83 (1H, s, NH of sulphonamide). Thus, confirmed the proposed structures for above N-mannich bases of corresponding 2-substituted benzimidazole derivatives. The IR spectrum of each N-mannich bases of SR7 to SR9 showed the characteristic IR absorption bands in the region of 3385 - 3416 cm-1 due to the presence of 2° N-H (secondary amino) streching of piperazine ring. The structural confirmation of each N-mannich bases of SR7 to SR9 was further made using 1H NMR spectra. It showed signals at δ, ppm: 2.37 – 2.93 (8H, m, -CH2 of piperazine), 5.47 – 5.61 (2H, s, CH2 proton) and 1.13 – 1.15 (1H, s, NH of piperazine). Thus, confirmed the proposed structures for above N-mannich bases of corresponding 2-substituted benzimidazole derivatives. The structural confirmation of synthesized compounds of SR1 to SR9 was further made using Mass spectra. The molecular ion (M+) peaks such as 132.12, 146.21, 160.11, 316.37, 330.40, 344.43, 230.30, 244.33 and 258.36 for SR1, SR2, SR3, SR4, SR5, SR6, SR7, SR8 and SR9 respectively corresponded with their molecular weights. The predicted chemical structure of title compounds was further supported by the fragmentation peaks. The compounds were screened for their antibacterial and antifungal activities. The activities reported by means of zone of inhibition in millimeter. All the compounds showed very good antibacterial and antifungal activities at the tested dose level. The sulphanilamide group containing N-mannich bases were more superior for inhibiting the growth of Staphylococcus aureus and Bacillus subtilis than piperazine containing N-mannich bases. Among the compounds, SR4 to SR6, the compound SR5 was more active than the other compounds against the growth of Staphylococcus aureus. Likewise, the compound SR6 was more active than SR4 and SR5 to inhibit the growth of Bacillus subtilis. The piperazine group containing N-mannich bases were more superior for inhibiting the growth of Escherichia coli and Pseudomonas aeruginosa than sulphanilamide group containing N-mannich bases. Among the compounds SR7 to SR9, the compound SR8 was more active than the other compounds against the growth of Escherichia coli and Pseudomonas aeruginosa. Among the tested compounds, piperazine derivatives were more superior to sulphanilamide derivatives against gram negative bacteria. But sulphanilamide derivatives were more active than piperazine derivatives against gram positive bacteria. The anti-fungal evaluation of compounds (SR4 to SR9), the piperazine group containing N-mannich bases were more superior for inhibiting the growth of Candida albicans and Trichophyton rubrum than sulphanilamide group containing N-mannich bases. Among the compounds of SR7 to SR9, the compound SR9 was more active than the other compounds against the growth of Candida albicans and Trichophyton rubrum. Even though, the anti microbial activity of tested compounds was less than their standard compounds are ciprofloxacin (antibacterial) and ketoconazole (antifungal) in the present study. In future study, it could be increased (or) equalized by altering the number of carbon atoms in side chain (or) introducing aromatic ring (or) substituted aromatic ring (or) heterocyclic ring (or) by introducing double bond in side chain in the 2nd position of benzimidazole nucleus. In other way, the synthesis of 2-substituted benzimidazoles can be altering the complex with amines, like as pyrrolidine, imidazole, piperidine, morpholine and N-methyl piperazine etc. in the 1st position of benzimidazole nucleus. Since a fewer species have been used in this study, it was warranted to screen these compounds with varied species and resistant strains. Further experiments were needed to elucidate their exact mechanism of activity. These results suggest that the benzimidazole ring is an important pharmacophore in modern drug discovery and the tested derivatives of benzimidazoles have excellent scope for further development as commercial antimicrobial agents in the chemotherapeutic approach in human. Our findings will prove useful to those chemists, pharmacists, medicinal chemists who are interested in the synthesis of potential Mannich bases as drugs with minimum side effects and also have comparatively low cost.
| Item Type: | Thesis (Masters) |
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| Uncontrolled Keywords: | NMannich Bases; Benzimidazole Derivatives; Piperazine derivatives; N-mannich bases |
| Subjects: | PHARMACY > Pharmaceutical Chemistry |
| Depositing User: | Ravindran C |
| Date Deposited: | 17 Aug 2017 06:49 |
| Last Modified: | 17 Aug 2017 06:49 |
| URI: | http://repository-tnmgrmu.ac.in/id/eprint/2657 |
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