SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL ACTIVITIES OF SOME NEW SUBSTITUTED IMIDAZOLES

SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL ACTIVITIES OF SOME NEW SUBSTITUTED IMIDAZOLES

1. Rambabu ¹ J. Subbarao,* ¹ and P. Pavan Kumar ²

Department of Pharmaceutical Chemistry ¹, Chebrolu Hanumaiah Institute of Pharmaceutical Sciences, Guntur, A.P., India.

Department of Pharmacology ², Padmavathi College of Pharmacy, Dharmapuri, Tamilnadu, India.

ABSTRACT:  In the present study, a new series of 2, 4, 5- trisubstituted imidazoles derivatives were synthesized taking different aldehydes as substitutions. The preliminary characterization of synthesized compounds identified by physical constants determination and TLC. The chemical structures were confirmed by means of IR, ¹H-NMR and Mass spectral data. The synthesized compounds were screened for their anti-microbial and antifungal activity using standard methods. Both gram positive and gram negative organisms such as E.coli, B.subtilis, S.aureus, A. niger, C.albicans were used. The compounds screened for their antibacterial and antifungal activities A₁, A₂, A₄ have shown promising antibacterial and antifungal activity against as compared to standard drugs Ciprofloxacin and Griseofulvin. The compounds were also screened for their antidepressant activities using forced swimming test in mice in which A₁, A₂ and A₆ are found to be most significant while compounds A₄ and A₅ showed moderate activity as compared to standard drug Fluoxetin. The compound A₄, 4-(4, 5-diphenyl-1H-imidazole-2-yl) phenol exhibited excellent activity.

Imidazole, TLC,

NMR, antimicrobial,

antifungal and activity

INTRODUCTION: Imidazole is a planar 5-membered ring and is amphoteric. That is, it can function as both an acid and as a base. As an acid, the pK_a of Imidazole is 14.5, making it less acidic than carboxylic acids, phenols, and imides, but slightly more acidic than alcohols. The acidic proton is located on N-1. As a base, the pK_a of the conjugate acid (cited above as pK_BH⁺ to avoid confusion between the two) is approximately 7, making imidazole approximately sixty times more basic than pyridine.

The basic site is N-3, protonation gives the imidazolium cation, which is symmetrical. The compound is classified as aromatic due to the presence of a sextet of π-electrons, consisting of a pair of electrons from the protonated nitrogen atom and one from each of the remaining four atoms of the ring.  Different drugs containing these basic moieties with good pharmacological activity have been reported earlier. They undergo different types of chemical reactions and are found useful in synthesis of variety of heterocyclic compounds. Imidazole and their derivatives were used for the synthesis of various types of medicinal compounds having a good therapeutic value.

Literature survey reveals that, imidazole derivatives exhibited diverse pharmacological activities. Such as, antimicrobial activity,^1-6 anti-HCV and anti tumor activity,⁷ antinociceptive activity, leishmanicidal activity,⁸ anticonvulsant activity,⁹ GABA uptake inhibitory activity,¹² cytotoxic,^13,14 anticancer activity,¹⁵ antiproliferative activity,^{16, 17} aromatase inhibitory activities,¹⁸ antitubercular,¹⁹ anti fungal agents ²⁰ etc. Based on above observation it is worthwhile to synthesis newer compounds for their pharmacological activities. The aim of present study is to synthesize new potential 2, 4, 5-trisubstituted Imidazole derivatives (A_1-6) and to evaluate possible pharmacological activities like antifungal, antibacterial and antidepressant activities.

MATERIALS AND METHODS:

Melting points were determined by open capillary tubes and were found uncorrected. IR were recorded on FT-IR spectrometer (BRUKER) using KBr disc method. ¹HNMR spectra were recorded on NMR spectrometer (BRUKER AV-300MHz) in DMSO. The compounds were analysed for elemental analysis and their percentages were found to be very near that of the calculated values. Physical parameters data of compounds are recorded in Table 1 and spectral data recorded in Table 2.

TABLE 1: PHYSICAL PARAMETERS AND ELEMENTAL ANALYSIS OF COMPOUNDS

 TABLE 2: SPECTRAL ANALYSIS OF SYNTHESISED COMPOUNDS

Synthesis of 2, 4, 5-triphenyl-1H-imidazole [A₁ to A₆]

0.01 mole of Benzil was refluxed with 0.01 mole of an aromatic aldehyde in presence of 5 ml of glacial acetic acid and 0.01 moles of ammonium acetate for 4 hours. After which the resulting reaction mixture was cooled to room temperature. The reaction mixture was then poured in 15 ml of water and kept for refrigeration overnight. The resulting precipitate was collected, dried and recrystallized from hot ethanol. Scheme was illustrated in Figure1. Physical data were given in the Table 3.

FIG 1: SCHEME FOR THE SYNTHESIS OF COMPOUNDS

TABLE 3: PHYSICAL DATA OF COMPOUNDS

Antibacterial activity:

The compounds were tested in-vitro for their antibacterial activity against two microorganisms viz. Gram positive organisms: Staphylococcus aureus (ATCC 29737) and Bacillus subtilis (ATCC 6633), Gram negative organism: Escherichia coli (NCTC 10418) which are pathogenic in human beings using Cup-plate agar diffusion method using Nutrient agar.

Antifungal activity:

The compounds were tested in-vitro for their antifungal activity against Aspergillus niger (NCIM 596) and Candida albicans (NCIM 3102) using Cup-plate agar diffusion method using Sabouraud-Dextrose agar.

 Antidepressant activity:

All the compounds were screened for antidepressant activity also. Behavioural despair was proposed as a model to test for antidepressant activity by Porsolt et al. (1977, 1978). It was suggested that mice or rats forced to swim in a restricted space from which they cannot escape are induced to a characteristic behaviour of immobility. This behaviour reflects a state of despair which can be reduced by several agents which are therapeutically effective in human depression.

 RESULTS AND DISCUSSION:

All the synthesised compounds were characterized and identified by using different physico-chemical parameters. Such as, TLC, melting point, elemental analysis, IR and¹HNMR. From the literature survey it reveals that, the substituted imidazoles have been reported for number of pharmacological activities. The prepared compounds were screened for their anti-bacterial activity by using cup-plate agar diffusion method against various gram positive, gram negative and fungal stains. Some of the compounds show comparable activity with that of the standard (Ciprofloxacin and Griseofulvin).

The compounds screened for their antibacterial and antifungal activities A₁, A₂, A₄ have shown promising antibacterial and antifungal activity against E.coli (NCTC 10418), B. subtilis (ATCC 6633), S. aureus (ATCC 29737), A.niger (NCIM 596) and C.albicans (NCIM 3102) as compared to standard drug Ciprofloxacin and Griseofulvin. The results were shown in Table 4 and Fig 2 and 3.  The compounds were also screened for their antidepressant activity at 100 mg/kg dose level. However, the compounds A₁, A₂ and A₆ are found to be most significant while compounds A₄ and A₅ showed moderate activity as compared to standard drug Fluoxetin. Results were recorded in Table 5 and the graphical representation given in Fig 4.

TABLE 4: ANTI-BACTERIAL AND ANTI-FUNGAL ACTIVITY OF SYNTHESIZED COMPOUNDS

-Not identified against organism

FIG 2: GRAPHICAL PRESENTATION OF ANTIBACTERIAL ACTIVITY

FIG 3: GRAPHICAL PRESENTATION OF ANTIFUNGAL ACTIVITY

 TABLE 5: ANTIDEPRESSANT ACTIVITY OF THE SYNTHESIZED IMIDAZOLE DERIVATIVES

Compounds were tested at 100 mg kg^-1 dose level, I.P.

FIG 4: GRAPHICAL PRESENTATION OF ANTIDEPRESSANT ACTIVITY

CONCLUSION: The present work is a bonafide and novel for the synthesis of derivatives 2,4,5-trisubstituted imidazoles. In this view, we have made extensive review on substituted imidazole derivatives for their medicinal values with the help of chemical abstracts, journals, internet surfing and text books. Compounds A₁, A₂, A₄ have shown promising antibacterial and antifungal activity. The compounds A₁, A₂ and A₆ have shown promising antidepressant activity also.

The proposed work has given out many active antibacterial, antifungal and antidepressant agents. Some of the compounds have showed moderate activities. These compounds with suitable modification can be explored better for their therapeutic activities in the future. The promising biological activities may consider these compounds as a lead for drug development and drug discovery in future. The toxicity studies of these compounds will be carried out in future to find the effective therapeutic index.

ACKNOWLEDGEMENT: Authors greatly acknowledge to Padmavathi College of Pharmacy, Dharmapuri, Tamilnadu, India., for allowing to carry out the pharmacological studies. We are also thankful to Chebrolu Hanumaiah Institute of Pharmaceutical Sciences, Guntur, A.P., India., for their constant support to this work.

 REFERENCES:

1. Dariusz Matosiuk, Sylwia Fidecka, Lucyna Antkiewicz-Michaluk, Izabela Dybala and Anna E Koziol: Synthesis and pharmacological activity of 1-aryl- 5, 6(1H)dioxo-2,3-dihydroimidazo[1,2-a]imidazoles. European Journal of Medicinal Chemistry 2002; 37: 845-853.

2. Adam M Pieczonka, Aleksandra Strzelczyk, Beata Sadowska, Grzegorz Mlosto and Pawe Staczek: Synthesis and evaluation of antimicrobial activity of hydrazones derived from 3-oxido-1H-imidazole-4-carbohydrazides. European Journal of Medicinal Chemistry 2013; 64:389-95.
3. Baskar Lakshmanan, Papiya Mitra Mazumder, Dinakar Sasmal and Swastika Ganguly: Synthesis, characterization and anti microbial activity of some 1-substituted imidazoles. Der Pharmacia Lettre 2010; 2(4): 82-89.
4. Desai NC, Maheta AS, Rajpara KM, Joshi VV, Vaghani HV and Satodiya HM: Green synthesis of novel quinoline based imidazole derivatives and evaluation of their antimicrobial activity. Journal of Saudi Chemical Society 2011.
5. AM Vijesh, Arun M Isloor, Sandeep Telkar, Peethambar SK, Sankappa Rao and Nishitha Isloor: Synthesis, characterization and antimicrobial studies of some new pyrazole incorporated imidazole derivatives. European Journal of Medicinal Chemistry 2011; 46:3531-36.
6. Shweta Sharma, Saloni Gangal and Abdul Rauf: Convenient one-pot synthesis of novel 2-substituted benzimidazoles tetrahydrobenzimidazoles and imidazoles and evaluation of their in vitro antibacterial and antifungal activities. European Journal of Medicinal Chemistry 2009; 44:1751-57.

7. Khabnadideh, Z. Rezaei, A. Khalafi-Nezhad, R. Bahrinajafi, R. Mohamadi and Farrokhroz AA: Synthesis of N-Alkylated Derivatives of Imidazole as Antibacterial Agents. Bioorganic & Medicinal Chemistry Letters 2003; 13:2863–65.
8. Karlo Wittine, Maja Stipkovic Babic, Damjan Makuc, Janez Plavec, Sandra Kraljevic Pavelic, Mirela Sedic, Krešimir Pavelic, Pieter Leyssen, Johan Neyts, Jan Balzarini and Mladen Mintas: Novel 1,2,4-triazole and imidazole derivatives of L-ascorbic and imino-ascorbic acid synthesis, anti-HCV and antitumor activity evaluations. Bioorganic & Medicinal Chemistry 2012; 20:3675–85.
9. Patrice Vanelle, Jacobine Meuche, José Maldonado, Michel P Crozetb, Florence Delmas and Pierre Timon-David: Functional derivatives of 5-benzo[1,3]dioxol-5-yl-1-methyl-1H-imidazole-2- carbaldehyde and evaluation of leishmanicidal activity. Eur. J. Med. Chem 2000; 35:157−162.
10. Arzu Karakurt, Mehmet A Alagöz, Burcu Sayo_gl, Ünsal Çalıs and Sevim Dalkara: Synthesis of some novel 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone oxime ester derivatives and evaluation of their anticonvulsant activity. European Journal of Medicinal Chemistry 2012; 57:275-282.
11. Wen Chen, Xiao-Yan Deng, Yan Li, Li-Juan Yang, Wei-Chao Wan, Xue-Quan Wan, Hong-Bin Zhang and Xiao-Dong Yang: Synthesis and cytotoxic activities of novel hybrid 2-phenyl-3-alkylbenzofuran and imidazole/triazole compounds. Bioorganic & Medicinal Chemistry Letters xxx: 2013.
12. Silke Hack, Babette Wörlein, Georg Höfner, Jörg Pabel and Klaus T Wanner: Development of imidazole alkanoic acids as mGAT3 selective GABA uptake Inhibitors. European Journal of Medicinal Chemistry 2011; 46:1483-98.
13. Xiao-Dong Yang, Wei-Chao Wana, Xiao-Yan Deng, Yan Li, Li-Juan Yang , Liang Li and Hong-Bin Zhang: Design, synthesis and cytotoxic activities of novel hybrid compounds between 2-phenylbenzofuran and imidazole. Bioorganic & Medicinal Chemistry Letters 2012; 22:2726–29.
14. Amir Assadieskandar, Mohsen Amini, Seyed Nasser Ostad, Gholam Hossein Riazi, Tayebe Cheraghi-Shavi, Bentolhoda Shafiei and Abbas Shafiee: Design, synthesis,cytotoxic evaluation and tubulin inhibitory activity of 4-aryl-5-(3,4,5-trimethoxyphenyl)-2-alkylthio-1H-imidazole derivatives. Bioorganic & Medicinal Chemistry 2013; 21:2703–09.
15. Khalid MH, Tokunaga Y, Caputy AJ and Walters E: Inhibition of tumor growth and prolonged survival of rats with intracranial gliomas following administration of clotrimazole. J Neurosurg 2005; 103(1):79-86.
16. Junghun Lee, Hwan Kim, Hana Yu, Jae Yoon Chung, Chang-Hyun Oh, Kyung Ho Yoo, Taebo Sim and Jung-Mi Hah: Discovery and initial SAR of pyrimidin-4-yl-1H-imidazole derivatives with antiproliferative activity against melanoma cell lines. Bioorganic & Medicinal Chemistry Letters 2010; 20:1573–77.
17. Chung-Kyu Ryu, Ra-Young Lee, Seung-Yon Lee, Hwa-Jin Chung, Sang Kook Leea and Kwang-Hoe Chung: Design, synthesis and evaluation of 2-phenyl-1H-benzo[d]- imidazole-4,7-diones as vascular smooth muscle cell proliferation inhibitors. Bioorganic & Medicinal Chemistry Letters 2008; 18:2948–51.
18. Rui Wang, Hong-Fan Shi, Jing-Feng Zhao, Yan-Ping He, Hong-Bin Zhang and Jian-Ping Liu: Design, synthesis and aromatase inhibitory activities of novel indole-imidazole derivatives. Bioorganic & Medicinal Chemistry Letters 2013; 23:1760–62.
19. Jyoti Pandey, Vinod K Tiwari, Shyam S Verma , Vinita Chaturvedi, Bhatnagar S, Sinha S, Gaikwad AN and Rama P Tripathi: Synthesis and antitubercular screening of imidazole derivatives. European Journal of Medicinal Chemistry 2009; 44:3350–55.
20. Bogle RG, Whitley GS, Soo SC, Johnstone AP and Vallance P: Effect of anti-fungal imidazoles on mRNA levels and enzyme activity of inducible nitric-oxide synthase. Br J Pharmacol 1994; 111(4):1257-61.
21. Mirjalili BF, Bamonirib AH and Zamani L: One-pot synthesis of 1, 2, 4, 5-tetrasubstituted imidazoles promoted by nano-TiCl4.SiO2. Scientia Iranica C 2012; 19 (3):565–68.
22. Prabhu M and Radha R: Synthesis, characterization and evaluation of anti-bacterial and antihelmintic activity of some novel aryl imidazole derivatives. Asian J Pharm and Clinical Research 2012; 5(4): 154-59.
23. Vijayta Gupta: A review on biological activitiy of imidazole and thiazole moieties and their derivatives. Science International 2013; 1(7): 253-60.
24. Mittal A: Synthetic nitroimidazoles, biological activities and mutagenicity relationships. Sci.Pharm 2009; 77: 497-520.
25. Azam F, Ikskas IA, Khokra SL and Prakash O: Synthesis of some novel N4-(naphtha [1,2-d]thiazol-2-yl) semicarbazides as potential anticonvulsants. Eur J Med Chem 2009; 44: 203-11.
26. Govinda Rao K and Dipankar Chakraborty: Synthesis, Characterization and Antibacterial Evaluation of Some Potent 2-Substituted Benzimidazole Analogues. International Journal of Pharmaceutical Sciences and Drug Research 2014; 6(1): 67-69.
27. Ansari KF and Lal C: Synthesis, physicochemical properties and antimicrobial activity of some new benzimidazole derivatives. Eur J Med Chem 2009; 44: 4028-33.
28. Ansari KF and Lal C: Synthesis and biological activity of some heterocuclic compounds containing benzimidazole and β-lactam moiety. J Chem Sci 2009; 121(6): 1017-25.
29. Sharma D, Narasimhan B, Pradeep Kumar, Vikramjeet J, Rakesh N, Erik De Clercq and Balarini J: Synthesis, antimicrobial and antiviral evaluation of substituted imidazole derivatives. European J Med Chem 2009; 44(6):2347-53
    

    ---

How to cite this article:

Rambabu R, Subbarao J, and Kumar PP: Synthesis, Characterization and Biological Activities of Some New Substituted Imidazoles. Int J Pharm Sci Res 2015; 6(4): 1761-65.doi: 10.13040/IJPSR.0975-8232.6(4).1761-65.

 All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.