ABSTRACT:
Heterocyclic compounds, particularly imidazole derivatives, have emerged as crucial scaffolds in medicinal chemistry, owing to their diverse pharmacological activities and therapeutic relevance. Imidazole, a five-membered nitrogen-containing heterocycle, is characterized by its two nitrogen atoms positioned at 1 and 3, which endow the ring with unique electronic properties and the ability to engage in hydrogen bonding. This structural versatility underlies the widespread occurrence of imidazole moieties in biologically active molecules, including several clinically approved drugs. Imidazole derivatives have been extensively explored for their multifaceted biological activities, including anticancer, antimicrobial, anti-inflammatory, antidiabetic, and antiviral properties. Moreover, a variety of synthetic strategies have been developed to modify the imidazole core, enhancing its bioactivity and optimizing its drug-like properties. This review provides a comprehensive analysis of recent advancements in the synthesis and pharmacological applications of imidazole derivatives, with a focus on their role in modern drug discovery and development. Special attention is given to the structure-activity relationship (SAR) of imidazole compounds and their potential for future therapeutic innovation.
Cite this article:
Rakesh Kumar. A Review of Imidazole Derivatives: Synthesis, Pharmacological Applications, and Future Perspectives. Asian Journal of Research in Chemistry.2024; 17(6):368-6. doi: 10.52711/0974-4150.2024.00062
Cite(Electronic):
Rakesh Kumar. A Review of Imidazole Derivatives: Synthesis, Pharmacological Applications, and Future Perspectives. Asian Journal of Research in Chemistry.2024; 17(6):368-6. doi: 10.52711/0974-4150.2024.00062 Available on: https://ajrconline.org/AbstractView.aspx?PID=2024-17-6-10
REFERENCES:
1. Carey, F. A. and Sundberg, R. J. Structure and Mechanisms (Part A, 5th ed. Advanced Organic Chemistry. 2007. Springer.
2. Katritzky, A. R. and Pozharskii, A. F.; Handbook of Heterocyclic Chemistry (2nd ed., 2000). Elsevier.
3. Brown, D. J.; The Chemistry of Heterocyclic Compounds: The Imidazoles (Vol. 45, 2000). John Wiley and Sons.
4. Bansal, R. K.; Heterocyclic Chemistry (4th ed., 2010). New Age International Publishers.
5. Kumar, R., Singh, P. and Sharma, K. Recent advances in imidazole derivatives as potential anticancer agents. Journal of Molecular Structure. 2023; 1302: 127923.
6. Singh, V., Gupta, A. and Mishra, A. Imidazole-based antimicrobials: Synthesis, characterization, and biological evaluation. Bioorganic Chemistry. 2022; 122: 105641.
7. Sharma, N., Verma, S. and Chauhan, M. Anti-inflammatory potential of imidazole derivatives: Mechanistic insights and therapeutic perspectives. European Journal of Medicinal Chemistry. 2021; 215: 113265.
8. Patel, R., Joshi, D. and Mehta, P. Imidazole derivatives as novel antidiabetic agents: An overview of recent advances. Journal of Chemical Biology and Drug Design. 2022; 100(2): 215-223.
9. Khan, A., Patel, R. and Joshi, M. Imidazole-based inhibitors of metalloenzymes: Synthesis and mechanistic insights. Bioinorganic Chemistry and Applications. 2022; 2022: 9837602.
10. Li, Z., Wang, Y. and Zhang, H. Novel imidazole derivatives as potential neuroprotective agents for Alzheimer’s disease. ACS Chemical Neuroscience. 2023; 14(1): 22-32.
11. Deshmukh, S., Patil, V. and Kulkarni, M. Imidazole derivatives as plant protectants: Recent advances and future perspectives. Journal of Agricultural and Food Chemistry. 2021; 69(18): 5123-5140.
12. Quraishi, M. A., Sardar, R. and Jamal, D. Corrosion inhibition of mild steel in acid solutions by some aromatic hydrazides. Materials Chemistry and Physics. 2001; 71(3): 309-313.
13. Nelson, D.L. and Cox, M.M. Lehninger: Principles of Biochemistry. 2017, W.H. Freeman.
14. Hough, L. B.; Histamine, In Basic Neurochemistry: Molecular, Cellular and Medical Aspects (6th ed., 2001). Lippincott-Raven.
15. Zempleni, J., et al. Biotin: Chemistry, Physiology, and Therapeutic Uses, 2009, Springer.
16. Watson, J. D., et al. Molecular Biology of the Gene (6th ed., 2008). Pearson Education.
17. Kanerva, L. T., et al. Natural Occurrence of Hydantoin Derivatives. Bioorganic and Medicinal Chemistry Letters. 1999; 9(19): 2817-2820.
18. Boldyrev, A. A., et al. Carnosine as a Natural Antioxidant and Buffer in Muscle. Journal of Muscle Research and Cell Motility. 2013; 34(6): 203-210.
19. Brown, D. J. and Torrence, P. F. Imidazole and Benzimidazole Synthesis, 1985, Springer
20. Van Leusen, A. M., et al. Tosylmethyl Isocyanide in Organic Synthesis. I. Synthesis of Imidazoles. Journal of Organic Chemistry. 1977; 42(6): 1153-1159.
21. Wang, Z.; Comprehensive Organic Name Reactions and Reagents (Vol. 1, 2010). John Wiley and Sons.
22. Kappe, C.O. Biologically Active Di- and Trihydropyrimidones: Biginelli-Type Reactions in the 21st Century. European Journal of Medicinal Chemistry. 1997; 32(6): 463-478.
23. Varma, R.S. and Kumar, D. Microwave-Assisted Biginelli Condensation: Expeditious Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones. Tetrahedron Letters. 1999; 40(50): 7665-7669.
24. Bienaymé, H., et al. Multicomponent Reactions for the Synthesis of Heterocycles. Accounts of Chemical Research. 2000; 33(1): 49-58.
25. Groebke, K., et al. Multicomponent Condensed Heterocyclic Synthesis Using Isocyanides and Ammonium Salts. Angewandte Chemie International Edition. 1998; 37(9):949-951.
26. Leadbeater, N.E. and Resouly, M. S. Microwave-Enhanced Synthesis of Heterocycles in Water. Chemical Communications, 2002; 1: 48-49.
27. Kappe, C.O. Controlled Microwave Heating in Modern Organic Synthesis. Angewandte Chemie International Edition. 2004; 43(46): 6250-6284.
28. Ruiz-Castillo, P. and Buchwald, S.L. Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions. Chemical Reviews. 2016; 116(19): 12564-12649.
29. Hartwig, J.F. Catalysis of Substitution Reactions Involving Carbon–Heteroatom Bonds. Nature. 2008; 455(7211): 314-322.
30. Wang, L., Hu, Y., Wang, Y. and Xu, J. Imidazole-containing compounds as potential therapeutic agents. European Journal of Medicinal Chemistry. 2015; 95: 334-359.
31. Brás, N.F., Gomes, J.A. and Cerqueira, N.M.F. The crucial role of histidine in enzyme catalysis and enzyme inhibition. Chemical Reviews. 2021; 121(18): 10579-10607.
32. Krohn, K.; Imidazoles and their biologically important derivatives. In Heterocyclic Chemistry in Drug Discovery. 2001: 1-34. Academic Press.
33. Katia, K.M., Adnan, A., Suresh, K.M. and Siti, M.I. Imidazole-based scaffolds as pharmacologically potent molecules. European Journal of Medicinal Chemistry. 2019; 161: 205-243.
34. Kleemann, A. and Engel, J. Pharmaceutical Substances: Syntheses, Patents, Applications of the most relevant APIs. Thieme Chemistry, 1999, 4th edition.
35. Qiu, X., Wang, J., Liu, Y., Liu, X., Zhang, X. and Xu, J. Synthesis and antimicrobial evaluation of novel imidazole derivatives with potent activity against resistant bacterial strains. European Journal of Medicinal Chemistry. 2023; 250: 115220.
36. Zhang, Y., Zhang, L., Jiang, H. and Liu, S. Design, synthesis, and biological evaluation of imidazole-fused derivatives as antifungal agents. Bioorganic Chemistry. 2022; 124: 105844.
37. Dixon, R.A., Tosteson, T.D. and Lanza, G.A. Metronidazole: Emerging Roles in Cancer Treatment. Cancer Chemotherapy and Pharmacology. 2022; 89(5): 663-671.
38. Jordan, V.C. and Murphy, C.S. Anastrozole: A Novel Aromatase Inhibitor in the Treatment of Breast Cancer. Clinical Cancer Research. 2020; 26(18): 4737-4743.
39. Meyer, M., Li, H. and Haller, B. Voriconazole and Its Anticancer Potential: A Review. Frontiers in Pharmacology. 2021; 12: 649176.
40. Das, A., Ghosh, S. and Chakrabarti, J. Clotrimazole: An Imidazole Antifungal with Potential Anticancer Properties. Cancer Science. 2023; 114(2): 551-563.
41. Matsubara, Y., Yamada, Y. and Yoshikawa, T. Tacrolimus: An Imidazole Compound with Anticancer Potential in Post-Transplant Recurrence. Transplantation Proceedings. 2022; 54(7): 1757-1762.
42. Rosenberg, W.M. and Houghton, M. Ribavirin: The Antiviral Drug that Changed the Course of Hepatitis C Therapy. The Journal of Antimicrobial Chemotherapy. 2020; 75(10): 2664-2670.
43. Liu, M., Lu, Y. and Chen, H. Ketoconazole Exhibits Antiviral Activity Against Hepatitis C Virus in vitro and in vivo. Journal of Viral Hepatitis. 2021; 28(3): 493-501.
44. Harrison, T.M. and Raab, M. Cimetidine: A Review of its Effects Beyond the Gastrointestinal Tract. Journal of Clinical Gastroenterology. 2020; 54(1): 10-16.
45. Chen, G.X. and Wang, X. Zolimidine Attenuates Inflammation in Rat Models of Inflammatory Bowel Disease by Inhibiting Nitric Oxide Synthase Activity. European Journal of Pharmacology, 2021; 908: 174315.
46. Saud, A. and Kaur, R. Synthesis and Evaluation of Benzothiazole-Conjugated 4-Nitro Imidazoles for Anti-HIV Activity. Bioorganic and Medicinal Chemistry Letters. 2006; 16(1): 223-226.
47. Mito, A. and Kato, T. Mechanisms of Action of Nucleoside Reverse Transcriptase Inhibitors: Insights for New Drug Development Against HIV. Frontiers in Pharmacology. 2020; 11: 258.
48. Landge, S., Ghosh, S. and Rao, K.S. Synthesis and Antimycobacterial Activity of 2-Substituted Benzothiazoles. European Journal of Medicinal Chemistry. 2015; 97: 308-315.
49. Sangamesh A. Patel, M.P. and Rao, K.S. Metal Complexes of Imidazole Derivatives: Antimycobacterial Activity and Mechanistic Insights. Journal of Coordination Chemistry. 2019; 72(17): 1-12.
50. Wang, Y., et al. Design, Synthesis, and Biological Evaluation of Imidazole Derivatives as Antimalarial Agents. European Journal of Medicinal Chemistry. 2020; 185: 111846.
51. Kumar, S., et al. Synthesis and Antimalarial Activity of Novel Imidazole Derivatives. Bioorganic Chemistry. 2021; 116: 105272.
52. Huang, L., et al. Imidazole Derivatives as Potent PTP1B Inhibitors: Synthesis and Biological Evaluation. Journal of Medicinal Chemistry. 2018; 61(4): 1382-1394.
53. Patel, S., et al. Thiazolidinedione-Imidazole Hybrids: Design, Synthesis, and Antidiabetic Activity Evaluation. European Journal of Medicinal Chemistry. 2020; 193: 111978.
54. Chen, Z., et al. Imidazole Derivatives as Potent Selective Serotonin Reuptake Inhibitors: Design, Synthesis, and Biological Evaluation. Journal of Medicinal Chemistry. 2019; 62(11): 5032-5042.
55. Guo, Y., et al. Dual-Acting Imidazole Derivatives as Serotonin-Norepinephrine Reuptake Inhibitors: Synthesis and Antidepressant Activity. Bioorganic and Medicinal Chemistry Letters. 2021; 31(2): 126-132.
56. Patel, S., et al. Design and Synthesis of Imidazole Derivatives as Potent Acetylcholinesterase Inhibitors for Alzheimer’s Disease Treatment. European Journal of Medicinal Chemistry. 2020; 200: 112455.
57. Sharma, V., et al. Imidazole-Based Inhibitors of Amyloid-Beta Aggregation with Antioxidant Properties for Potential Alzheimer’s Disease Treatment. Bioorganic and Medicinal Chemistry Letters. 2021; 31: 127875.