Imidazole Derivatives Biological Activity And Synthetic Approaches

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Imidazole Derivatives Biological Activity And Synthetic Approaches

  1. 1. Imidazole Derivatives : Biological Activity And Synthetic Approaches
  2. 2. <ul><li>Introduction </li></ul><ul><li>Biological importance of natural imidazole derivatives </li></ul><ul><li>Biological activity of synthetic imidazole derivatives </li></ul><ul><li>Retrosynthetic analysis for imidazole </li></ul><ul><li>Conventional methods for imidazole synthesis </li></ul><ul><li>Synthesis of imidazoles with modern methods </li></ul><ul><ul><li>Catalytic methods </li></ul></ul><ul><ul><li>Non-catalytic methods </li></ul></ul><ul><li>Conclusions </li></ul>Contents
  3. 3. <ul><li>Imidazole : Name and structure :- </li></ul><ul><li>Imidazole :- Heterocyclic 5-member ring structure, out of which three are carbon and the remaining two are nitrogen, arranged at 1 and 3 positions. </li></ul><ul><li>IUPAC nomenclature :- “1,3-diazole”. </li></ul><ul><li>  </li></ul>3-D structure :- Stability and aromaticity:- Introduction
  4. 4. <ul><li>Physical properties :- </li></ul><ul><li>Polar, miscible withwater and other polar solvents. </li></ul><ul><li>Basic in nature. Both properties are due to high π-electron density. </li></ul><ul><li>Excellent nucleophilic. </li></ul><ul><li>corrosion inhibitor for transition metals such as copper </li></ul><ul><li>Polybenzimidazole(PBI) : A thermostable polymer - fire-retardant. </li></ul>1,3-Hydrogen shift :- Rapid 1,3-hydrogen shift, Reveals equivalent character of both the nitrogens at positions 1 and 3. Introduction
  5. 5. <ul><li>Histidine :- </li></ul><ul><li>Essential amino acid. </li></ul><ul><li>Precursor for histamine –biosynthesis. </li></ul><ul><li>Biotin :- </li></ul><ul><li>Vitamin B 7 . </li></ul><ul><li>Coenzyme for diff. carboxylase. </li></ul>Alkaloids :- Biological importance of natural imidazole derivatives
  6. 6. <ul><li>Amoebicidal drugs :- </li></ul>Chemically 5-nitroimidazole drugs Nitro group acts as electron acceptor Converted to reduced form ferredoxin enzyme of anaerobic organisms Carbohydrate and protein metabolism Clinical use :- amoebicidal in amoebic dysentery, also against Gram negative bacteria. - Biological activity of synthetic imidazole derivatives
  7. 7. <ul><li>Antifungal drugs :- </li></ul>Commonly known as Antifungal azoles Fungal cell-wall Cholesterol biosynthesis Fungal cytochrome p450 enzyme ‘14-α-Sterol demethylase’ Clinical use :- against most fungal infections, either topically or systemically. - Biological activity of synthetic imidazole derivatives
  8. 8. Antithyroid drugs :- Thyroid Peroxidase Murray, R. K. et al. In Harper's Illustrated Biochemistry . 26 th ed. 2003; pp 447-449. Clinical use :- conditions of hyperthyroidism such as Grave’s disease, toxic uninodular / multinodular goiter, thyroid storm etc. - Biological activity of synthetic imidazole derivatives
  9. 9. <ul><li>Drugs affecting sympathetic nervous system :- </li></ul>α 1 -agonist :- Nephazoline, tetrahydrozoline, xylometazoline, oxymetazoline etc. <ul><li>α 2 -agonist : -Clonidine, brominidine </li></ul><ul><ul><ul><li>apraclonidine etc. </li></ul></ul></ul><ul><li>Clinical use :- </li></ul><ul><li>Nasal decongestant </li></ul><ul><li>Mydriatic agents </li></ul><ul><li>In hypotensive crisis (rarely). </li></ul><ul><li>Clinical use :- </li></ul><ul><li>As antihypertensive drugs </li></ul><ul><li>In symptomatic treatment of </li></ul><ul><li>glaucoma. </li></ul>-: Adrenoceptor agonist drugs :- Biological activity of synthetic imidazole derivatives
  10. 10. <ul><li>Drugs affecting sympathetic nervous system :- </li></ul>α 1 -antagonist :- Tolazoline, Phentolamine <ul><li>Clinical use :- In symptomatic treatment of </li></ul><ul><ul><ul><li>pheochromocytoma. </li></ul></ul></ul>β-antagonist :- Teoprolol <ul><li>Clinical use :- Antihypertensive drug </li></ul><ul><ul><ul><li>without postural </li></ul></ul></ul><ul><ul><ul><li>hypotension. </li></ul></ul></ul>-: Adrenoceptor antagonist drugs :- Biological activity of synthetic imidazole derivatives
  11. 11. Histamine receptors agonist drugs :- -: Histamine :- Structure Receptor types and asociated activity :- <ul><li>H 1 -receptors :- Mediator of allergic reactions after release from Mast Cell. </li></ul><ul><li>H 2 -receptors :- Key role in gastric acid secretion in stomach. </li></ul><ul><li>H 3 -receptors :- As a neurotransmitter in central and peripheral nervous system playing role of regulating release of other neurotransmitters like acetylcholine, dopamine, noradrenaline, serotonin etc. </li></ul><ul><li>Very flexible structure enables diversification in activity at different </li></ul><ul><li>receptors. </li></ul><ul><li>Drug-structure should be rigid for optimum selectivity. </li></ul>Biological activity of synthetic imidazole derivatives
  12. 12. <ul><li>H 1 -receptor antagonists :- </li></ul><ul><li>Examples :- Clemizole, antazoline, </li></ul><ul><ul><ul><li>epinastine, astemizole etc. </li></ul></ul></ul>Histamine receptors antagonist drugs :- Clinical use :- Antiallergic, antiemetic, mild sedatives. H 2 -receptor antagonists :- Example :- Cimetidine Clinical use :- Antiulcer drug. Biological activity of synthetic imidazole derivatives
  13. 13. Antiulcer drugs :- <ul><li>Drug target :- </li></ul><ul><li>H + K + - ATPase Pump ( also known as Proton Pump ). </li></ul><ul><li>Present in Parietal cell membrane in stomach. </li></ul><ul><li>Regulates the gastric acid secretion through exchange of K + for protons, making </li></ul><ul><li>the gastric acid acidic upto pH level of about 1-2. </li></ul>Biological activity of synthetic imidazole derivatives
  14. 14. Mechanism of proton pump inhibition :- Clinical use :- Anti-ulcer drugs Lindberg, P. et al. J. Med. Chem. 1986, 29 , 1327-1329. Parietal cells in stomach-wall Excitatatory nerve-signal by ANS Activated parietal cell Gastric acid secretion Histamine Enzyme H + K + - ATPase pump - Biological activity of synthetic imidazole derivatives
  15. 15. <ul><ul><li>Anxiolytic drugs :- </li></ul></ul>Inactive GABA A receptors GABA GABA A receptors GABA GABA bound activated GABA A receptors Chloride channels opening Decreased excitability of neurons Decreased thought process lead to sleep and relief in anxiety Clinical use :- Sedatives, Hypnotics, Anxiolytics. + Biological activity of synthetic imidazole derivatives
  16. 16. Eicher, T. et al. In The Chemistry of Heterocycles:Structure, Reactions, Syntheses and Applications . 2nd ed.; WILEY-VCH GmbH & Co.: Weinheim, 2003; pp 170-172. Retrosynthetic analysis for imidazole
  17. 17. The pioneer synthesis :- By this route, imidazole was first synthesized by H. Debus in 1858 from glyoxal, ammonia and formaldehyde, and was known as “glyoxaline”. Debus, H. Ann. Chem. 1858, 107 , 199 Conventional methods for imidazole synthesis
  18. 18. TosMIC based imidazole synthesis :- Leusen, A. M. et al. J. Org. Chem. 1977, 42 , 1153-1159. Conventional methods for imidazole synthesis
  19. 19. Synthesis of imidazole from amidines :- Shilcrat, S. C. et al. J. Org. Chem. 1997, 62 , 8449-8454. Conventional methods for imidazole synthesis
  20. 20. Hetero-Cope Rearrangement :- <ul><li>General limitations of the conventional methods :- </li></ul><ul><li>Harsh reaction conditions. </li></ul><ul><ul><li>High temperature conditions. </li></ul></ul><ul><ul><li>High pH i.e. alkaline conditions. </li></ul></ul><ul><ul><li>Use of toxic organic solvents. </li></ul></ul><ul><li>Low yield, hence less efficiency. </li></ul><ul><li>High amount of wastes and side products, </li></ul><ul><li>thus lack of selectivity. </li></ul><ul><li>Environmental safety-problems. </li></ul>Lantos, I. et al. J. Org. Chem. 1993, 58 , 7092-7095. Conventional methods for imidazole synthesis
  21. 21. Follow catalytic &/or multicomponent reaction strategies or entirely different concept such as reaction by EMR irradiation. -: Catalytic reactions for imidazole synthesis :- Synthesis of imidazoles by modern methods
  22. 22. Palladium-catalyzed intramolecular cyclization reaction :- Zaman, S. et al. Org. Lett. 2005, 7 , 609-611. -: Palladium catalyzed syntheses :- Synthesis of imidazoles by modern methods
  23. 23. Palladium catalyzed multicomponent coupling reaction :- Mihovilovic, M. D. et al. Angew. Chem. 2007, 46 , 3612-3615. -: Palladium catalyzed syntheses :- Synthesis of imidazoles by modern methods
  24. 24. Ag-acetate catalyzed cyclodimerization :- Cu-catalyzed cross-cycloaddition :- -: d 10 metal catalysts :- Grigg, R. et al. Tetrahedron 1999, 55 , 2025-2044. Kanazawa, C. et al. J. Am. Chem. Soc. 2006, 128 , 10662-10663. Synthesis of imidazoles by modern methods
  25. 25. ZrCl 4 -catalyzed imidazole synthesis :- Ytterbium-triflate catalyzed 3-component condensation :- -: Lewis acids as catalysts :- Sharma, G. V. M. et al. Chem. Inform. 2007, 38 , 2991-2993. Wang, L.-M. et al. J. Flu. Chem. 2006, 127 , 1570-1573. Synthesis of imidazoles by modern methods
  26. 26. Thiazolium-catalyzed 3-component coupling reaction :- HClO 4 –SiO 2 catalyst for imidazole synthesis :- -: Lewis acids as catalysts :- Frantz, D. et al. Org. Lett. 2004, 6 , 843-846. Nagarapu, L. et al. J. Mol. Catal. 2007, 267 , 53-56. Synthesis of imidazoles by modern methods
  27. 27. <ul><ul><li>-: Non-catalytic reactions for imidazole synthesis :- </li></ul></ul>Synthesis of 1,2-diaryl -1H-imidazoles :- Bellina, F. et al. Tetrahedron 2007, 63 , 4571-4624. Synthesis of imidazoles by modern methods
  28. 28. Microwave-assisted synthesis :- <ul><ul><li>-: Non-catalytic reactions for imidazole synthesis :- </li></ul></ul>Shih, M. H. et al. Tetrahedron 2007, 63 , 2990-2999. Synthesis of imidazoles by modern methods
  29. 29. Catalyst-free 3-component reaction in water :- <ul><ul><li>-: Non-catalytic reactions for imidazole synthesis :- </li></ul></ul><ul><li>Advantages of modern methods of imidazole synthesis :- </li></ul><ul><li>Better yield. </li></ul><ul><li>Better green-chemistry profile because of less requirement of harmful organic </li></ul><ul><li>solvents. </li></ul><ul><li>Better selectivity of the reactions . </li></ul><ul><li>No harsh conditions especially when compared with conventional reactions, so easy </li></ul><ul><li>to carry out. </li></ul><ul><li>Less waste and by-products, which increases over-all reaction efficiency. </li></ul>Adib, M. et al. Tetrahedron Lett. 2007, 48 , 7263-7265. Synthesis of imidazoles by modern methods
  30. 30. <ul><li>Imidazole -- Very important class among the medicinal compounds. </li></ul><ul><li>Large number of imidazole derivatives have been are being developed for different </li></ul><ul><li>therapeutic actions. </li></ul><ul><li>Being a polar and ionisable aromatic compound, it improves pharmacokinetic </li></ul><ul><li>characteristics of lead molecules and thus used as a remedy to optimise solubility </li></ul><ul><li>and bioavailability parameters of proposed poorly soluble lead molecules. </li></ul><ul><li>Having structural similarity with histidine, imidazole compounds can bind with </li></ul><ul><li>protein molecules with ease compared to the same other heterocyclic moieties. </li></ul><ul><li>Thus imidazole offers better pharmacodynamic characteristics. </li></ul><ul><li>From synthesis view-point, modern methods like catalytic syntheses and </li></ul><ul><li>multicomponent reactions have proven themselves better alternatives. </li></ul><ul><li>because of better economical, ecological and toxicological profiles. Looking to the </li></ul><ul><li>futuristic approaches towards Green-chemistry, modern methods must be utilized </li></ul><ul><li>and be further developed to further better synthetic methods. </li></ul>Conclusions

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