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Imidazole Derivatives    Biological Activity And Synthetic Approaches
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Imidazole Derivatives Biological Activity And Synthetic Approaches

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My seminar presentation at Dept. of Medicinal Chemistry, NIPER.

My seminar presentation at Dept. of Medicinal Chemistry, NIPER.

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  • 1. Imidazole Derivatives : Biological Activity And Synthetic Approaches
  • 2.
    • Introduction
    • Biological importance of natural imidazole derivatives
    • Biological activity of synthetic imidazole derivatives
    • Retrosynthetic analysis for imidazole
    • Conventional methods for imidazole synthesis
    • Synthesis of imidazoles with modern methods
      • Catalytic methods
      • Non-catalytic methods
    • Conclusions
    Contents
  • 3.
    • Imidazole : Name and structure :-
    • Imidazole :- Heterocyclic 5-member ring structure, out of which three are carbon and the remaining two are nitrogen, arranged at 1 and 3 positions.
    • IUPAC nomenclature :- “1,3-diazole”.
    •  
    3-D structure :- Stability and aromaticity:- Introduction
  • 4.
    • Physical properties :-
    • Polar, miscible withwater and other polar solvents.
    • Basic in nature. Both properties are due to high π-electron density.
    • Excellent nucleophilic.
    • corrosion inhibitor for transition metals such as copper
    • Polybenzimidazole(PBI) : A thermostable polymer - fire-retardant.
    1,3-Hydrogen shift :- Rapid 1,3-hydrogen shift, Reveals equivalent character of both the nitrogens at positions 1 and 3. Introduction
  • 5.
    • Histidine :-
    • Essential amino acid.
    • Precursor for histamine –biosynthesis.
    • Biotin :-
    • Vitamin B 7 .
    • Coenzyme for diff. carboxylase.
    Alkaloids :- Biological importance of natural imidazole derivatives
  • 6.
    • Amoebicidal drugs :-
    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.
    • Antifungal drugs :-
    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. 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.
    • Drugs affecting sympathetic nervous system :-
    α 1 -agonist :- Nephazoline, tetrahydrozoline, xylometazoline, oxymetazoline etc.
    • α 2 -agonist : -Clonidine, brominidine
        • apraclonidine etc.
    • Clinical use :-
    • Nasal decongestant
    • Mydriatic agents
    • In hypotensive crisis (rarely).
    • Clinical use :-
    • As antihypertensive drugs
    • In symptomatic treatment of
    • glaucoma.
    -: Adrenoceptor agonist drugs :- Biological activity of synthetic imidazole derivatives
  • 10.
    • Drugs affecting sympathetic nervous system :-
    α 1 -antagonist :- Tolazoline, Phentolamine
    • Clinical use :- In symptomatic treatment of
        • pheochromocytoma.
    β-antagonist :- Teoprolol
    • Clinical use :- Antihypertensive drug
        • without postural
        • hypotension.
    -: Adrenoceptor antagonist drugs :- Biological activity of synthetic imidazole derivatives
  • 11. Histamine receptors agonist drugs :- -: Histamine :- Structure Receptor types and asociated activity :-
    • H 1 -receptors :- Mediator of allergic reactions after release from Mast Cell.
    • H 2 -receptors :- Key role in gastric acid secretion in stomach.
    • 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.
    • Very flexible structure enables diversification in activity at different
    • receptors.
    • Drug-structure should be rigid for optimum selectivity.
    Biological activity of synthetic imidazole derivatives
  • 12.
    • H 1 -receptor antagonists :-
    • Examples :- Clemizole, antazoline,
        • epinastine, astemizole etc.
    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. Antiulcer drugs :-
    • Drug target :-
    • H + K + - ATPase Pump ( also known as Proton Pump ).
    • Present in Parietal cell membrane in stomach.
    • Regulates the gastric acid secretion through exchange of K + for protons, making
    • the gastric acid acidic upto pH level of about 1-2.
    Biological activity of synthetic imidazole derivatives
  • 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.
      • Anxiolytic drugs :-
    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. 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. 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. TosMIC based imidazole synthesis :- Leusen, A. M. et al. J. Org. Chem. 1977, 42 , 1153-1159. Conventional methods for imidazole synthesis
  • 19. Synthesis of imidazole from amidines :- Shilcrat, S. C. et al. J. Org. Chem. 1997, 62 , 8449-8454. Conventional methods for imidazole synthesis
  • 20. Hetero-Cope Rearrangement :-
    • General limitations of the conventional methods :-
    • Harsh reaction conditions.
      • High temperature conditions.
      • High pH i.e. alkaline conditions.
      • Use of toxic organic solvents.
    • Low yield, hence less efficiency.
    • High amount of wastes and side products,
    • thus lack of selectivity.
    • Environmental safety-problems.
    Lantos, I. et al. J. Org. Chem. 1993, 58 , 7092-7095. Conventional methods for imidazole synthesis
  • 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. 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. 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. 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. 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. 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.
      • -: Non-catalytic reactions for imidazole synthesis :-
    Synthesis of 1,2-diaryl -1H-imidazoles :- Bellina, F. et al. Tetrahedron 2007, 63 , 4571-4624. Synthesis of imidazoles by modern methods
  • 28. Microwave-assisted synthesis :-
      • -: Non-catalytic reactions for imidazole synthesis :-
    Shih, M. H. et al. Tetrahedron 2007, 63 , 2990-2999. Synthesis of imidazoles by modern methods
  • 29. Catalyst-free 3-component reaction in water :-
      • -: Non-catalytic reactions for imidazole synthesis :-
    • Advantages of modern methods of imidazole synthesis :-
    • Better yield.
    • Better green-chemistry profile because of less requirement of harmful organic
    • solvents.
    • Better selectivity of the reactions .
    • No harsh conditions especially when compared with conventional reactions, so easy
    • to carry out.
    • Less waste and by-products, which increases over-all reaction efficiency.
    Adib, M. et al. Tetrahedron Lett. 2007, 48 , 7263-7265. Synthesis of imidazoles by modern methods
  • 30.
    • Imidazole -- Very important class among the medicinal compounds.
    • Large number of imidazole derivatives have been are being developed for different
    • therapeutic actions.
    • Being a polar and ionisable aromatic compound, it improves pharmacokinetic
    • characteristics of lead molecules and thus used as a remedy to optimise solubility
    • and bioavailability parameters of proposed poorly soluble lead molecules.
    • Having structural similarity with histidine, imidazole compounds can bind with
    • protein molecules with ease compared to the same other heterocyclic moieties.
    • Thus imidazole offers better pharmacodynamic characteristics.
    • From synthesis view-point, modern methods like catalytic syntheses and
    • multicomponent reactions have proven themselves better alternatives.
    • because of better economical, ecological and toxicological profiles. Looking to the
    • futuristic approaches towards Green-chemistry, modern methods must be utilized
    • and be further developed to further better synthetic methods.
    Conclusions