Abstract
Aryl (alkyl) azole
group compounds have antifungal, anticonvulsant and antibacterial activities. Inhibition of heme oxygenase, indolamine
2,3-dioxygenase-1, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)
enzymes is evident in the literature. There
are also reports that compounds containing this aryl (alkyl) azole group,
which are currently used in fungal infections, and activate antioxidant systems
in vivo. In
this study, 2-(1H-1,2,4-triazole-1-yl)-1-(2,4-dichlorophenyl)
ethanol and three new aromatic
side chain ester derivatives were synthesized based on the aryl (alkyl) azole
structure. Four imidazole derivatives based on the aryl (alkyl) azole structure
which were synthesized in another study and molecules in this study were
evaluated for AChE and BChE enzyme inhibition and antioxidant activities. While
enzyme inhibition were evaluated with Ellman’s modified method, antioxidant
activities were evaluated with DPPH and FRAP methods. In this study synthesized
molecules’ structure were elucidated with IR, 1H-NMR, 13C-NMR
and LC-MS spectral analysis. While no activity was observed in the
1,2,4-triazole derivatives both for enzyme inhibition and antioxidant activity,
in the imidazole derivative compounds low activity for enzyme inhibition and
DPPH radical scavenging activity was observed. In FRAP method there were no
activity in imidazole derivatives. While IC50was more concentrated than
1000 µMfor imidazole, standard Galantamin’s IC50 value was21.30 and
37.03 µM for enzyme inhibition. For antioxidant activity, standard Gallic acid
IC 50 was68.83 µM and imidazole derivatives IC50 were more
concentrated than 1000 µM. The absence of activity of our compounds suggests
that large structures such as the aromatic ring in the side chain may be
effective in enzyme interaction. We plan to synthesize new derivatives bearing
alkyl (saturated, unsaturated, halogen substituents, etc.) groups in the side
chain in the aryl (alkyl) azole group compounds and evaluate AChE and BChE
enzyme inhibition and antioxidant activities.
References
- 1. Verma A, Joshi S, Singh D. Imidazole: Having versatile biological activities. Journal of Chemistry. Hindawi Publishing Corporation. http://dx.doi.org./10.1155/2013/329412
- 2. Sahu JK, Ganguly S, Kaushik A. Triazoles: A valuable insight into recent developments and biological activities. Chinese Journal of Natural Medicines 2013; 11: 456-465.
- 3. Karakurt A, Dalkara S, Özalp M, Özbey S, Kendi E, Stables JP. Synthesis of some 1-(2-naphthyl)-2-(imidazole-1-yl)ethanone oxime and oxime ether derivates and their anticonvulsant and antimicrobial activities. European Journal of Medicinal Chemistry 2001; 36: 421-433.
- 4. Calıs U, Dalkara S, Ertan M, Sunal R. The significance of the imidazole ring in anticonvulsant activity of (arylalkyl)imidazoles. Archiv Der Pharmazie 1988; 321: 841-846.
- 5. Karakurt A, Aytemir MD, Stables JP, Ozalp, M, Kaynak FB, Ozbey S, et al. Synthesis of some oxime ether derivatives of 1-(2-naphthyl)-2(1,2,4-triazol-1-yl)ethanone and their anticonvulsant and antimicrobial activities. Archiv Der Pharmazie 2006; 339: 513-520.
- 6. Vita DD, Scipiona L, Tortorella S, Mellini P, Rienzo BD, Simonetti G, et al. Synthesis and antifungal activity of a new series of 2-(1H –imidazol-1-il)-1-phenylethanol derivates. European Journal of Medicinal Chemistry 2012; 49:334-342.
- 7. Dogan IS, Sarac S, Sari S, Kart D, Gokhan SE, Vural, I, et al. New azole derivatives showing antimicrobial effects and their mechanism of antifungal activity by molecular modeling studies. European Journal of Medicinal Chemistry 2017; 127: 124-138.
- 8. Kolesarova V, Sinko G, Sivikova K, Dianovsky J. Invitro inhibition of blood cholinesterase activities from cattle by triazole fungicides. Internatonal Journal of Cytology, Cytosystematic and Cytogenetics 2013; 66: 436-350.
- 9. Wahbi Y, Caujolle R, Tournaire C, Payard M, Linas MD, Seguela JP. Aromatic ethers of 1-aryl 2-(1 H- azolyl)ethanol: study of antifungal activity. European Journal of Chemistry 1995; 30: 955-962.
- 10. Höfle G, Steglich W. 4-Dialkylaminopyridines as acylation catalysts. Synthesis 1972; 619-621.
- 11. İmmediata T, Day A. Beta-naphtyl derivates of ethanolamine and N-substitued ethanolamines. Department of Chemistry and Chemical Engineering of the University of Pennsylvania. 1940; 512-527.
- 12. Godefrol EF, Heeres J, Cutsem JV, Janssen PA. The preparation and antimycotic properties of derivates of 1-phenethylimidazole. Research laboratoria, Janssen Pharmaceutica, Beerse, Belgium 1969; 12: 784-791.
- 13. Orhan DD, Şenol FS, Hosbas S, Orhan İE. Assesment of cholinesterase and tyrosinase inhibitory and antioxidant properties of Viscum albüm L. Samples collected from different host plants and its two principal substances. İndustrial Crops and Products 2014; 62:341-349.
- 14. . Blois MS. Antioxidant determinations by the use of a stable free radical, Nature 1958; 181:1199-1200.
- 15. Oyaizu M. Studies on products of browning reactions-antioxidative activities of browning reaction prepared from glucosamine, Japanese Journal of Nutrition 1986; 44: 307-315.
- 16. Acar U, Abumohsen U, Özkay Y, Karaca H, Kaplancıklı ZA. Synthesis and biological screening of some novel triazole derivates. Turkish Journal of Pharmaceutical Sciences 2015; 12: 221-230.
- 17. Pasqualotto AC, Denning DW. New and emerging treatments for fungal infections. Journal of Antimicrobial Chemotherapy 2008; 1: 19-30.
- 18. Radic Z, Manetsch R, Krasinski A, Raushel J, Yamauchi J, Garcia C, Kolb H, Sharpless KB, Taylor P. Molecular basis of interactions of cholinesterases with tight binding inhibitors. Chemico-Biological Interactions 2005; 157-158: 133-141.
- 19. Mohammadi M, Saeedi M, Zafarghandi NS, Mahdavi M, Sabourian R, Razkenari EK, Alinezhad H, Khanavi M, Foroumadi A, Shafiee A, Akbarzadeh T. Potent acetylcholinesterase inhibitors: Design, synthesis, biological evaluation, and docking study of acridone linked to 1,2,3-triazole derivates. European Journal of Medicinal Chemistry 2015;92:799-806.
- 20. Nisa M, Munawar MA, Chattha FA, Kousar S, Munir J, Ismail T, Ashraf M, Khan MA. Synthesis of novel triazoles and a tetrazole of escitalopram as cholinesterase inhibitors. Bioorganic & Medicinal Chemistry 2015; 23: 6014-6024.).
- 21. Koparir M, Orek C, Koparir P, Sarac K. Synthesis, experimental, theoretical characterization and biological activities of 4-ethyl-5-(2-hydroxyphenyl)-2H-1,2,4-triazole-3(4H)-thione. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 2013; 105: 522-531.
- 22. Sancak K, Ünver Y, Ünlüer D, Düğdü E, Kör G, Çelik F, Birinci E. Synthesis and characterization, and antioxidant activites of new trisubstituted triazoles. Turkish Journal of Chemistry 2012; 36: 457-466
- 23. Rawal B. Bactericidal action of ascorbic asid on pseudomonas aeruginosa: alteration of cell surface as a possible mechanism. Chemotherapy 1978; 24: 166-171.
- 24. Amabile-Cuevas C, Pina-Zentella R, Wah-Laborde M. Decreased resistance to antibiotics and plasmid loss in plasmid-carrying strains of Staphylococcus aureus treated with ascorbic acid. Mutation Research 1991; 264: 119-125
- 25. D’Auria FD, Tecca M, Strippoli R, Simonetti N. In vitro activity of propyl gallate-azole drug combination against fluconazole-and itraconazole-resistant Candida albicans strains. Letters in Applied Microbiology 2000; 32: 220-223.
- 26. Strippoli V, D’Auria FD, Tecca M, Callari A, Simonetti G. Propyl gallate increses antifungal imidazole activity against C. albicans. International Journal of Antimicrobial Agents 2000; 16: 73-76.
- 27. Karakurt A, Özalp M, Işık Ş, Stables JP, Dalkara S. Synthesis, Anticonvulsant and Antimicrobial Activities of Some New 2-acetylnaphthelene Derivates. Bioorganic & Medicinal Chemistry 2010; 18: 2902-2911.
Abstract
Aril(alkil)azol
grubu bileşikler antifungal, antikonvülsan, antibakteriyel aktivitelere
sahiptir. Hem oksijenaz enzim inhibisyonu, indolamin 2,3-dioksigenaz-1 enzim
inhibisyonu, asetilkolinesteraz (AChE) ve bütirilkolinesteraz (BChE) enzim
inhibisyonu aktivitelerinin değerlendirildiği çalışmalar da mevcuttur. Bu
çalışmada, aril (alkil) azol yapısında, 2(1H-1,2,4-triazol-1-il)-1-(2,4-diklorofenil)
etanol bileşiği ve bu bileşikten hareketle üç adet yeni aromatik yan zincir
içeren ester türevleri sentezlendi. Başka bir çalışmada sentezlenen yapısında
triazol yerine izosteri olan imidazol halkası taşıyan, dört adet bileşik ve bu
çalışmada sentezlenen bileşiklerin AChE ve BChE enzim inhibisyonu Ellman
metodunun modifiye şekli ile değerlendirilirken, antioksidan aktivitesi
1,1-difenil-2-pikrilhidrazil (DPPH) radikal süpürücü aktivite yöntemi ile
değerlendirildi. Sentezlenen yeni bileşiklerin yapıları IR, 1H-NMR, 13C-NMR
ve LC-MS spektroskopik yöntemlerle kanıtlandı. 1, 2, 4-Triazol türevlerinde
herhangi bir aktivite görülmezken, imidazol türevi bileşiklerde AChE enzim
inhibisyonu ve DPPH radikal süpürücü aktivite gözlenmiştir. İmidazol
türevlerinde enzim inhibisyonu aktiviteler IC50 (%50 inhibitör
derişimi) değeri 1000 µM’dan yüksek derişimlerde iken, standart olan Galantamin
bileşiğinde IC50 değeri 21.30 µM ve 37.03 µM’da gözlenmiştir.
Antioksidan aktivite, standart olan gallik asit için IC50 68.83 µM
iken, imidazol türevlerinde IC50 1000 µM’dan yüksek derişimlerde
gözlenmiştir. Bileşiklerde aktivite gözlenmemesi, yan zincirdeki aromatik
halkanın enzim etkileşiminde sterik engel oluşturduğunu düşündürmüştür. Aril (alkil)
azol grubu bileşiklerde, yan zincirde alkil (doymuş, doymamış, halojenli
sübstitüe vb) grubu taşıyan yeni türevler sentezlenerek bu aktivitelerin
değerlendirilmesi planlanmaktadır.
References
- 1. Verma A, Joshi S, Singh D. Imidazole: Having versatile biological activities. Journal of Chemistry. Hindawi Publishing Corporation. http://dx.doi.org./10.1155/2013/329412
- 2. Sahu JK, Ganguly S, Kaushik A. Triazoles: A valuable insight into recent developments and biological activities. Chinese Journal of Natural Medicines 2013; 11: 456-465.
- 3. Karakurt A, Dalkara S, Özalp M, Özbey S, Kendi E, Stables JP. Synthesis of some 1-(2-naphthyl)-2-(imidazole-1-yl)ethanone oxime and oxime ether derivates and their anticonvulsant and antimicrobial activities. European Journal of Medicinal Chemistry 2001; 36: 421-433.
- 4. Calıs U, Dalkara S, Ertan M, Sunal R. The significance of the imidazole ring in anticonvulsant activity of (arylalkyl)imidazoles. Archiv Der Pharmazie 1988; 321: 841-846.
- 5. Karakurt A, Aytemir MD, Stables JP, Ozalp, M, Kaynak FB, Ozbey S, et al. Synthesis of some oxime ether derivatives of 1-(2-naphthyl)-2(1,2,4-triazol-1-yl)ethanone and their anticonvulsant and antimicrobial activities. Archiv Der Pharmazie 2006; 339: 513-520.
- 6. Vita DD, Scipiona L, Tortorella S, Mellini P, Rienzo BD, Simonetti G, et al. Synthesis and antifungal activity of a new series of 2-(1H –imidazol-1-il)-1-phenylethanol derivates. European Journal of Medicinal Chemistry 2012; 49:334-342.
- 7. Dogan IS, Sarac S, Sari S, Kart D, Gokhan SE, Vural, I, et al. New azole derivatives showing antimicrobial effects and their mechanism of antifungal activity by molecular modeling studies. European Journal of Medicinal Chemistry 2017; 127: 124-138.
- 8. Kolesarova V, Sinko G, Sivikova K, Dianovsky J. Invitro inhibition of blood cholinesterase activities from cattle by triazole fungicides. Internatonal Journal of Cytology, Cytosystematic and Cytogenetics 2013; 66: 436-350.
- 9. Wahbi Y, Caujolle R, Tournaire C, Payard M, Linas MD, Seguela JP. Aromatic ethers of 1-aryl 2-(1 H- azolyl)ethanol: study of antifungal activity. European Journal of Chemistry 1995; 30: 955-962.
- 10. Höfle G, Steglich W. 4-Dialkylaminopyridines as acylation catalysts. Synthesis 1972; 619-621.
- 11. İmmediata T, Day A. Beta-naphtyl derivates of ethanolamine and N-substitued ethanolamines. Department of Chemistry and Chemical Engineering of the University of Pennsylvania. 1940; 512-527.
- 12. Godefrol EF, Heeres J, Cutsem JV, Janssen PA. The preparation and antimycotic properties of derivates of 1-phenethylimidazole. Research laboratoria, Janssen Pharmaceutica, Beerse, Belgium 1969; 12: 784-791.
- 13. Orhan DD, Şenol FS, Hosbas S, Orhan İE. Assesment of cholinesterase and tyrosinase inhibitory and antioxidant properties of Viscum albüm L. Samples collected from different host plants and its two principal substances. İndustrial Crops and Products 2014; 62:341-349.
- 14. . Blois MS. Antioxidant determinations by the use of a stable free radical, Nature 1958; 181:1199-1200.
- 15. Oyaizu M. Studies on products of browning reactions-antioxidative activities of browning reaction prepared from glucosamine, Japanese Journal of Nutrition 1986; 44: 307-315.
- 16. Acar U, Abumohsen U, Özkay Y, Karaca H, Kaplancıklı ZA. Synthesis and biological screening of some novel triazole derivates. Turkish Journal of Pharmaceutical Sciences 2015; 12: 221-230.
- 17. Pasqualotto AC, Denning DW. New and emerging treatments for fungal infections. Journal of Antimicrobial Chemotherapy 2008; 1: 19-30.
- 18. Radic Z, Manetsch R, Krasinski A, Raushel J, Yamauchi J, Garcia C, Kolb H, Sharpless KB, Taylor P. Molecular basis of interactions of cholinesterases with tight binding inhibitors. Chemico-Biological Interactions 2005; 157-158: 133-141.
- 19. Mohammadi M, Saeedi M, Zafarghandi NS, Mahdavi M, Sabourian R, Razkenari EK, Alinezhad H, Khanavi M, Foroumadi A, Shafiee A, Akbarzadeh T. Potent acetylcholinesterase inhibitors: Design, synthesis, biological evaluation, and docking study of acridone linked to 1,2,3-triazole derivates. European Journal of Medicinal Chemistry 2015;92:799-806.
- 20. Nisa M, Munawar MA, Chattha FA, Kousar S, Munir J, Ismail T, Ashraf M, Khan MA. Synthesis of novel triazoles and a tetrazole of escitalopram as cholinesterase inhibitors. Bioorganic & Medicinal Chemistry 2015; 23: 6014-6024.).
- 21. Koparir M, Orek C, Koparir P, Sarac K. Synthesis, experimental, theoretical characterization and biological activities of 4-ethyl-5-(2-hydroxyphenyl)-2H-1,2,4-triazole-3(4H)-thione. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 2013; 105: 522-531.
- 22. Sancak K, Ünver Y, Ünlüer D, Düğdü E, Kör G, Çelik F, Birinci E. Synthesis and characterization, and antioxidant activites of new trisubstituted triazoles. Turkish Journal of Chemistry 2012; 36: 457-466
- 23. Rawal B. Bactericidal action of ascorbic asid on pseudomonas aeruginosa: alteration of cell surface as a possible mechanism. Chemotherapy 1978; 24: 166-171.
- 24. Amabile-Cuevas C, Pina-Zentella R, Wah-Laborde M. Decreased resistance to antibiotics and plasmid loss in plasmid-carrying strains of Staphylococcus aureus treated with ascorbic acid. Mutation Research 1991; 264: 119-125
- 25. D’Auria FD, Tecca M, Strippoli R, Simonetti N. In vitro activity of propyl gallate-azole drug combination against fluconazole-and itraconazole-resistant Candida albicans strains. Letters in Applied Microbiology 2000; 32: 220-223.
- 26. Strippoli V, D’Auria FD, Tecca M, Callari A, Simonetti G. Propyl gallate increses antifungal imidazole activity against C. albicans. International Journal of Antimicrobial Agents 2000; 16: 73-76.
- 27. Karakurt A, Özalp M, Işık Ş, Stables JP, Dalkara S. Synthesis, Anticonvulsant and Antimicrobial Activities of Some New 2-acetylnaphthelene Derivates. Bioorganic & Medicinal Chemistry 2010; 18: 2902-2911.
Details
| Primary Language | Turkish |
|---|---|
| Subjects | Health Care Administration |
| Journal Section | Articles |
| Authors | |
| Publication Date | April 28, 2019 |
| Submission Date | April 27, 2018 |
| Acceptance Date | October 15, 2018 |
| Published in Issue | Year 2019 Volume: 12 Issue: 1 |
Cite
MEU Journal of Health Sciences Assoc was began to the publishing process in 2008 under the supervision of Assoc. Prof. Gönül Aslan, Editor-in-Chief, and affiliated to Mersin University Institute of Health Sciences. In March 2015, Prof. Dr. Caferi Tayyar Şaşmaz undertook the Editor-in Chief position and since then he has been in charge.
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