Synthesis and biological activities of some aryl (alkyl)azole derivatives

Öz

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.

Anahtar Kelimeler

• Aryl(alkyl)azole,antioxidant,4-triazole,1 2 4-triazole

Aril(alkil)azol türevlerinin sentezi ve biyolojik aktiviteleri

Öz

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. 

Anahtar Kelimeler

• 4-triazol,Aril (alkil) azol,antioksidan,AChE ve BChE enzim inhibisyonu,1 2 4-triazol

Kaynakça

1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 10. Höfle G, Steglich W. 4-Dialkylaminopyridines as acylation catalysts. Synthesis 1972; 619-621.
11. 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. 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. 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. 14. . Blois MS. Antioxidant determinations by the use of a stable free radical, Nature 1958; 181:1199-1200.
15. 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. 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. 17. Pasqualotto AC, Denning DW. New and emerging treatments for fungal infections. Journal of Antimicrobial Chemotherapy 2008; 1: 19-30.
18. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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.