Synthesis and Bioactivities of Benzoxazolone Derivative Chalcone Compounds

Öz

In this study, three compounds, 6-(3-aryl-2-propen-1-oyl)-2(3H)-benzoxazolones, whose aryl part is designed as benzene, furan or thiophene were synthesized successfully and their chemical structures were confirmed by ¹H NMR, ¹³C NMR, and HRMS spectra. Compound 2, 6-[3-(Furan-2-yl)-2-propen-1-oyl]-2(3H)-benzoxazolone, was reported for the first time with its synthesis in this study. Cytotoxic activities (except compound 1), carbonic anhydrase inhibitory activities (1-3) and acetylcholine esterase (AChE) inhibitory activities (1-3) of synthesized compounds were reported for the first time in this study. The AChE enzyme inhibitory activities of all compounds were higher than the reference compound, while the cytotoxicities and hCA I/II inhibitory activities of the compounds were lower than the reference compounds. Only compound 2 showed similar inhibitory activity with reference drug AZA against hCA I. Furthermore, in this study, it was shown that introducing the phenyl ring as the aryl moiety of the compounds was a more useful modification than the thiophene or furan rings in terms of the cytotoxic and AChE enzyme inhibitory activities. On the other hand, all synthesized compounds were found to be as candidate molecules for further studies due to their high AChE inhibitory activities.

Anahtar Kelimeler

• Acetylcholinesterase,benzoxazolone,carbonic anhydrase,chalcone,cytotoxicity

Proje Numarası

2016/118

Benzoksazolon Türevi Şalkon Bileşiklerinin Sentezi ve Biyoaktivitelerinin Araştırılması

Öz

Bu çalışmada, genel kimyasal yapısı 6-(3-Aril-2-propen-1-oil)-2(3H)-benzoksazolon olan ve aril kısmı benzen, furan veya tiyofen olarak tasarlanan üç adet bileşik başarıyla sentezlenmiş ve yapıları ¹H NMR, ¹³C NMR ve HRMS spektrumları ile aydınlatılmıştır. Bileşik 2, 6-[3-(Furan-2-il)-2-propen-1-oil]-2(3H)-benzoksazolon, sentezi ile ilk kez bu çalışmada rapor edilmiştir. Sentezlenen bileşiklerin sitotoksik aktiviteleri (bileşik 1 hariç), karbonik anhidraz inhibitör aktiviteleri (1-3) ve asetilkolin esteraz inhibitör aktiviteleri (1-3) ise ilk kez bu çalışma ile rapor edilmiştir. Bileşiklerin tümünün AChE enzim inhibitör aktiviteleri referans bileşikten yüksekken, sitotoksik ve hCA I/II inhibitör aktiviteleri referans bileşiklerden düşüktür. Yalnızca bileşik 2, referans bileşik AZA’ya benzer hCA I inhibisyon göstermiştir. Ayrıca, bileşiklerin aril kısmına fenil halkasının getirilmesinin, tiyofen veya furan halkasına göre, sitotoksik ve AChE enzim inhibitör aktiviteleri açısından daha faydalı bir modifikasyon olduğu bu çalışma ile ortaya konulmuştur. Bundan başka, sentezlenen bileşiklerin yüksek AChE inhibitör aktiviteleri nedeniyle ileriki çalışmalar için uygun öncü bileşikler oldukları görülmüştür. 

Anahtar Kelimeler

• Asetilkolin esteraz,benzoksazolon,karbonik anhidraz,şalkon,sitotoksisite

Destekleyen Kurum

Atatürk Üniversitesi

Proje Numarası

2016/118

Teşekkür

Çalışma sırasında, bileşiklerin sentezlenmesindeki katkılarından dolayı Prof. Dr. Halise İnci GÜL’e, NMR spektrumlarının yorumlanmasındaki katkılarından dolayı Prof. Dr. Cavit KAZAZ’a, sentezlenen bileşiklerin karbonik anhidraz ve asetilkolin esteraz inhibisyon aktivite çalışmalarındaki katkılarından dolayı Prof. Dr. İlhami GÜLÇİN'e, sitotoksik aktivite çalışmalarındaki katkılarından dolayı Prof. Dr. Hiroshi Sakagami’ye ve çalışmayı destekleyen Atatürk Üniversitesi Araştırma Fon Saymanlığı’na (BAP Proje No: 2016/118) teşekkürlerimi sunarım.

Kaynakça

1. Abonia, R., Insuasty, D., Castillo, J., Insuasty, B., Quiroga, J., Nogueras, M., and Cobo, J. (2012). Synthesis of novel quinoline-2-one based chalcones of potential anti-tumor activity. European journal of medicinal chemistry, 57, 29-40.
2. Alterio, V., Di Fiore, A., D’Ambrosio, K., Supuran, C. T., and De Simone, G. (2012). Multiple binding modes of inhibitors to carbonic anhydrases: how to design specific drugs targeting 15 different isoforms? Chemical reviews, 112(8), 4421-4468.
3. Anand, P., and Singh, B. (2013). A review on cholinesterase inhibitors for Alzheimer’s disease. Archives of pharmacal research, 36(4), 375-399.
4. Baviskar, B.A, Baviskar, B., Shiradkar, M., Deokate, U., and Khadabadi, S. (2009). Synthesis and Antimicrobial Activity of SomeNovel Benzimidazolyl Chalcones. Journal of Chemistry, 6(1), 196-200.
5. Bilginer, S., Gul, H.I., Erdal, F.S., Sakagami, H., Levent, S., Gulcin, I., and Supuran, C. T. (2019). Synthesis, cytotoxicities, and carbonic anhydrase inhibition potential of 6-(3-aryl-2-propenoyl)-2 (3H)-benzoxazolones. Journal of enzyme inhibition and medicinal chemistry, 34(1), 1722-1729.
6. Bilginer, S., Gul, H.I., Mete, E., Das, U., Sakagami, H., Umemura, N., and Dimmock, J.R. (2013). 1-(3-Aminomethyl-4-hydroxyphenyl)-3-pyridinyl-2-propen-1-ones: a novel group of tumour-selective cytotoxins. Journal of enzyme inhibition and medicinal chemistry, 28(5), 974-980.
7. Bilginer, S., Unluer, E., Gul, H. I., Mete, E., Isik, S., Vullo, D., and Supuran, C. T. (2014). Carbonic anhydrase inhibitors. Phenols incorporating 2-or 3-pyridyl-ethenylcarbonyl and tertiary amine moieties strongly inhibit Saccharomyces cerevisiae β-carbonic anhydrase. Journal of enzyme inhibition and medicinal chemistry, 29(4), 495-499.
8. Bonte, J. P., Lesieur, D., Lespagnol, C., Cazın, J. C., and Cazin, M. (1975). 6‐Acyl‐Benzoxazolınone 2. Mıtt. Synthese Eınıger Ihrer Umwandlungsprodukte. Chemischer Informationsdienst, 6(10).

9. Cacabelos, R. (2008). Pharmacogenomics in Alzheimer's disease. In Pharmacogenomics in Drug Discovery and Development (pp. 213-357): Springer.
10. Chen, M., Christensen, S. B., Blom, J., Lemmich, E., Nadelmann, L., Fich, K., and Kharazmi, A. (1993). Licochalcone A, a novel antiparasitic agent with potent activity against human pathogenic protozoan species of Leishmania. Antimicrobial agents and chemotherapy, 37(12), 2550-2556.
11. Chen, M., Christensen, S. B., Zhai, L., Rasmussen, M., Theander, T., Frøkjaer, S., and Kharazmi, A. (1997). The novel oxygenated chalcone, 2, 4-dimethoxy-4'-butoxychalcone, exhibits potent activity against human malaria parasite Plasmodium falciparum in vitro and rodent parasites Plasmodium berghei and Plasmodium yoelii in vivo. Journal of Infectious Diseases, 176(5), 1327-1333.
12. Cunha, G. M. d. A., Fontenele, J. B., Nobre Júnior, H. V., de Sousa, F. C., Silveira, E. R., Nogueira, N. A., and Costa‐Lotufo, L. V. (2003). Cytotoxic activity of chalcones isolated from Lonchocarpus sericeus (Pocr.) Kunth. Phytotherapy Research: An International Journal Devoted to Pharmacological and Toxicological Evaluation of Natural Product Derivatives, 17(2), 155-159.
13. De, R. V., Scambia, G., Benedetti, P. P., Ranelletti, F., Bonanno, G., Ercoli, A., and Mancuso, S. (1995). Effect of synthetic and naturally occurring chalcones on ovarian cancer cell growth: structure-activity relationships. Anti-cancer drug design, 10(6), 481-490.
14. Di Resta, C., and Ferrari, M. (2019). New molecular approaches to Alzheimer's disease. Clinical biochemistry.
15. Dimmock, J., Kumar, P., Allen, T., Kao, G., Halleran, S., and Balzarini, J. (1997). Synthesis and cytotoxic evaluation of some carbohydrazones and thiocarbohydrazones of various unsaturated ketones and related Mannich bases. Die Pharmazie, 52(3), 182-186.
16. El-Hady, H. A., and Abubshait, S. A. (2015). Synthesis of imidazolinone and benzoxazole derivatives, and evaluation of their anticancer activity. Research on chemical intermediates, 41(3), 1833-1841.
17. Erciyas, E., Erkaleli, H., and Cosar, G. (1994). Antimicrobial evaluation of some styryl ketone derivatives and related thiol adducts. Journal of pharmaceutical sciences, 83(4), 545-548.
18. Ferlay, J., Colombet, M., Soerjomataram, I., Mathers, C., Parkin, D., Piñeros, M., and Bray, F. (2019). Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. International journal of cancer, 144(8), 1941-1953.
19. Gul, H. I., Cizmecioglu, M., Zencir, S., Gul, M., Canturk, P., Atalay, M., and Topcu, Z. (2009). Cytotoxic activity of 4′-hydroxychalcone derivatives against Jurkat cells and their effects on mammalian DNA topoisomerase I. Journal of enzyme inhibition and medicinal chemistry, 24(3), 804-807.
20. Gul, H. I., Mete, E., Eren, S. E., Sakagami, H., Yamali, C., and Supuran, C. T. (2017). Designing, synthesis and bioactivities of 4-[3-(4-hydroxyphenyl)-5-aryl-4, 5-dihydro-pyrazol-1-yl] benzenesulfonamides. Journal of enzyme inhibition and medicinal chemistry, 32(1), 169-175.
21. Gul, H. I., Mete, E., Taslimi, P., Gulcin, I., and Supuran, C. T. (2017). Synthesis, carbonic anhydrase I and II inhibition studies of the 1, 3, 5-trisubstituted-pyrazolines. Journal of enzyme inhibition and medicinal chemistry, 32(1), 189-192.
22. Gul, H. I., Yamali, C., Bulbuller, M., Kirmizibayrak, P. B., Gul, M., Angeli, A., and Supuran, C. T. (2018). Anticancer effects of new dibenzenesulfonamides by inducing apoptosis and autophagy pathways and their carbonic anhydrase inhibitory effects on hCA I, hCA II, hCA IX, hCA XII isoenzymes. Bioorganic chemistry, 78, 290-297.
23. Gul, H. I., Yamali, C., Gunesacar, G., Sakagami, H., Okudaira, N., Uesawa, Y., and Kagaya, H. (2018). Cytotoxicity, apoptosis, and QSAR studies of phenothiazine derived methoxylated chalcones as anticancer drug candidates. Medicinal Chemistry Research, 27(10), 2366-2378.
24. Gul, H. I., Yamali, C., Yesilyurt, F., Sakagami, H., Kucukoglu, K., Gulcin, I., and Supuran, C. T. (2017). Microwave-assisted synthesis and bioevaluation of new sulfonamides. Journal of enzyme inhibition and medicinal chemistry, 32(1), 369-374.
25. Gul, H.I., Demirtas, A., Ucar, G., Taslimi, P., and Gulcin, I. (2017). Synthesis of Mannich bases by two different methods and evaluation of their acetylcholine esterase and carbonic anhydrase inhibitory activities. Letters in drug design & discovery, 14(5), 573-580.
26. Gulcan, H. O., Kupeli, E., Unlu, S., Yesilada, E., and Sahin, M. F. (2003). 4‐(5‐Chloro‐2 (3H)‐benzoxazolon‐3‐yl) Butanoic Acid Derivatives: Synthesis, Antinociceptive and Anti‐inflammatory Properties. Archiv der Pharmazie: An International Journal Pharmaceutical and Medicinal Chemistry, 336(10), 477-482.
27. Hasan, A., Khan, K. M., Sher, M., Maharvi, G. M., Nawaz, S. A., Choudhary, M.,and Supuran, C. T. (2005). Synthesis and inhibitory potential towards acetylcholinesterase, butyrylcholinesterase and lipoxygenase of some variably substituted chalcones. Journal of enzyme inhibition and medicinal chemistry, 20(1), 41-47.
28. Ivanova, Y., Momekov, G., & Petrov, O. (2009). Synthesis of novel substituted 1, 3-diarylpropenone derivatives and their in vitro cytotoxic activity. Letters in Drug Design & Discovery, 6(5), 353-357.
29. Ivanova, Y., Momekov, G., Petrov, O., Karaivanova, M., and Kalcheva, V. (2007). Cytotoxic Mannich bases of 6-(3-aryl-2-propenoyl)-2(3H)-benzoxazolones. European journal of medicinal chemistry, 42(11-12), 1382-1387.
30. Ivanova, Y. B., Momekov, G. T., and Petrov, O. I. (2013). New heterocyclic chalcones. Part 6. Synthesis and cytotoxic activities of 5-or 6-(3-aryl-2-propenoyl)-2 (3H)-benzoxazolones. Heterocyclic Communications, 19(1), 23-28.
31. Kandepu, N. M. (2002). Mannich bases of chalcones and cyclohexanones as candidate cytotoxic agents.
32. Kazaz C., Bilginer S., Engin F.S., Gül H.I. (2017). Synthesis of New 2(3H)-Benzoxazolone,6-[1-oxo-3-(2- furanyl)-2-propenyl] and Spectral Investigation With Advanced NMR Techniques and The NMR Shift Reagent [Eu(fod)3] Paper presented at the TRAMECH IX, Fez, Morocco, 260.
33. Koca, M., Yerdelen, K. O., Anil, B., Kasap, Z., Sevindik, H., Ozyurek, I., and Turkaydin, K. (2016). Design, synthesis and biological activity of 1H-indene-2-carboxamides as multi-targeted anti-Alzheimer agents. Journal of enzyme inhibition and medicinal chemistry, 31(sup2), 13-23.
34. Köksal, M., Gökhan, N., Erdoğan, H., Özalp, M., and Ekizoğlu, M. (2002). Synthesis of 3-(4-substituted benzoylmethyl)-2-benzoxazolinones and screening antimicrobial activities. Il Farmaco, 57(7), 535-538.
35. Lahtchev, K., Batovska, D., St P, P., Ubiyvovk, V., and Sibirny, A. (2008). Antifungal activity of chalcones: A mechanistic study using various yeast strains. European journal of medicinal chemistry, 43(10), 2220-2228.
36. Langella, E., Alterio, V., D’Ambrosio, K., Cadoni, R., Winum, J.-Y., Supuran, C. T., and Di Fiore, A. (2019). Exploring benzoxaborole derivatives as carbonic anhydrase inhibitors: a structural and computational analysis reveals their conformational variability as a tool to increase enzyme selectivity. Journal of enzyme inhibition and medicinal chemistry, 34(1), 1498-1505.
37. Lespagnol, A., Mercier, J., Sestier, R., and Marinacce, P. (1952). * Etude De La Benzoxazolone Et De Certaıns De Ses Derıves. Bulletın De La Socıete De Chımıe Bıologıque, 34(5-6), 597-605.
38. Liu, H.-r., Liu, X.-j., Fan, H.-q., Tang, J.-j., Gao, X.-h., and Liu, W.-K. (2014). Design, synthesis and pharmacological evaluation of chalcone derivatives as acetylcholinesterase inhibitors. Bioorganic & medicinal chemistry, 22(21), 6124-6133.
39. Loveman, E., Green, C., Kirby, J., Takeda, A., Picot, J., Payne, E., and Clegg, A. (2006). The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer's disease. In NIHR Health Technology Assessment programme: Executive Summaries: NIHR Journals Library.
40. Miranda, C. L., Stevens, J. F., Ivanov, V., McCall, M., Frei, B., Deinzer, M. L., and Buhler, D. R. (2000). Antioxidant and prooxidant actions of prenylated and nonprenylated chalcones and flavanones in vitro. Journal of agricultural and food chemistry, 48(9), 3876-3884.
41. Mulazim, Y., Berber, C., Erdogan, H., Ozkan, M. H., and Kesanli, B. (2017). Synthesis and analgesic activities of some new 5-chloro-2(3H)-benzoxazolone derivatives. The EuroBiotech Journal, 1(3), 235-240.
42. Murty, M., Ram, K. R., Rao, R. V., Yadav, J., Rao, J. V., Cheriyan, V. T., and Anto, R. J. (2011). Synthesis and preliminary evaluation of 2-substituted-1, 3-benzoxazole and 3-[(3-substituted) propyl]-1, 3-benzoxazol-2(3H)-one derivatives as potent anticancer agents. Medicinal Chemistry Research, 20(5), 576-586.
43. Nowakowska, Z. (2007). A review of anti-infective and anti-inflammatory chalcones. European journal of medicinal chemistry, 42(2), 125-137.
44. Palaska, E. (2004). Antkanser İlaçlar. In Farmasötik Kimya: Hacettepe Üniversitesi Yayınları.
45. Rivas-Vazquez, R. A. (2001). Cholinesterase inhibitors: Current pharmacological treatments for Alzheimer's disease. Professional Psychology: Research and Practice, 32(4), 433.
46. Rocha, L., Almeida, J., Macedo, R., & Barbosa-Filho, J. (2005). A review of natural products with antileishmanial activity. Phytomedicine, 12(6-7), 514-535.
47. Supuran, C. T. (2008). Carbonic anhydrases-an overview. Current pharmaceutical design, 14(7), 603-614.
48. Supuran, C.T. (2017). Advances in structure-based drug discovery of carbonic anhydrase inhibitors. Expert opinion on drug discovery, 12(1), 61-88.
49. Supuran, C.T. (2018). Carbon-versus sulphur-based zinc binding groups for carbonic anhydrase inhibitors? Journal of enzyme inhibition and medicinal chemistry, 33(1), 485-495.
50. Supuran, C. T., and Scozzafava, A. (2007). Carbonic anhydrases as targets for medicinal chemistry. Bioorganic & medicinal chemistry, 15(13), 4336-4350.
51. Thacker, P.S., Shaikh, P., Angeli, A., Arifuddin, M., and Supuran, C. T. (2019). Synthesis and biological evaluation of novel 8-substituted quinoline-2-carboxamides as carbonic anhydrase inhibitors. Journal of enzyme inhibition and medicinal chemistry, 34(1), 1172-1177.
52. Toru, O., Yoshihito, O., and Shaji, S. (2000). Jpn. Kokai Tokkyo Koho JP 11, 349, 521. Paper presented at the Chem. Abstr.
53. Vigroux, A., and Bergon, M. (1995). Synthesis of prodrugs and a mutual prodrug of chlorzoxazone and acetaminophen based on a masked benzoxazolone. Bioorganic & medicinal chemistry letters, 5(5), 427-430.
54. Wang, H., and Ng, T. (2002). Demonstration of antifungal and anti-human immunodeficiency virus reverse transcriptase activities of 6-methoxy-2-benzoxazolinone and antibacterial activity of the pineal indole 5-methoxyindole-3-acetic acid. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, 132(2), 261-268.
55. Yamali, C., Gul, H. I., Ece, A., Taslimi, P., and Gulcin, I. (2018). Synthesis, molecular modeling, and biological evaluation of 4‐[5‐aryl‐3‐(thiophen‐2‐yl)‐4, 5‐dihydro‐1H‐pyrazol‐1‐yl] benzenesulfonamides toward acetylcholinesterase, carbonic anhydrase I and II enzymes. Chemical biology & drug design, 91(4), 854-866.
56. Yamali, C., Gul, H. I., Sakagami, H., and Supuran, C. T. (2016). Synthesis and bioactivities of halogen bearing phenolic chalcones and their corresponding bis Mannich bases. Journal of enzyme inhibition and medicinal chemistry, 31(sup4), 125-131.
57. Yamali, C., Tugrak, M., Gul, H. I., Tanc, M., and Supuran, C. T. (2016). The inhibitory effects of phenolic Mannich bases on carbonic anhydrase I and II isoenzymes. Journal of enzyme inhibition and medicinal chemistry, 31(6), 1678-1681.
58. Yerdelen, K.O. and Gul, H.I. (2013). Synthesis and anticholinesterase activity of fumaramide derivatives. Medicinal Chemistry Research, 22(10), 4920-4929.
59. Zhang, P., Xu, S., Zhu, Z., and Xu, J. (2019). Multi-target design strategies for the improved treatment of Alzheimer's disease. European journal of medicinal chemistry, 176. 228-247.
60. Zvěřová, M. (2019). Clinical aspects of Alzheimer's disease. Clinical biochemistry, 72, 3-6.