In Vitro Leishmanicidal Activity of Different Chalcone, Phthalonitrile and Their Peripheral Tetra Zinc Phthalocyanine Derivatives

Öz

In this study, in vitro leishmanicidal activity of different chalcone compounds (5-8), phthalonitrile derivatives (5a-8a), and zinc phthalocyanine (5b-8b) complexes bearing chalcone compound in peripheral positions were investigated. Phthalonitrile derivatives were obtained in the reaction of 4-nitrophthalonitrile with chalcone compound obtained by the reaction of acetophenone and various aldehydes. Zinc phthalocyanine complexes containing chalcone in the peripheral position were obtained as a result of the reaction of the synthesized phthalonitrile derivative with Zn(CH₃COO)₂ metal salt. The characterization of the synthesized original compounds (8, 8a and 8b) was performed by various spectroscopic methods (IR, 1H and 13C NMR, MALDI-TOF-MS and UV-Vis). Leishmaniasis is a disease lead to by parasites of the genus Leishmania, which can result in death as well as various clinical syndromes, generally in developing countries. New drug studies are needed because the drugs used in the treatment are toxic and resistance develops against them. In this study, the leishmaniacidal activities of synthesized chalcone, phthalonitrile and phthalocyanine series substances against Leishmania infantum and Leishmania major parasites were evaluated for the first time.

Anahtar Kelimeler

• Chalcone
• phthalocyanine
• leishmania promastigotes
• anti-lesichmania

Farklı Kalkon, Ftalonitril ve Periferal Tetra Çinko Ftalosiyanin Türevlerinin In Vitro Layşmanyasidal Aktivitesi

Öz

Bu çalışmada, farklı kalkon bileşikleri (5-8), ftalonitril türevleri (5a-8a) ve periferik pozisyonlarda kalkon bileşiği taşıyan çinko ftalosiyanin (5b-8b) komplekslerinin in vitro layşmanisidal aktiviteleri araştırıldı. Asetofenon ve çeşitli aldehitlerin reaksiyonu ile elde edilen kalkon bileşikleri ile 4-nitroftalonitrilin reaksiyonundan ftalonitril türevleri elde edilmiştir. Sentezlenen ftalonitril türevinin Zn(CH₃COO)₂ metal tuzu ile reaksiyonu sonucunda periferal pozisyonda kalkon içeren çinko ftalosiyanin kompleksleri elde edilmiştir. Sentezlenen orijinal bileşiklerin (8, 8a ve 8b) karakterizasyonu çeşitli spektroskopik yöntemlerle (IR, 1H ve 13C NMR, MALDI-TOF-MS ve UV-Vis) gerçekleştirilmiştir. Layşmaniasis, genellikle gelişmekte olan ülkelerde, Layşmania cinsi parazitlerinin neden olduğu, ölüme ve çeşitli klinik sendromlara neden olabilen bir hastalıktır. Tedavide kullanılan ilaçların toksik olması ve bunlara karşı direnç gelişmesi nedeniyle yeni ilaç çalışmalarına ihtiyaç duyulmaktadır. Bu çalışmada, sentezlenen kalkon, ftalonitril ve ftalosiyanin serisi maddelerin Layşmania infantum ve Layşmania major parazitlerine karşı layşmaniasidal aktiviteleri ilk kez değerlendirilmiştir.

Anahtar Kelimeler

• Kalkon
• ftalosiyanin
• layşmanyaz promastigotları
• anti-layşmanyaz aktivite

Kaynakça

1. [1] WHO, https://www.who.int/news-room/fact-sheets/detail/leishmaniasis (Date of access: 02.02.2022)
2. [2] Cavalcante, G. M., Camara, C. A., Silva, E. M. S. D., Santos, M. S., Leite, A. B., Queiroz, A. C., Evelyn Da Silva, A., Araújo, M. V., Alexandre-Moreira, M. S., Silva, T. M. S. (2021). Leismanicidal Activity of Propolis Collected in the Semiarid Region of Brazil., Front. Pharmacol., 12, 702032.
3. [3] Monzote, L. (2009). Current Treatment of Leishmaniasis: A Review. The Open Antimicrobial Agents Journal, 1, 9-19.
4. [4] Burza, S., Croft, S. L., Boelaert, M. (2018). Leishmaniasis, Lancet, 392, 951–70.
5. [5] Anversa, L., Tiburcio, M. G. S., Richini-Pereira, V. B., Ramirez, L. E. (2018). Human leishmaniasis in Brazil: A general review, Rev. Assoc. Med. Bras., 64 (3), 281-289.
6. [6] Gupta, K., Gaur, R., Sharma, A., Akther, J., Saini, M., Bhakuni, R. S., Pathania, R. (2019). A novel bi-functional chalcone inhibits multi-drug resistant Staphylococcus aureus and potentiates the activity of fluoroquinolones, Bioorg. Chem., 83, 214.
7. [7] Birari, B., Gupta, S., Mohan, C. G., Bhutani, K. K. (2011). Antiobesity and lipid lowering effects of Glycyrrhiza chalcones: experimental and computational studies, Phytomedicine, 18, 795.
8. [8] Stellenboom, N. (2019). Comparison of the inhibitory potential towards carbonicanhydrase, acetylcholinesterase and butyrylcholinesteraseof chalcone and chalcone epoxide, J Biochem Mol Toxicol., 33, 22240.

9. [9] Sharma, V., Kumar. V., Kumar, P. (2013). Heterocyclic chalcone analogues as potential anticancer agents, Anti-Cancer Agents Med. Chem., 13, 422.
10. [10] Eden, W. T., Alighiri, D., Wijayati, N., Mursiti, S. (2021). Synthesis of Chalcone Derivative from Clove Leaf Waste as a Natural Antioxidant, Pharmaceutical Chemistry Journal, 55, 3.
11. [11] Tajuddeen, N., Isah, M. B., Suleiman, M. A., Van Heerden, F. R., Ibrahim, M. A. (2018). The chemotherapeutic potential of chalcones against leishmaniases: a review, Int. J. Antimicrob. Agents, 51, 311-318.
12. [12] Boeck, P., Bandeira Falcao, C. A., De´sar Leal, P., Yunes, R. A., Filho, V. C., Torres-Santos, E. C., Rossi-Bergmann, B. (2006). Synthesis of chalcone analogues with increased antileishmanial activity, Bioorganic & Medicinal Chemistry, 14, 1538–1545.
13. [13] Konidala, S. K., Kotra, V., Reddy Danduga, R. C. S., Kola, P. K. (2020). Coumarin-chalcone hybrids targeting insulin receptor: Design, synthesis, anti-diabetic activity, and molecular docking, Bioorganic Chemistry, 104, 104207.
14. [14] Wang, Z. X., Gao, S., Ma, M., Ren, G., Liu, H., Chen, X. (2015). Synthesis and antifungal activity of chalcone derivatives, Nat. Prod. Res., 29, 1804-10.
15. [15] Mohan, S., Hobani, Y. H., Shaheen, E., Abou Elhamd, A. S., Abdelhaleem, A., Alhazmi, H. A., Abdelwahab, S. I. (2020). Ameliorative effect of Boesenbergin A, a chalcone isolated from Boesenbergia rotunda (Fingerroot) on oxidative stress and inflammation in ethanol-induced gastric ulcer in vivo, Journal of Ethnopharmacology, 261, 113104.
16. [16] Ahmad, I., Thakur, J. P., Chanda, D., Saikia, D., Khan, F., Dixit, S., Kumar, A., Konwar, R., Negi, A. S., Gupta, A. (2013). Syntheses of lipophilic chalcones and their conformationally restricted analogues as antitubercular agents, Bioorg. Med. Chem. Lett., 23, 1322.
17. [17] Chen, Y.H., Wang, W.H., Wang, Y.H., Lin, Z.Y., Wen, C.C., Chern, C.Y. (2013). Evaluation of the Anti-Inflammatory Effect of Chalcone and Chalcone Analogues in a Zebrafish Model, Molecules, 18 (2), 2052-2060.
18. [18] Zhuang, C., Zhang, W., Sheng, C., Zhang, W., Xing, C., Miao, Z. (2017). Chalcone: A Privileged Structure in Medicinal Chemistry, Chem. Rev., 117, 7762-7810.
19. [19] Tang, X., Su, S., Chen, M., He, J., Xia, R., Guo, T., Chen, Y., Zhang, C., Wang, J., Xue, W. (2019). Novel chalcone derivatives containing a 1,2,4-triazine moiety: design, synthesis, antibacterial and antiviral activities, RSC Adv., 9, 6011.
20. [20] Hanack, M., Schneider, T., Barthel, M., Shirk, J. S., Pong, R. G. S. (2001). Indium phthalocyanines and naphthalocyanines for optical limiting, Coord. Chem. Rev., 219-221, 235-258.
21. [21] Özenc, F., Günel, A., Barana, A. (2018). DNA-binding, enzyme inhibition, andphotochemical properties of chalcone containing metallophthalocyanine compounds, Bioorganic Chemistry, 81, 71-78.
22. [22] Riquelme, J., Neira, K., Marco, J. F., Hermosilla-Ibáñez, P., Orellana, W., Zagal, J. H., Tasca, F. (2018). Biomimicking vitamin B12. A Co phthalocyanine pyridine axial ligand coordinated catalyst for the oxygen reduction reaction, Electrochim Acta, 265, 547-555.
23. [23] Azimi, F., Marjani, A. P., Keshipour, S. (2021). Fe(II)‑phthalocyanine supported on chitosan aerogel as a catalyst for oxidation of alcohols and alkyl arenes, Scientific Reports, 11, 23769.
24. [24] Aktas Kamiloglu, A., Karaca, H., Celik, G., Acar, I., Kantekin, H. (2020). New chalcone-substituted metallophthalocyanines: Synthesis, characterization, and investigation of their properties, Journal of Chemical Research, 44 (7,8), 367-375.
25. [25] Orman, E. B., Pişkin, M., Odabaş, Z., Özkaya, A. R. (2021). Electrochemical, Spectroelectrochemical, and Electrocatalytic Dioxygen Reducing Properties of Peripheral Tetra-2,6-dimethoxyphenoxy Substituted Phthalocyanines, Electroanalysis, 33, 2310- 2322.
26. [26] Bayrak, R., Kırlangıç Ata, S., Yılmaz, I., Yalçın, I., Erman, M., Ünver, Y., Degirmencioglu, I. (2021). Synthesis and Spectro-Electrochemical Properties of New Metallophthalocyanines Having High Electron Transfer Capability, Journal of Molecular Structure, 1231, 129677.
27. [27] Shalini, S., Balasundara Prabhu, R., Prasanna, S., Mallick, T. K., Senthilarasu, S. (2015). Review on natural dye sensitized solar cells: operation, materials and methods, Renew Sustain Energy Rev., 51, 1306-1325.
28. [28] Palacin, S. (2000). Phthalocyanines in Langmuir and Langmuir-Blodgett films: from molecular design to supramolecular architecture, Adv. Colloid Interface Sci., 87, 165-181.
29. [29] Banasz, R., Wałęsa-Chora, M. (2019). Polymeric complexes of transition metal ions as electrochromic materials: Synthesis and properties, Coord. Chem. Rev., 389, 1-18.
30. [30] Sen, P., Managa, M., Nyokong, T. (2019). New type of metal-free and Zinc(II), In(III), Ga(III) phthalocyanines carrying biologically active substituents: Synthesis and photophysicochemical properties and photodynamic therapy activity, Inorg Chim Acta, 491, 1-8.
31. [31] Koca, A., Kalkan, A., Bayır, Z. A. (2011). Electrocatalytic oxygen reduction and hydrogen evolution reactions on phthalocyanine modified electrodes: Electrochemical, in situ spectroelectrochemical, and in situ electrocolorimetric monitoring, Electrochim Acta, 56, 5513-5525.
32. [32] Aktas Kamiloglu, A., Direkel, S., Yalazan, H., Kantekin, H., Acar, I. (2020). Octa- and tetra-substituted phthalocyanines with methoxyeugenol group: Synthesis, characterization and in vitro antimicrobial activity, Journal of Coordination Chemistry, 73 (7), 1177-1190.
33. [33] Klyamer, D. D., Basova, T. V., Krasnov, P. O., Sukhikh, A. S. (2019). Effect of fluorosubstitution and central metals on the molecular structure and vibrational spectra of metal phthalocyanines, J. Mol. Struct., 1189, 73-80.
34. [34] Erbahar, D. D., Harbeck, M., Gümüş, G., Gürol, I., Ahsen, V. (2014). Self-assembly of phthalocyanines on quartz crystal microbalances for QCM liquid sensing applications, Sensors Actuators B: Chem., 190, 651-656.
35. [35] Ağırtaş, M. S., Cabir, B., Gonca, S., Ozdemir, S. (2021). Antioxidant, Antimicrobial, DNA Cleavage, Fluorescence Properties and Synthesis of 4- (3,4,5- Trimethoxybenzyloxy) Phenoxy) Substituted Zinc, Phthalocyanine Polycyclic Aromatic Compounds, DOI: 10.1080/10406638.2021.1922469.
36. [36] Aktaş Kamiloğlu, A., Yalazan, H., Durmuş, M., Çelik, G., Ömeroğlu, İ., Acar, İ., Kantekin, H. (2021). Synthesis, spectroscopic, and photophysicochemical behavior of Zn(II) and Mg(II) phthalocyanine– chalcone conjugates, Journal of Coordination Chemistry, 74(15), 2491-2507.
37. [37] Aktas Kamiloğlu, A., Ömeroğlu, İ., Yalazan, H., Durmuş, M., Çelik, G., Kantekin, H. (2022). Photophysical, Photochemical Properties of Chalcone Substituted Zinc(II) and Magnesium(II) Metallophthalocyanines Bearing Thiophene Units, Journal of Inclusion Phenomena and Macrocyclic Chemistry, DOİ: 10.1007/s10847-022-01152-3
38. [38] Aktaş Kamiloğlu, A. (2021). Photochemical properties of fluoro-chalcone substituted peripherally tetra Zn(II)Pc and Mg(II)Pc, Journal of Inclusion Phenomena and Macrocyclic Chemistry, 99(3), 185-196.