Synthesis, characterization, and inhibitory properties of novel N-benzylbenzimidazole-silver(I) complexes on carbonic anhydrase and polyphenol oxidase enzymes

Öz

The biological properties of silver complexes are well known but the studies about the enzyme inhibitory properties of them are very rare. On the other hand, it is known that one of the anticancer mechanisms of action of benzimidazole derivatives is enzyme inhibition. Therefore, in this study, five novel N-benzylbenzimidazole-silver(I) complexes were synthesized and fully characterized by 1H NMR, 13C NMR, IR, mass spectroscopic methods and elemental analyses. The inhibitory properties of the synthesized complexes were tested on the activity of human carbonic anhydrase I - II and polyphenol oxidase, and it was observed that the complexes inhibited the activity of these enzymes with the IC50 values of 29.58-32.65 µM, 21.05-23.65 µM and 30.38-44.45 µM, respectively. We suggest that by also considering the low toxicity of silver compounds to human body at low concentrations, the evaluated complexes in this study are promising agents in the treatment of glaucoma and hyperpigmentation as carbonic anhydrase and polyphenol oxidase inhibitors.

Anahtar Kelimeler

• benzimidazole
• silver
• carbonic anhydrase
• polyphenol oxidase

Yeni N-benzilbenzimidazol-gümüş(I) komplekslerinin sentezi, karakterizasyonu, karbonik anhidraz ve polifenol oksidaz enzimleri üzerindeki inhibitör özellikleri

Öz

Gümüş komplekslerinin biyolojik özellikleri çok iyi bilinmesine rağmen enzim inhibisyonu özelliklerine yönelik çalışmalar oldukça sınırlıdır. Diğer taraftan benzimidazol türevlerinin anti-kanser etki mekanizmalarından birinin enzim inhibisyonu olduğu bilinmektedir. Bu nedenle bu çalışmada, beş yeni N-benzilbenzimidazol-gümüş(I) kompleksi sentezlendi, 1H NMR, 13C NMR, IR ve kütle spektroskopik yöntemleri ve elementel analiz sonuçları ile tamamen karakterize edildi. Elde edilen komplekslerin insan karbonik anhidraz I - II ve polifenol oksidaz enzimleri üzerindeki inhibisyon etkileri incelendi ve komplekslerin bu enzimlerin aktivitelerini sırasıyla 29.58-32.65 µM, 21.05-23.65 µM ve 30.38-44.45 µM’lık IC50 değerleri ile inhibe ettiği gözlendi. Gümüş bileşiklerinin insan vücudunda düşük konsantrasyonlarda toksik etki göstermediği de göz önüne alınırsa, bu çalışmada test edilen kompleksler karbonik anhidraz inhibitörü olarak glokom tedavisinde ve polifenol oksidaz inhibitörü olarak ise hiper-pigmentasyon hastalığı tedavisinde kullanılmak için umut verici adaylardır.      

Anahtar Kelimeler

• Benzimidazol
• gümüş
• karbonik anhidraz
• polifenol oksidaz

Kaynakça

1. Aggarwal M, Kondeti B, McKenna R, 2013. Anticonvulsant/antiepileptic carbonic anhydrase inhibitors: a patent review. Expert Opinion on Therapeutic Patents, 23: 717-724.
2. Armstrong JMcD, Myers DV, Verpoorte JA, Edsall JT, 1966. Purification and properties of human erythrocyte carbonic anhydrases. Journal of Biological Chemistry, 241(21): 5137-5149.
3. Arslan O, 1994. Glaukoma Tedavisinde Kullanılmaya Aday Karbonik Anhidraz İnhibitörlerinin Sentezi ve İnhibisyon Etkilerinin Araştırılması. Atatürk Üniversitesi Fen Bilimleri Enstitüsü, Doktora Tezi (Basılmış)
4. Arslan O, Erzengin M, Sinan S, Özensoy Ö, 2004. Purification of mulberry (Morus alba L.) polyphenol oxidase by affinity chromatography and investigation of its kinetic and electrophoretic properties. Food Chemistry, 88: 479-484.
5. Barker HA, Smyth RD, Weissbach H, Toohey JI, Ladd JN, Volcani BE, 1960. Isolation and properties of crystalline cobamide coenzymes containing benzimidazole or 5,6-dimethylbenzimidazole. Journal of Biological Chemistry, 235(2): 480-488.
6. Büyükkıdan N, Bülbül M, Kasımoğulları R, Büyükkıdan B, 2013. Synthesis and characterization of metal complexes of heterocyclic sulfonamide as carbonic anhydrase inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry, 28(2): 311-315.
7. Chang TS, 2009. An updated review of tyrosinase inhibitors. International Journal of Molecular Sciences, 10:2440-2475.
8. Elie CR, David G, Schmitzer AR, 2015. Strong antibacterial properties of anion transporters: A result of depolarization and weakening of the bacterial membrane. Journal of Medicinal Chemistry, 58(5): 2358-2366.

9. Gaba M, Mohan C, 2016. Development of drugs based on imidazole and benzimidazole bioactive heterocycles: recent advances and future directions. Medicinal Chemistry Research, 25: 173-210.
10. Herrmann WA, 2002. N-Heterocyclic carbenes: A new concept in organometallic catalysis. Angewandte Chemie International Edition, 41(8): 1290-1309.
11. Hindi KM, Panzner MJ, Tessier CA, Cannon CL, Youngs WJ, 2009. The medicinal applications of imidazolium carbene metal complexes. Chemical Reviews, 109:3859-3884.
12. Kandel M, Gornall AG, Wong SCC, Kandel SI, 1970. Some characteristics of human, bovine and horse carbonic anhydrases as revealed by inactivation studies. Journal of Biological Chemistry, 245(9): 2444-2450.
13. Karataş MO, Alıcı B, Çakır Ü, Çetinkaya E, Demir D, Ergün A, Gençer N, Arslan O, 2013. Synthesis and carbonic anhydrase inhibitory properties of coumarin derivatives. Journal of Enzyme Inhibition and Medicinal Chemistry, 28(2):299-304.
14. Karataş MO, Alıcı B, Çetinkaya E, Bilen Ç, Gençer N, Arslan O, 2014. Synthesis, characterization and tyrosinase inhibitory properties of benzimidazole derivatives. Russian Journal of Bioorganic Chemistry, 40(4):461-466.
15. Karlık Ö, Balcıoğlu S, Karataş MO, Ateş B, Alıcı B, Özdemir N, 2018. Synthesis, structural characterization and cytotoxicity studies of T-shaped silver(I) complexes derived from 1-benzyl-3H-benzimidazolium p-toluenesulfonates. Polyhedron, 142:63-70.
16. Klasen HJ, 2000. Historical review of the use of silver in the treatment of burns. I. Early uses. Burns, 26: 117-130.
17. Liu LX, Wang XQ, Zhou B, Yang LJ, Li Y, Zhang HB, Yang XD, 2015. Synthesis and antitumour activity of novel N-substituted carbazole imidazolium salt derivatives. Scientific Reports, 5:13101-13120.
18. Medici S, Peana M, Crisponi G, Nurchi VM, Lachowicz JI, Remelli M, Zoroddu MA, 2016. Silver coordination compounds: A new horizon in medicine. Coordination Chemistry Reviews, 327-328: 349-359.
19. Monti BM, Supuran CT, De Simone G, 2013. Anticancer carbonic anhydrase inhibitors: a patent review (2008-2013). Expert Opinion on Therapeutic Patents, 23: 737-749.
20. Oehninger L, Rubbiani R, Ott I, 2013. N-Heterocyclic carbene metal complexes in medicinal chemistry. Dalton Transactions, 42: 3269-3284.
21. Özdemir İ, Şahin N, Gök Y, Demir S, Çetinkaya B, 2005. In situ generated 1-alkylbenzimidazole-palladium catalyst fort he Suzuki coupling of aryl chlorides. Journal of Molecular Catalysis A. Chemical, 234: 181-185.
22. Özdemir UO, Özbek N, Genç ZK, İlbiz F, Gündüzalp AB, 2017. New bioactive silver(I) complexes: Synthesis, characterization, anticancer, antibacterial and anticarbonic anhydrase II activities. Journal of MolecularStructure, 1138:55-63.
23. Scozzafava A, Supuran CT, Carta F, 2013. Antiobesity carbonic anhydrase inhibitors: a literature and patent review. Expert Opinion on Therapeutic Patents, 23: 725-735.
24. Singla P, Luxami V, Paul K, 2014. Benzimidazole-biologically attractive scaffold for protein kinase inhibitors. RSC Advances, 4: 12422-12440.
25. Supuran CT, 2010. Carbonic anhydrase inhibitors. Bioorganic and Medicinal Chemistry Letters, 20: 3467-3474.
26. Wu H, Yuan J, Bai Y, Pan G, Wang H, Kong J, Fan X, Liu H, 2012. Synthesis, structure, DNA-binding properties and antioxidant activity of silver(I) complexes containing V-shaped bis-benzimidazole ligands. Dalton Transactions, 41:8829-8838.
27. Wu H, Zhang Y, Chen C, Zhang J, Bai Y, Shi F, Wang X, 2014. DNA binding studies and antioxidant activities of two-, three- and four-coordinate silver(I) complexes containing bis(2-benzimidazolyl)aniline derivatives. New Journal of Chemistry, 38: 3688-3698.
28. Yadav G, Ganguly S, 2015. Structure activity relationship (SAR) study of benzimidazole scaffold for different biological activities: A mini-review. European Journal of Medicinal Chemistry, 97:419-443.