İMİDAZOLİNON BAZLI SÜLFONAMİD TÜREVLERİ: SENTEZ, KARAKTERİZASYON VE BAZI METABOLİK ENZİMLERE KARŞI İNHİBİTÖR ÖZELLİKLERİ

Yıl 2023, Cilt: 47 Sayı: 3, 915 - 926, 20.09.2023

Mehtap Tuğrak Sakarya , Halise İnci Gül , Cem Yamalı , Yeliz Demir , İlhami Gülçin

https://doi.org/10.33483/jfpau.1311157

Öz

Amaç: Çalışmanın amacı, güçlü ve seçici enzim inhibitörleri olarak imidazolinon bazlı sülfonamid türevlerinin yeni sentetik bileşiklerini araştırmaktır. Sentezlenen bir dizi bileşik ve bunların asetilkolin esteraz (AChE) ve insan (h) karbonik anhidraz (CA) izoformları I ve II'ye karşı inhibe edici etkileri araştırılmıştır.
Gereç ve Yöntem: Bileşiklerin yapısı HRMS, 1H ve 13C NMR ile doğrulanmıştır. Bileşiklerin farmakolojik potansiyeli, in vitro enzim bazlı analizler ile belirlenmiştir.
Sonuç ve Tartışma: Bu çalışmada, imidazolinon bazlı sülfonamit bileşikleri serisi 4-(2,4-dimetoksibenziliden)-2-feniloksazol-5(4H)-on, sodyum asetat, buzlu asetik asit ve sulfaguanidin (3), sulfanilamid (4), sulfadiazin (5) gibi uygun sülfonamid türevlerinden hareketle sentezlendi. Bu bileşikler, asetilkolin esteraz (AChE) ve insan (h) karbonik anhidraz (CA) izoformları I ve II'ye karşı güçlü inhibe edici etki gösterdi. Bileşik 4 (Ki= 19.53±1.23 nM), hCA I'e karşı güçlü ve seçici bir inhibitör iken, bileşik 3'ün (Ki=16.49±2.20 nM) hCA II'ye karşı güçlü inhibitör olduğu bulundu. 11.68±1.45 nM Ki'ye sahip bileşik 5, AChE enzimine karşı güçlü bir inhibitör etki gösterdi. İmidazolinon bazlı sülfonamidler, seçici CA inhibitörleri ve anti-Alzheimer bileşiklerinin tasarımında ileriki çalışmalarda kullanılabilirler.

Anahtar Kelimeler

İmidazolin, sentez, asetilkolinesteraz, karbonik anhidraz, Alzheimer hastalığı

IMIDAZOLINONE-BASED SULFONAMIDE DERIVATIVES: SYNTHESIS, CHARACTERIZATION, AND INHIBITORY PROPERTY AGAINST SOME METABOLIC ENZYMES

Öz

Objective: The purpose of the work was to investigate new synthetic compounds of imidazolinone-based sulfonamide derivatives as potent and selective enyzme inhibitors. A number of compounds synthesized and their inhibitory action against acetylcholine esterase (AChE), and human (h) carbonic anhydrase (CA) isoforms I and II were investigated.
Material and Method: The identity of the compounds has been confirmed by HRMS, 1H NMR, and 13C NMR. The pharmacological potential of the compounds has been determined by in vitro enzyme-based assays.
Result and Discussion: In this study, a series of imidazolinone-based sulfonamide derivatives were synthesized from 4-(2,4-dimethoxybenzylidene)-2-phenyloxazol-5(4H)-one, sodium acetate, glacial acetic acid, and suitable sulfonamide derivatives such as sulfaguanidine (3), sulfanilamide (4), sulfadiazine (5). These compounds showed potent inhibitory action against acetylcholine esterase (AChE), and human (h) carbonic anhydrase (CA) isoforms I and II. Compound 4 (Ki=19.53±1.23 nM) was a potent and selective inhibitor against hCA I while compound 3 (Ki=16.49±2.20 nM) was found to be potent inhibitor against hCA II. Compound 5 with Ki of 11.68±1.45 nM showed a potent inhibitory effect against the AChE enzyme. Imidazolinone-based sulfonamides can be used in the design of selective CAs inhibitors and anti-Alzheimer's compounds for further studies.

Anahtar Kelimeler

İmidazolinone, synthesis, acetylcholinesterase, carbonic anhydrase, Alzheimer’s disease

Kaynakça

• 1. Heravi, M.M., Zadsirjan, V. (2020). Prescribed drugs containing nitrogen heterocycles: An overview. RSC Advances, 10 (72), 44247-44311. [CrossRef]
• 2. Jampilek, J. (2019). Heterocycles in medicinal chemistry. Molecules, 24 (21). [CrossRef]
• 3. Fang, W.Y., Ravindar, L., Rakesh, K.P., Manukumar, H.M., Shantharam, C.S., Alharbi, N.S., Qin, H.L. (2019). Synthetic approaches and pharmaceutical applications of chloro-containing molecules for drug discovery: A critical review. European Journal of Medicinal Chemistry, 173, 117-153. [CrossRef]
• 4. Kerru, N., Singh-Pillay, A., Awolade, P., Singh, P. (2018) Current anti-diabetic agents and their molecular targets: A review. European Journal of Medicinal Chemistry, 152, 436-488. [CrossRef]
• 5. Smith, B.R., Eastman, C.M., Njardarson, J.T. (2014). Beyond C, H, O, and N! Analysis of the elemental composition of U.S. FDA approved drug architectures. Journal of Medicinal Chemistry, 57(23), 9764-9773. [CrossRef]
• 6. Li, X., He, L., Chen, H., Wu, W., Jiang, H. (2013). Copper-catalyzed aerobic C(sp2)-H functionalization for C-N bond formation: Synthesis of pyrazoles and indazoles. The Journal of Organic Chemistry, 78(8), 3636-3646. [CrossRef]
• 7. Santos, C.M.M., Freitas, M., Fernandes, E. (2018). A comprehensive review on xanthone derivatives as alpha-glucosidase inhibitors. European Journal of Medicinal Chemistry, 157(5), 1460-1479. [CrossRef]
• 8. Kerru, N., Singh, P., Koorbanally, N., Raj, R., Kumar, V. (2017). Recent advances (2015-2016) in anticancer hybrids. European Journal of Medicinal Chemistry, 142, 179-212. [CrossRef]
• 9. Eftekhari-Sis, B., Zirak, M., Akbari, A. (2013). Arylglyoxals in synthesis of heterocyclic compounds. Chemical Reviews, 113(5), 2958-3043. [CrossRef]
• 10. Ju, Y., Varma, R.S. (2006). Aqueous N-heterocyclization of primary amines and hydrazines with dihalides: microwave-assisted syntheses of N-azacycloalkanes, isoindole, pyrazole, pyrazolidine, and phthalazine derivatives. The Journal of Organic Chemistry, 71(1), 135-141. [CrossRef]
• 11. Leeson, P.D., Springthorpe, B. (2007). The influence of drug-like concepts on decision-making in medicinal chemistry. Nature Reviews. Drug Discovery, 6(11), 881-890. [CrossRef]
• 12. Sivakumar, B., Ilango, K. (2023). 5-Imidazolinone derivatives as a potent pharmacological agents-a review. Russian Journal of Bioorganic Chemistry, 49(2), 167-179. [CrossRef]
• 13. Almirante, L., Mugnaini, A., Rugarli, P., Gamba, A., Zefelippo, E.N., De Toma, N., Murmann, W. (1969). Derivatives of imidazole. III. Synthesis and pharmacological activites of nitriles, amides, and carboxylic acid derivatives of imidazo[1,2-alpha]pyridine. Journal of Medicinal Chemistry, 12(1), 122-126. [CrossRef]
• 14. Godefroi, E.F., Platje, J.T. (1972). DL-1-(alpha-methylbenzyl)-2-methylimidazole-5-carboxylate esters. Synthesis and pharmacological properties. Journal of Medicinal Chemistry, 15(3), 336-337. [CrossRef]
• 15. Kagthara, P.R., Shah, N.S., Doshi, R.K., Parekh, H.H. (1998). Synthesis of some arylamides, sulphonamides and 5-oxo-imidazolines as novel bioactive compounds derived from benzimidazole. Heterocyclic Communication, 4(6), 561-566. [CrossRef]
• 16. Haseena Banu, B., Bharathi, K., Prasad, K.V.S.R.G. (2012). Synthesis and evaluation of imidazolidine: containing dipeptide derivatives. Journal of Pharmacy Research, 5(3), 1297-1299.
• 17. Georgey, H.H., Manhi, F.M., Mahmoud, W.R., Mohamed, N.A., Berrino, E., Supuran, C.T. (2019). 1,2,4-Trisubstituted imidazolinones with dual carbonic anhydrase and p38 mitogen-activated protein kinase inhibitory activity. Bioorganic Chemistry, 82, 109-116. [CrossRef]
• 18. Qadir, M.A., Ahmed, M., Aslam, H., Waseem, S., Imtiaz Shafiq, S. (2015). Amidine sulfonamides and benzene sulfonamides: Synthesis and their biological evaluation. Journal of Chemistry, 2015, 1-8. [CrossRef]
• 19. Gadad, A.K., Mahajanshetti, C.S., Nimbalkar, S., Raichurkar, A. (2000). Synthesis and antibacterial activity of some 5-guanylhydrazone/thiocyanato-6-arylimidazo[2,1-b]-1,3,4-thiadiazole-2-sulfonamide derivatives. European Journal of Medicinal Chemistry, 35(9), 853-857. [CrossRef]
• 20. Maren, T.H. (1976). Relatons between structure and biological activity of sulfonamides. Annual Review of Pharmacology and Toxicology, 16, 309-327. [CrossRef]
• 21. Supuran, C.T., Scozzafava, A., Jurca, B.C., Ilies, M.A. (1998). Carbonic anhydrase inhibitors-Part 49: Synthesis of substituted ureido and thioureido derivatives of aromatic/heterocyclic sulfonamides with increased affinities for isozyme I. European Journal of Medicinal Chemistry, 33(2), 83-93. [CrossRef]
• 22. Renzi, G., Scozzafava, A., Supuran, C.T. (2000). Carbonic anhydrase inhibitors: Topical sulfonamide antiglaucoma agents incorporating secondary amine moieties. Bioorganic and Medicinal Chemistry Letters, 10(7), 673-676. [CrossRef]
• 23. Li, J.J., Anderson, G.D., Burton, E.G., Cogburn, J.N., Collins, J.T., Garland, D.J., Gregory, S.A., Huang, H.C., Isakson, P.C., Koboldt, C.M., Logusch, E.W., Norton, M.B., Perkins, W.E., Reinhard, E.J., Seibert, K., Veenhuizen, A.W., Zhang, Y., Reitz, D.B. (1995). 1,2-Diarylcyclopentenes as selective cyclooxygenase-2 inhibitors and orally active anti-inflammatory agents. Journal of Medicinal Chemistry, 38(22), 4570-4578. [CrossRef]
• 24. Yoshino, H., Ueda, N., Niijima, J., Sugumi, H., Kotake, Y., Koyanagi, N., Yoshimatsu, K., Asada, M., Watanabe, T., Nagasu, T., Tsukahara, K., Iijima, A., Kitoh, K. (1992). Novel sulfonamides as potential, systemically active antitumor agents. Journal of Medicinal Chemistry, 35(13), 2496-2497. [CrossRef]
• 25. Doungsoongnuen, S., Worachartcheewan, A., Pingaew, R., Suksrichavalit, T., Prachayasittikul, S., Ruchirawat, S., Prachayasittikul, V. (2011). Investigation on biological activities of anthranilic acid sulfonamide analogs. EXCLI Journal, 10, 155-161.
• 26. El-Sayed, N.S., El-Bendary, E.R., El-Ashry, S.M., El-Kerdawy, M.M. (2011). Synthesis and antitumor activity of new sulfonamide derivatives of thiadiazolo[3,2-a]pyrimidines. European Journal of Medicinal Chemistry, 46(9), 3714-3720. [CrossRef]
• 27. Tugrak, M., Gul, H.I., Demir, Y., Levent, S., Gulcin, I. (2021). Synthesis and in vitro carbonic anhydrases and acetylcholinesterase inhibitory activities of novel imidazolinone-based benzenesulfonamides. Archiv der Pharmazie, 354(4), e2000375. [CrossRef]
• 28. Gilmour, K.M. (2010). Perspectives on carbonic anhydrase. Comparative biochemistry and physiology. Part A, Molecular and Integrative Physiology, 157(3), 193-197. [CrossRef]
• 29. Angeli, A., Carta, F., Bartolucci, G., Supuran, C.T. (2017). Synthesis of novel acyl selenoureido benzensulfonamides as carbonic anhydrase I, II, VII and IX inhibitors. Bioorganic and Medicinal Chemistry, 25(13), 3567-3573. [CrossRef]
• 30. Aggarwal, M., Kondeti, B., McKenna, R. (2013). Insights towards sulfonamide drug specificity in alpha-carbonic anhydrases. Bioorganic and Medicinal Chemistry, 21(6), 1526-1533. [CrossRef]
• 31. Supuran, C.T. Structure-based drug discovery of carbonic anhydrase inhibitors. (2012). Journal of Enzyme Inhibition and Medicinal Chemistry, 27 (6), 759-772. [CrossRef]
• 32. Alterio, V., Di Fiore, A., D'Ambrosio, K., Supuran, C.T., 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), 4421-68. [CrossRef]
• 33. Masini, E., Carta, F., Scozzafava, A., Supuran, C.T. (2013). Antiglaucoma carbonic anhydrase inhibitors: A patent review. Expert Opinion on Therapeutic Patents, 23(6), 705-716. [CrossRef]
• 34. Carta, F., Supuran, C.T. (2013). Diuretics with carbonic anhydrase inhibitory action: A patent and literature review (2005-2013). Expert Opinion on Therapeutic Patents, 23(6), 681-691. [CrossRef]
• 35. Arechederra, R.L., Waheed, A., Sly, W.S., Supuran, C.T., Minteer, S.D. (2013). Effect of sulfonamides as carbonic anhydrase VA and VB inhibitors on mitochondrial metabolic energy conversion. Bioorganic and Medicinal Chemistry, 21(6), 1544-1548. [CrossRef]
• 36. Thiry, A., Dogne, J.M., Masereel, B., Supuran, C.T. (2006). Targeting tumor-associated carbonic anhydrase IX in cancer therapy. Trends in Pharmacological Sciences, 27(11), 566-573. [CrossRef]
• 37. Zhang, Z.P., Yin, Z.F., Li, J.Y., Wang, Z.P., Wu, Q.J., Wang, J., Liu, Y., Cheng, M.S. (2019). Synthesis, molecular docking analysis, and carbonic anhydrase inhibitory evaluations of benzenesulfonamide derivatives containing thiazolidinone. Molecules, 24(13), 2418-2429. [CrossRef]
• 38. Garibov, E., Taslimi, P., Sujayev, A., Bingol, Z., Cetinkaya, S., Gulcin, I., Beydemir, S., Farzaliyev, V., Alwasel, S.H., Supuran, C.T. (2016). Synthesis of 4,5-disubstituted-2-thioxo-1,2,3,4-tetrahydropyrimidines and investigation of their acetylcholinesterase, butyrylcholinesterase, carbonic anhydrase I/II inhibitory and antioxidant activities. Journal of Enzyme Inhibition and Medicinal Chemistry, 31(sup3), 1-9. [CrossRef]
• 39. Haider, A., Inam, W., Khan, S.A., Hifza., Mahmood, W., Abbas, G. (2016). Beta-glucan attenuated scopolamine induced cognitive impairment via hippocampal acetylcholinesterase inhibition in rats. Brain Research, 1644, 141-148. [CrossRef]
• 40. Gulcin, I., Beydemir, S., Buyukokuroglu, M.E. (2004). In vitro and in vivo effects of dantrolene on carbonic anhydrase enzyme activities. Biological and Pharmaceutical Bulletin, 27(5), 613-616. [CrossRef]
• 41. Işık, M., Demir, Y., Durgun, M., Türkeş, C., Necip, A., Beydemir, Ş. (2020). Molecular docking and investigation of 4‑(benzylideneamino)‑ and 4‑(benzylamino)‑benzenesulfonamide derivatives as potent AChE inhibitors. Chemical Papers, 74, 1395-1405. [CrossRef]
• 42. Saglik, B.N., Cevik, U.A., Osmaniye, D., Levent, S., Cavusoglu, B.K., Demir, Y., Ilgin, S., Ozkay, Y., Koparal, A.S., Beydemir, S., Kaplancikli, Z.A. (2019). Synthesis, molecular docking analysis and carbonic anhydrase I-II inhibitory evaluation of new sulfonamide derivatives. Bioorganic Chemistry, 91, 103153. [CrossRef]
• 43. Caglayan, C., Taslimi, P., Turk, C., Gulcin, I., Kandemir, F.M., Demir, Y., Beydemir, S. (2020). Inhibition effects of some pesticides and heavy metals on carbonic anhydrase enzyme activity purified from horse mackerel (Trachurus trachurus) gill tissues. Environmental Science and Pollution Research International, 27(10), 10607-10616. [CrossRef]
• 44. Caglayan, C., Taslimi, P., Demir, Y., Kucukler, S., Kandemir, F.M., Gulcin, I. (2019). The effects of zingerone against vancomycin-induced lung, liver, kidney and testis toxicity in rats: The behavior of some metabolic enzymes. Journal of Biochemical and Molecular Toxicology, 33(10), e22381. [CrossRef]
• 45. Osmaniye, D., Turkes, C., Demir, Y., Ozkay, Y., Beydemir, S., Kaplancikli, Z.A. (2022). Design, synthesis, and biological activity of novel dithiocarbamate-methylsulfonyl hybrids as carbonic anhydrase inhibitors. Archiv der Pharmazie, 355(8), e2200132. [CrossRef]
• 46. Turkan, F., Huyut, Z., Demir, Y., Ertas, F., Beydemir, S. (2019). The effects of some cephalosporins on acetylcholinesterase and glutathione S-transferase: An in vivo and in vitro study. Archives of Physiology and Biochemistry, 125(3), 235-243. [CrossRef]
• 47. Askin, S., Tahtaci, H., Turkes, C., Demir, Y., Ece, A., Akalin Ciftci, G., Beydemir, S. (2021). Design, synthesis, characterization, in vitro and in silico evaluation of novel imidazo[2,1-b][1,3,4]thiadiazoles as highly potent acetylcholinesterase and non-classical carbonic anhydrase inhibitors. Bioorganic Chemistry, 113, 105009. [CrossRef]
• 48. Gumus, M., Babacan, S.N., Demir, Y., Sert, Y., Koca, I., Gulcin, I. (2022). Discovery of sulfadrug-pyrrole conjugates as carbonic anhydrase and acetylcholinesterase inhibitors. Archiv der Pharmazie, 355(1), e2100242. [CrossRef]
• 49. Tugrak, M., Gul, H.I., Demir, Y., Gulcin, I. (2021). Synthesis of benzamide derivatives with thiourea-substituted benzenesulfonamides as carbonic anhydrase inhibitors. Archiv der Pharmazie, 354(2), e2000230. [CrossRef]
• 50. Sever, B., Turkes, C., Altintop, M.D., Demir, Y., Beydemir, S. (2020). Thiazolyl-pyrazoline derivatives: In vitro and in silico evaluation as potential acetylcholinesterase and carbonic anhydrase inhibitors. International Journal of Biological Macromolecules, 163, 1970-1988. [CrossRef]
• 51. Turkes, C., Demir, Y., Beydemir, S. (2022). Some calcium-channel blockers: Kinetic and in silico studies on paraoxonase-I. Journal of Biomolecular Structure and Dynamics, 40 (1), 77-85. [CrossRef]
• 52. Lipinski, C.A., Lombardo, F., Dominy, B.W., Feeney, P.J. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews, 46(1-3), 3-26. [CrossRef]
• 53. Daina, A., Michielin, O., Zoete, V. (2017). SwissADME: A free web tool to evaluate pharmacokinetics, drug likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, 7, 42717. [CrossRef]