Derya OSMANİYE, Yusuf ÖZKAY

Synthesis and Characterization of New Compounds Including Propargyl Side Chain as Potential MAO-B Inhibitor

In this study, some new propargyl derivatives were synthesized considering potential monoamine oxidase-B (MAO-B) inhibition potency of propargyl moiety. In synthesis studies, 2-chlorobenzimidazole was reacted with propargyl bromide in the presence of NaH and compound 1 was obtained. Compound 1 was treated with various benzylamine derivatives and final products (2a-2c) were gained. Structures of obtained compounds were established by spectroscopic methods. Effects of the synthesized compounds against MAO enzymes were observed by using in-vitro fluorimetric method. Activity studies revealed that synthesis compounds inhibited MAO enzymes to different extends..

Potansiyel MAO-B İnhibitörü Olarak Propargil Yan Zinciri İçeren Yeni Bileşiklerin Sentezi ve Karakterizasyonu

Bu çalışma kapsamında, propargil grubunun Monoaminoksidaz-B (MAO-B) enzimi üzerindeki potansiyel inhibitör etkinliği dikkate alınarak bazı yeni propargil grubu içeren bileşikler sentezlenmiştir. Sentez çalışmalarında, 2- klorobenzimidazol NaH varlığında propargil bromür ile reaksiyona sokulmuş bileşik 1 elde edilmiştir. Bileşik 1 çeşitli benzilamin türevleri ile potasyum karbonat katalizörlüğünde muamele edilerek sonuç ürünlerine (2a-2c) ulaşılmıştır. Elde edilen bileşiklerin yapıları 1HNMR ve 13C-NMR ve HRMS spektroskopik yöntemleri ile doğrulanmıştır. Sentezlenen bileşiklerin MAO enzimleri üzerindeki etkileri in-vitro şartlarda florimetrik yöntem kullanılarak araştırılmıştır. Yapılan aktivite çalışmaları sonucunda sentezlenen bileşiklerin MAO enzimlerini değişen düzeylerde inhibe ettiği tespit edilmiştir.

PDF

___

[1] Zindo, F. T., Malan, S. F., Omoruyi, S. I., Enogieru, A. B., Ekpo, O. E., Joubert, J. (2019). Design, synthesis and evaluation of pentacycloundecane and hexacycloundecane propargylamine derivatives as multifunctional neuroprotective agents. European journal of medicinal chemistry, 163, 83-94.
[2] Kumar, B., Kumar, V., Prashar, V., Saini, S., Dwivedi, A. R., Bajaj, B., Mehta, D., Parkash, J., Kumar, V. (2019). Dipropargyl substituted diphenylpyrimidines as dual inhibitors of monoamine oxidase and acetylcholinesterase. European journal of medicinal chemistry, 177, 221-234.
[3] Sasidharan, R., Baek, S. C., Leelabaiamma, M. S., Kim, H., Mathew, B. (2018). Imidazole bearing chalcones as a new class of monoamine oxidase inhibitors. Biomedicine & Pharmacotherapy, 106, 8-13.
[4] Szökő, É., Tábi, T., Riederer, P., Vécsei, L., Magyar, K. (2018). Pharmacological aspects of the neuroprotective effects of irreversible MAO-B inhibitors, selegiline and rasagiline, in Parkinson’s disease. Journal of Neural Transmission, 125(11), 1735-1749.
[5] Zhou, S., Chen, G., & Huang, G. (2018). Design, synthesis and biological evaluation of lazabemide derivatives as inhibitors of monoamine oxidase. Bioorganic & medicinal chemistry, 26(17), 4863-4870.
[6] Finberg, J. P. (2019). Inhibitors of MAO-B and COMT: Their effects on brain dopamine levels and uses in Parkinson’s disease. Journal of Neural Transmission, 126(4), 433-448.
[7] Kumar, B., Kumar, M., Dwivedi, A. R., Kumar, V. (2018). Synthesis, Biological Evaluation and Molecular Modeling Studies of Propargyl‐Containing 2, 4, 6‐Trisubstituted Pyrimidine Derivatives as Potential Anti‐Parkinson Agents. ChemMedChem, 13(7), 705-712.
[8] Mathew, B., Parambi, D. G., Mathew, G. E., Uddin, M. S., Inasu, S. T., Kim, H., Marathakam, A., Unnikrishnan, M., Carradori, S. (2019). Emerging therapeutic potentials of dual‐acting MAO and ACh inhibitors in Alzheimer's and Parkinson's diseases. Archiv der Pharmazie, 352(11), 1900177.
[9] Tripathi, R. K. P., Ayyannan, S. R. (2019). Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update. Medicinal research reviews, 39(5), 1603-1706.
[10] Cakmur, R. (2011). Parkinson hastalığı ve medikal tedavisi. Klinik Gelişim, 53-58.
[11] Demirkiran, M., Jankovic, J. (1995). Paroxysmal dyskinesias: clinical features and classification. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society, 38(4), 571-579.
[12] Uzbay, T. (2007). Nöropsikofarmakoloji: Rasyonel ilaç kullanımı. Medikal Yayıncılık, İstanbul, 110-115.
[13] Kayaalp, O. (2005). Rasyonel Tedavi Yönünden Tıbbi Farmakoloji. Hacettepe Taş Yayınları, Ankara, 913-918.
[14] Mancuso, R., Veltri, L., Russo, P., Grasso, G., Cuocci, C., Romeo, R., Gabriele, B. (2018). Palladiumcatalyzed carbonylative synthesis of functionalized benzimidazopyrimidinones. Synthesis, 50(02), 267-277.
[15] Can, Ö. D., Osmaniye, D., Özkay, Ü. D., Sağlık, B. N., Levent, S., Ilgın, S., Baysal, M., Özkay, Y., Kaplancıklı, Z. A. (2017). MAO enzymes inhibitory activity of new benzimidazole derivatives including hydrazone and propargyl side chains. European journal of medicinal chemistry, 131, 92-106.
[16] Can, N. Ö., Osmaniye, D., Levent, S., Sağlık, B. N., Korkut, B., Atlı, Ö., Özkay, Y., Kaplancıklı, Z. A. (2018). Design, synthesis and biological assessment of new thiazolylhydrazine derivatives as selective and reversible hMAO-A inhibitors. European journal of medicinal chemistry, 144, 68-81.
[17] Ilgın, S., Osmaniye, D., Levent, S., Sağlık, B. N., Acar Çevik, U., Çavuşoğlu, B. K., Özkay, Y., Kaplancıklı, Z. A. (2017). Design and synthesis of new benzothiazole compounds as selective hMAO-B inhibitors. Molecules, 22(12), 2187.
[18] Sağlık, B. N., Çavuşoğlu, B. K., Osmaniye, D., Levent, S., Çevik, U. A., Ilgın, S., Özkay, Y., Kaplancıklı, Z.A., Öztürk, Y. (2019). In vitro and in silico evaluation of new thiazole compounds as monoamine oxidase inhibitors. Bioorganic chemistry, 85, 97-108.
[19] Youdim, M. B., Gross, A., & Finberg, J. P. (2001). Rasagiline [N‐propargyl‐1R (+)‐aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B. British journal of pharmacology, 132(2), 500-506.
[20] Knudsen Gerber, D. (2011). Selegiline and rasagiline: twins or distant cousins? Guidelines. The Consultant Pharmacist®, 26(1), 48-51.
[21] Chioua, M., González‐Camuñas, A., Catarozzo, M. T., Alcaro, S., Ortuso, F., Yáñez, M., Marco‐Contelles, J. (2019). Synthesis, Monoamine Oxidase Inhibition and Computational Analysis of Diversely Substituted N‐Propargylated‐1, 3, 5‐triazines. ChemistrySelect, 4(28), 8334-8337.
[22] Knez, D., Colettis, N., Iacovino, L. G., Sova, M., Pislar, A., Konc, J., Lesnik, S., Higgs, J., Kamecki, F., Mangialavori, I., Dolsak, A., Zakelj, S., Tronteli, J., Kos, J., Binda, C., Marder, M., Dolsak, A. (2020). Stereoselective Activity of 1-Propargyl-4-styrylpiperidine-like Analogues That Can Discriminate between Monoamine Oxidase Isoforms A and B. Journal of Medicinal Chemistry, 63(3), 1361-1387.
23] Kumar, B., Kumar, M., Dwivedi, A. R., Kumar, V. (2018). Synthesis, Biological Evaluation and Molecular Modeling Studies of Propargyl‐Containing 2, 4, 6‐Trisubstituted Pyrimidine Derivatives as Potential Anti‐Parkinson Agents. ChemMedChem, 13(7), 705-712.
[24] Nag, S., Kettschau, G., Heinrich, T., Varrone, A., Lehmann, L., Gulyas, B., Thiele, A., Keller, E., Halldin, C. (2013). Synthesis and biological evaluation of novel propargyl amines as potential fluorine-18 labeled radioligands for detection of MAO-B activity. Bioorganic & medicinal chemistry, 21(1), 186-195.