Monoaminoksidaz İnhibitörü Olarak Propargil Yan Zinciri Taşıyan Yeni Şalkon Türevlerinin Sentezi, Karakterizasyonu ve Moleküler Modelleme Çalışmaları

Year 2022, Volume: 22 Issue: 2, 268 - 274, 30.04.2022

Derya Osmaniye Begüm Nurpelin Saglik

https://doi.org/10.35414/akufemubid.946219

Abstract

Monoamin oksidazlar (MAO), endojen ve ekzojen aminlerin oksidatif deaminasyonundan sorumlu enzim ailesidir. MAO-A ve MAO-B olarak isimlendirilen iki izoformdan oluşan MAO enzimi nörotransmiterlerin metabolizmasındaki rollerinden dolayı nöropsikiyatrik ve nörodejeneratif bozuklukların tedavisi için ilaçların geliştirilmesinde önemli hedeflerdir. Özellikle MAO-B inhibitörlerinin Parkinson hastalığı (PH) ve Alzheimer hastalığı (AH) gibi en sık görülen nörodejeneratif hastalıkların tedavisinde sıklıkla tercih edildiği bilinmektedir. Bu amaçla, bu çalışma kapsamında yeni propargil-şalkon türevleri sentezlenmiş ve yapı tayinleri 1H-NMR, 13C-NMR ve yüksek çözünürlüklü kütle spektroskopisi (HRMS) metotları kullanılarak aydınlatılmıştır. İn vitro aktivite testleri sonucunda elde edilen veriler 2c kodlu bileşiğin MAO-B inhibitörü olarak umut vaat edici olduğunu ortaya koymuştur. Gerçekleştirilen moleküler modelleme çalışmaları ile bileşik 2c’nin hMAO-B enzim aktif bölgesindeki bağlanma ve etkileşim noktaları belirlenmiştir.

Keywords

Monoaminoksidaz, Şalkon, Propargil, İn vitro enzim inhibisyonu, Moleküler docking

Synthesis, Characterization and Docking Studies of New Chalcone Derivatives Carrying Propargyl Side Chain as a Monoaminoxidase Inhibitor

Abstract

Monoamine oxidases (MAO) are a family of enzymes responsible for the oxidative deamination of endogenous and exogenous amines. The MAO enzyme, which consists of two isoforms named MAO-A and MAO-B, are important targets in the development of drugs for the treatment of neuropsychiatric and neurodegenerative disorders due to their role in the metabolism of neurotransmitters. It is known that MAO-B inhibitors are frequently preferred in the treatment of the most common neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). For this purpose, within the scope of this study, new propargyl-chalcone derivatives were synthesized and the structure determinations were elucidated using 1H-NMR, 13C-NMR and high-resolution mass spectroscopy (HRMS) methods. The data obtained as a result of in vitro activity tests showed that the compound 2c is promising as a selective MAO-B inhibitor. With the molecular modelling studies carried out, the binding and interaction points of the compound 2c in the hMAO-B enzyme active site were determined.

Keywords

Monoamineoxidase, Chalcone, Propargyl, In vitro enzyme inhibition, Molecular docking

References

• Binda, C., Wang, J., Pisani, L., Caccia, C., Carotti, A., Salvati, P., ... and Mattevi, A. 2007. Structures of human monoamine oxidase B complexes with selective noncovalent inhibitors: safinamide and coumarin analogs. Journal of medicinal chemistry, 50(23), 5848-5852.
• Can, Ö. D., Osmaniye, D., Özkay, Ü. D., Sağlık, B. N., Levent, S., Ilgın, S., Baysal, M., Özkay, Y. and 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.
• Can, N. Ö., Osmaniye, D., Levent, S., Sağlık, B. N., Korkut, B., Atlı, Ö., Özkay, Y. and Kaplancıklı, Z. A. 2018. Design, synthesis and biological assessment of new thiazolyl hydrazine derivatives as selective and reversible hMAO-A inhibitors. European journal of medicinal chemistry, 144, 68-81.
• Çeçen, M., Oh, J. M., Özdemir, Z., Büyüktuncel, S. E., Uysal, M., Abdelgawad, M. A., ... and Kim, H. 2020. Design, Synthesis, and Biological Evaluation of Pyridazinones Containing the (2-Fluorophenyl) Piperazine Moiety as Selective MAO-B Inhibitors. Molecules, 25(22), 5371.
• Distinto, S., Meleddu, R., Yanez, M., Cirilli, R., Bianco, G., Sanna, M. L., ... and Maccioni, E. 2016. Drug design, synthesis, in vitro and in silico evaluation of selective monoaminoxidase B inhibitors based on 3-acetyl-2-dichlorophenyl-5-aryl-2, 3-dihydro-1, 3, 4-oxadiazole chemical scaffold. European journal of medicinal chemistry, 108, 542-552.
• Glide, Version 7.1, Schrödinger, LLC: New York, NY, USA, 2016.
• Guglielmi, P., Mathew, B., Secci, D. and Carradori, S. 2020. Chalcones: Unearthing their therapeutic possibility as monoamine oxidase B inhibitors. European Journal of Medicinal Chemistry, 112650.
• Hammuda, A., Shalaby, R., Rovida, S., Edmondson, D. E., Binda, C. and Khalil, A. 2016. Design and synthesis of novel chalcones as potent selective monoamine oxidase-B inhibitors. European journal of medicinal chemistry, 114, 162-169.
• Ilgın, S., Osmaniye, D., Levent, S., Sağlık, B. N., Acar Çevik, U., Çavuşoğlu, B. K., Özkay, Y. and Kaplancıklı, Z. A. 2017. Design and synthesis of new benzothiazole compounds as selective hMAO-B inhibitors. Molecules, 22(12), 2187.
• Jismy, B., El Qami, A., Pišlar, A., Kos, J., Gobec, S., Knez, D. and Abarbri, M. 2021. Pyrimido [1, 2-b] indazole derivatives: Selective inhibitors of human monoamine oxidase B with neuroprotective activity. European Journal of Medicinal Chemistry, 209, 112911.
• Kumar, B., Kumar, V., Prashar, V., Saini, S., Dwivedi, A. R., Bajaj, B., ... and Kumar, V. 2019. Dipropargyl substituted diphenylpyrimidines as dual inhibitors of monoamine oxidase and acetylcholinesterase. European journal of medicinal chemistry, 177, 221-234.
• Lee, J., Lee, Y., Park, S. J., Lee, J., Kim, Y. S., Suh, Y. G., and Lee, J. 2017. Discovery of highly selective and potent monoamine oxidase B inhibitors: Contribution of additional phenyl rings introduced into 2-aryl-1, 3, 4-oxadiazin-5 (6H)-one. European journal of medicinal chemistry, 130, 365-378.
• LigPrep, Version 3.8, Schrödinger, LLC: New York, NY, USA, 2016.
• Maestro, Version 10.6, Schrödinger, LLC: New York, NY, USA, 2016.
• Mezeiova, E., Janockova, J., Andrys, R., Soukup, O., Kobrlova, T., Muckova, L., ... and Korabecny, J. 2021. 2-Propargylamino-naphthoquinone derivatives as multipotent agents for the treatment of Alzheimer’s disease. European Journal of Medicinal Chemistry, 211, 113112.
• Sağlık, B. N., Çavuşoğlu, B. K., Osmaniye, D., Levent, S., Çevik, U. A., Ilgın, S., Özkay, Y., Kaplancıklı, Z.A. and Öztürk, Y. 2019. In vitro and in silico evaluation of new thiazole compounds as monoamine oxidase inhibitors. Bioorganic chemistry, 85, 97-108.
• Sang, Z., Wang, K., Shi, J., Liu, W. and Tan, Z. 2019. Design, synthesis, in-silico and biological evaluation of novel chalcone-O-carbamate derivatives as multifunctional agents for the treatment of Alzheimer's disease. European journal of medicinal chemistry, 178, 726-739.
• Sang, Z., Wang, K., Zhang, P., Shi, J., Liu, W. and Tan, Z. 2019. Design, synthesis, in-silico and biological evaluation of novel chalcone derivatives as multi-function agents for the treatment of Alzheimer's disease. European journal of medicinal chemistry, 180, 238-252.
• Schrödinger, Version 2016-2, LLC: New York, NY, USA, 2016
• Tzvetkov, N. T., Stammler, H. G., Neumann, B., Hristova, S., Antonov, L. and Gastreich, M. 2017. Crystal structures, binding interactions, and ADME evaluation of brain penetrant N-substituted indazole-5-carboxamides as subnanomolar, selective monoamine oxidase B and dual MAO-A/B inhibitors. European journal of medicinal chemistry, 127, 470-492.
• Van der Walt, M. M., Terre’Blanche, G., Petzer, J. P. and Petzer, A. 2017. Benzyloxynitrostyrene analogues–A novel class of selective and highly potent inhibitors of monoamine oxidase B. European journal of medicinal chemistry, 125, 1193-1199.
• Zindo, F. T., Malan, S. F., Omoruyi, S. I., Enogieru, A. B., Ekpo, O. E. and 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.
• İnternet kaynakları 1-http:// www.pdb.org, (07.05.2021)