سنتز، بررسی زیست شناختی و مطالعات داکینگ مشتقات بنزایمیدازول به عنوان مهارکننده‌های آنزیم بوتیریل ‌کولین ‌استراز و استیل‌ کولین ‌استراز

نوع مقاله : مقاله علمی پژوهشی

نویسندگان

گروه شیمی آلی، دانشکده شیمی، دانشگاه مازندران، بابلسر، ایران

چکیده

فرضیه کولینرژیک یکی از فرضیه های بیماری آلزایمر است که نشان دهنده رابطه بین شروع و پیشرفت بیماری است. یکی از راه‌های اصلی افزایش سطح استیل کولین مهار آنزیم‌های کولین استراز است. هسته بنزایمیدازول به دلیل تمایل زیاد به انواع آنزیم‌ها و گیرنده‌های پروتئینی در تحقیقات شیمی دارویی اهمیت زیادی دارد. مطالعه حاضر در راستای سنتز مشتقات بنزایمیدازول، با هدف بررسی فعالیت مهارکنندگی آنزیم‌های بوتیریل کولین استراز (BuChE) و استیل کولین استراز (AChE) انجام شد. در این مطالعه تجربی، ابتدا فراورده 2-(کلرومتیل) بنزایمیدازول (2) به دست آمد، سپس سه مشتق نهایی بنزایمیدازولی 3، 4 و 5، به ترتیب از واکنش 1 میلی‌مول از این فراورده و 1 میلی‌مول پی‌پرازین یا N-فنیل‌پی‌پرازین و یا 2-فنیل‌اتان-1-آمین تهیه شدند. ساختار ترکیبات تهیه شده با روش‌های طیف سنجی 1H-NMR 13C-NMR, و FT-IR تائید شدند. مهار آنزیم BuChE و AChE با استفاده از تست المن مورد ارزیابی قرار گرفت. نتایج حاصل از این تست قدرت مهارکنندگی قابل توجه این ترکیبات را نشان داد. ترکیب 5 با µM 28/0 = IC50 بیشترین مهار را در مقابل آنزیم BuChE نشان داد. فعالیت مهاری ترکیب 5 در برابر BuChE بهتر از دونپزیل بود. علاوه بر این، برهمکنش ترکیب 5، داروهای گالانتامین و ریواستیگمین با آنزیم BuChE با استفاده از مطالعات داکینگ مورد بررسی قرار گرفت. در این مطالعات نیز ترکیب 5 با میزان انرژی kcal/mol 88/8- بهترین برهمکنش را با جایگاه فعال گیرنده نشان داد. با توجه به نتایج به‌دست آمده، ترکیب 5 امیدوارکننده‌ترین ترکیب برای توسعه مشتقات بنزایمیدازول در مقابل بیماری الزایمر می‌باشد.

کلیدواژه‌ها

موضوعات

عنوان مقاله [English]

Synthesis, biological investigation, and docking studies of benzimidazole derivatives as butyrylcholinesterase and acetylcholinesterase inhibitors

نویسندگان [English]

  • Maryam Rouhi
  • Sakineh Asghari
  • Zahra Ghanbari Masir
Department of Organic Chemistry, Faculty of Chemistry, University of Mazandaran, Babolsar, Iran
چکیده [English]

The cholinergic hypothesis is one of the hypotheses of Alzheimer's disease that shows the relationship between the onset and progression of the disease. One of the main ways to increase the level of acetylcholine is to inhibit cholinesterase enzymes. The benzimidazole core is very important in medicinal chemistry research due to its high affinity to various enzymes and protein receptors. The present study was conducted in the synthesis of benzimidazole derivatives with the aim of investigating butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) inhibitory activity. In the first step of experimental study, the product 2-(chloromethyl)benzimidazole (2) was obtained, then the final three benzimidazole derivatives 3, 4, and 5 were synthesized from the reaction of 1 mmol 2-(Chloromethyl)benzimidazole and 1 mmol of piperazine, N-phenylpiperazine, and 2-phenylethan-1-amine, respectively. The structure of the prepared compounds was confirmed by 1H-NMR, 13C-NMR, and FT-IR spectroscopic methods. The ability of the compounds to inhibit AChE and BuChE was evaluated using Ellman’s assay. The results of this test showed the significant inhibitory activities of these compounds. Compound 5 with IC50 = 0.28 µM showed the highest inhibition against BuChE enzyme. The inhibitory activity of compound 5 against BuChE was better than donepezil. In addition, the interaction of compound 5, galantamine, and rivastigmine with BuChE enzyme was investigated using docking studies. In these studies, compound 5 with an energy value of -8.88 kcal/mol showed the best interaction with the active site of the receptor. According to the obtained results, compound 5 is the most promising compound for the development of benzimidazole derivatives against Alzheimer's disease.

کلیدواژه‌ها [English]

  • Benzimidazole
  • Piperazine
  • Acetylcholinesterase
  • butyrylcholinesterase
  • Docking studies

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شیمى کاربردى روز
دوره 19، شماره 71
تیر 1403
صفحه 247-266

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