Bis-üreido Substitüe Antipirin Türevlerinin Yenilikçi Tasarımı, Sentezi ve İn Siliko Değerlendirilmesi: Moleküler Modelleme ve ADME Analizleri

Öz

Moleküler docking, ilgi çekici moleküller ile belirli protein yapıları arasındaki etkileşimleri tahmin eden bir hesaplama modelleme tekniğidir. Bu yaklaşım, bağlanma afinitelerini tahmin eder ve bağ etkileşimlerini görselleştirir, bu da onu ilaç keşfi için faydalı bir araç haline getirir. Moleküler docking, moleküler yapılar arasındaki potansiyel bağlanma bağlantılarını laboratuvar testlerinden önce inceleyerek yeni terapötik ilaçların rasyonel tasarımına olanak tanır. ADME (Absorpsiyon, Dağılım, Metabolizma ve Eliminasyon) incelemeleri, incelenen bileşiklerin farmakokinetik özelliklerini değerlendirerek moleküler docking çalışmalarını tamamlar ve bu bileşiklerin potansiyel terapötik adaylar olarak uygunluğunu belirler. Bu çalışmada, bis-üreido grubu ile antipirin ilacını birleştirerek bu moleküllerin farmakolojik özelliklerini geliştirmeyi hedefleyen yenilikçi bir bis-üreido substitüe antipirin türevleri serisinin tasarımı, sentezi ve in silico değerlendirmesi sunulmaktadır. Yeni sentezlenen bileşikler, FT-IR, ¹H-NMR ve ¹³C-NMR gibi spektroskopik yöntemlerle kapsamlı bir şekilde karakterize edilmiş ve ardından asetilkolinesteraz (AChE) ve bütirilkolinesteraz (BChE) ile olan etkileşimlerini analiz etmek için moleküler docking deneyleri gerçekleştirilmiştir. Ayrıca, bileşiklerin farmakokinetik özelliklerini ve ilaç benzeri özelliklerini belirlemek için in silico ADME değerlendirmeleri yapılmıştır. Özellikle, bileşik 10, AChE ve BChE'ye karşı sırasıyla -14,47 ve -11,75 kcal/mol bağlanma enerjileri ile güçlü bağlanma afiniteleri göstermiştir. Docking verileri, hem AChE hem de BChE için önemli inhibitör potansiyelini ortaya koyan yüksek bağlanma afinitelerini işaret etmektedir. Bu çalışma, modern farmasötik tasarım ve geliştirme süreçlerinde moleküler docking ve ADME incelemelerinin bir arada kullanılmasının önemini vurgulamaktadır.

Anahtar Kelimeler

• Antipirin
• In siliko
• ADME
• Bis-üreido
• Antikolinesteraz

Innovative Design, Synthesis, and In Silico Evaluation of Bis-Ureido Substituted Antipyrine Derivatives: Molecular Modeling and ADME Insights

Öz

Molecular docking is a computational modeling technique that predicts the interactions between molecules of interest and certain protein structures. This approach estimates binding affinities and visualizes bond interactions, making it a useful tool for drug discovery. Molecular docking helps to rationally design new therapeutic medicines by offering insight into potential binding connections between molecular structures prior to laboratory testing. ADME investigations supplement molecular docking by assessing the pharmacokinetic features of the examined compounds, consequently determining their eligibility as possible therapeutic candidates. In this study, we show the creative design, synthesis, and In silico evaluation of a novel series of bis-ureido substituted antipyrine derivatives, with a focus on their potential as cholinesterase inhibitors. Using molecular modeling tools, we combined the bis-ureido group with the antipyrine drug to improve the pharmacological properties of these molecules. The newly synthesized compounds were comprehensively characterized by spectroscopic approaches, including FT-IR, ¹H-NMR, and ¹³C-NMR, followed by molecular docking experiments to analyze their interactions with acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Additionally, In silico ADME assessments were performed to determine the compounds' pharmacokinetic characteristics and drug-likeness properties. Notably, compound 10 showed strong binding affinities against AChE and BChE, with binding energies of -14.47 and -11.75 kcal/mol, respectively. The docking data revealed high binding affinities, indicating a significant inhibitory potential for both AChE and BChE. This study points out the need of combining molecular docking and ADME investigations in contemporary pharmaceutical design and development.

Anahtar Kelimeler

• Antipytine
• In silico
• ADME
• Bis-ureido
• Anticholinesterase

Kaynakça

1. Abbas, Samir Y., Maha M. Abd El-Aziz, Samir M. Awad, and Mosaad S. Mohamed. (2023). Synthesis and Evaluation of Antipyrine Derivatives Bearing a Thiazole Moiety as Antibacterial and Antifungal Agents. Synthetic Communications 53(21):1812–1822.
2. Akhmadiev, Nail S., Ekaterina S. Mescheryakova, Vnira R. Akhmetova, Veronica R. Khairullina, Leonard M. Khalilov, and Askhat G. Ibragimov. (2021). Synthesis, Crystal Structure and Docking Studies as Potential Anti-Inflammatory Agents of Novel Antipyrine Sulfanyl Derivatives. Journal of Molecular Structure 1228:129734.
3. Akocak, Suleyman, Nebih Lolak, Simone Giovannuzzi, and Claudiu T. Supuran. (2023). Potent and selective carbonic anhydrase inhibition activities of pyrazolones bearing benzenesulfonamides Bioorganic and Medicinal Chemistry Letters 95:129479.
4. Akocak, Suleyman, Parham Taslimi, Nebih Lolak, Mesut Işık, Mustafa Durgun, Yakup Budak, Cüneyt Türkeş, İlhami Gülçin, and Şükrü Beydemir. (2021). Synthesis, Characterization, and Inhibition Study of Novel Substituted Phenylureido Sulfaguanidine Derivatives as α-Glycosidase and Cholinesterase Inhibitors. Chemistry and Biodiversity 18(4):e2000958.
5. 2024 Alzheimer’s disease facts and figures. Alzheimer’s Dement. 2024;20(5):3708–3821. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/alz.13809
6. Ansari, Anam, Abad Ali, Mohd Asif, and Shamsuzzaman. (2016). Review: Biologically Active Pyrazole Derivatives. New Journal of Chemistry 41(1):16–41.
7. Antunes-Ricardo, Marilena, Chiara Brullo, Debora Caviglia, Andrea Spallarossa, Silvana Alfei, Scott G. Franzblau, Bruno Tasso, and Anna Maria Schito. (2022). Microbiological Screening of 5-Functionalized Pyrazoles for the Future Development of Optimized Pyrazole-Based Delivery Systems. Pharmaceutics, (9):1770. Breijyeh, Zeinab, Rafik Karaman, Diego Muñoz-Torrero, and Roman Dembinski. (2020). Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules 25(24):5789.
8. Budak, Yakup, Umit M. Kocyigit, Meliha Burcu Gurdere, Kezban Ozcan, Parham Taslimi, Ilhami Gulcin, and Mustafa Ceylan. (2017). Synthesis and investigation of antibacterial activities and carbonic anhydrase and acetyl cholinesterase inhibition profiles of novel 4,5-dihydropyrazol and pyrazolyl-thiazole derivatives containing methanoisoindol-1,3-dion unit. Synhetic Communications.47(24):2313-2323.

9. Cheung J, Rudolph MJ, Burshteyn F, Cassidy MS, Gary EN, Love J, et al. (2012). Structures of Human Acetylcholinesterase in Complex with Pharmacologically Important Ligands. Journal of Medicinal Chemistry. 55(22):10282-10286.
10. Deture, Michael A., and Dennis W. Dickson. (2019). The Neuropathological Diagnosis of Alzheimer’s Disease. Molecular Neurodegeneration 14(1):1–18.
11. Durgun, Mustafa, Suleyman Akocak, Nebih Lolak, Fevzi Topal, Umit M. Kocyigit, Cuneyt Türkeş, Mesut Isık, and Sukru Beydemir. (2024). Design and Synthesis of Pyrazole Carboxamide Derivatives as Selective Cholinesterase and Carbonic Anhydrase Inhibitors: Molecular Docking and Biological Evaluation. Chemistry and Biodiversity. 21(2):e202301824.
12. Durmaz L, Gulcin I, Taslimi P, Tuzun B. (2023). Isofraxidin: Antioxidant, Anti-carbonic Anhydrase, Anti-cholinesterase, Anti-diabetic, and in Silico Properties. ChemistrySelect. 8(34):e202300170.
13. El-Feky, Said A. H., Zakaria K. Abd El-Samii, Nermine A. Osman, Jasmine Lashine, Mohamed A. Kamel, and Hamdy Kh Thabet. (2015). Synthesis, Molecular Docking and Anti-Inflammatory Screening of Novel Quinoline Incorporated Pyrazole Derivatives Using the Pfitzinger Reaction II. Bioorganic Chemistry 58:104–116.
14. Fahim, Asmaa M., Ahmad M. Farag, Arif Mermer, Hacer Bayrak, and Yakup Sirin. (2021). Synthesis of novel β-lactams: Antioxidant activity, acetylcholinesterase inhibition and computational studies. Journal of Molecular Structure. 1233:130092.
15. Fatima, Mahwish, Bharath Rathna Kumar. P, Venu Priya. R, and Sunil Kumar Kadiri. (2024). Synthesis, Characterization and Antioxidant Activity of Some New Antipyrine Derived Schiff Bases. Asian Journal of Research in Chemistry 73–77. doi: 10.52711/0974-4150.2024.00014.
16. Işık, Mesut, and Şükrü Beydemir. (2022). AChE MRNA Expression as a Possible Novel Biomarker for the Diagnosis of Coronary Artery Disease and Alzheimer’s Disease, and Its Association with Oxidative Stress. Archives of Physiology and Biochemistry 128(2):352–539.
17. Kandimalla, Ramesh, and P. Hemachandra Reddy. (2017). Therapeutics of Neurotransmitters in Alzheimer’s Disease. Journal of Alzheimer’s Disease 57(4):1049–1069.
18. Knorr L. (1883). Einwirkung von Acetessigester auf Phenylhydrazin. Berichte der deutschen chemischen Gesellschaft. 16(2):2597-2599.
19. Kumar, Devendra, Ankit Ganeshpurkar, Dileep Kumar, Gyan Modi, Sanjeev Kumar Gupta, and Sushil Kumar Singh. (2018). Secretase Inhibitors for the Treatment of Alzheimer’s Disease: Long Road Ahead. European Journal of Medicinal Chemistry 148:436–452.
20. Lane, C. A., J. Hardy, and J. M. Schott. (2018). Alzheimer’s Disease. European Journal of Neurology 25(1):59–70. Lolak, Nebih, Cüneyt Türkeş, Süleyman Akocak, Hatice Esra Duran, Mesut Işık, Mustafa Durgun, and Şükrü Beydemir. (2024). Interactions of novel 1,3-diaryltriazene-sulfamethazines with carbonic anhydrases: Kinetic studies and in silico simulations. Archives of Biochemistry and Biophysics. 761:110181.
21. Lolak, Nebih, Süleyman Akocak, Mustafa Durgun, Hatice Esra Duran, Adem Necip, Cüneyt Türkeş, Mesut Işık, and Şükrü Beydemir. (2023). Novel Bis-Ureido-Substituted Sulfaguanidines and Sulfisoxazoles as Carbonic Anhydrase and Acetylcholinesterase Inhibitors. Molecular Diversity 27(4):1735–1749.
22. Lolak, Nebih, Mehmet Boga, Gorkem Deniz Sonmez, Muhammed Tuneg, Aslinur Dogan, and Süleyman Akocak. (2022). In Silico Studies and DNA Cleavage, Antioxidant, Acetylcholinesterase, and Butyrylcholinesterase Activity Evaluation of Bis-Histamine Schiff Bases and Bis-Spinaceamine Substituted Derivatives. Pharmaceutical Chemistry Journal. 55:1338–1344.
23. Lolak, Nebih, Süleyman Akocak, Cüneyt Türkeş, Parham Taslimi, Mesut Işık, Şükrü Beydemir, İlhami Gülçin, and Mustafa Durgun. (2020). Synthesis, Characterization, Inhibition Effects, and Molecular Docking Studies as Acetylcholinesterase, α-Glycosidase, and Carbonic Anhydrase Inhibitors of Novel Benzenesulfonamides Incorporating 1,3,5-Triazine Structural Motifs. Bioorganic Chemistry 100:103897.
24. Lusardi, Matteo, Andrea Spallarossa, and Chiara Brullo. (2023). Amino-Pyrazoles in Medicinal Chemistry: A Review. International Journal of Molecular Sciences 24(9):7834.
25. Mamaghani, Manouchehr, Roghayeh Hossein Nia, Farhad Shirini, Khalil Tabatabaeian, and Mehdi Rassa. (2015). An Efficient and Eco-Friendly Synthesis and Evaluation of Antibactrial Activity of Pyrano[2,3-c]Pyrazole Derivatives. Medicinal Chemistry Research 24(5):1916–1926.
26. Marengo, Barbara, Elda Meta, Chiara Brullo, Chiara de Ciucis, Renata Colla, Andrea Speciale, Ombretta Garbarino, Olga Bruno, and Cinzia Domenicotti. (2020). Biological Evaluation of Pyrazolyl-Urea and Dihydro-Imidazopyrazolyl-Urea Derivatives as Potential Anti-Angiogenetic Agents in the Treatment of Neuroblastoma. Oncotarget 11(37):3459–3472.
27. Meden A, Knez D, Jukic M, Brazzolotto X, Grsic M, Pislar A, et al. (2019). Tryptophan-derived butyrylcholinesterase inhibitors as promising leads against Alzheimer's disease. Chemical Communications. 55:3765-3768.
28. Medetallibeyoglu, Hilal, Fikret Turkan, Sevda Manap, Ercan Bursal, Murat Beytur, Abdulmelik Aras, Onur Akyıldırım, Gul Kotan, Ozlem Gursoy Kol, and Haydar Yuksek. (2023). Synthesis and acetylcholinesterase enzyme inhibitory effects of some novel 4,5-Dihydro-1H-1,2,4-triazol-5-one derivatives; an in vitro and in silico study. Journal of Biomolecular Structure and Dynamics. 41(10): 4286-4294.
29. Muglu H, Yakan H, Erdogan M, Topal F, Topal M, Turkes C, Beydemir S. (2024). Novel asymmetric biscarbothioamides as Alzheimer's disease associated cholinesterase inhibitors: synthesis, biological activity, and molecular docking studies. New Journal of Chemistry. 48:10979-10989.
30. Nishio, Makoto, Masanori Matsuda, Fumiyoshi Ohyanagi, Yukitohi Sato, Sakae Okumura, Daisuke Tabata, Akinobu Morikawa, Ken Nakagawa, and Takeshi Horai. (2005). Antipyrine Test Predicts Pharmacodynamics in Docetaxel and Cisplatin Combination Chemotherapy. Lung Cancer 49(2):245–251.
31. Pérez-Fernández, Ruth, Pilar Goya, and José Elguero. (2013). A Review of Recent Progress (2002-2012) on the Biological Activities of Pyrazoles. Arkivoc 2014(2):233–293.
32. Reale, Marcella, Erica Costantini, Marta Di Nicola, Chiara D’Angelo, Sara Franchi, Marco D’Aurora, Maria Di Bari, Viviana Orlando, Sabrina Galizia, Serena Ruggieri, Liborio Stuppia, Claudio Gasperini, Ada Maria Tata, and Valentina Gatta. (2018). Butyrylcholinesterase and Acetylcholinesterase Polymorphisms in Multiple Sclerosis Patients: Implication in Peripheral Inflammation. Scientific Reports 8(1):1319.
33. Rostom, Sherif A. F., Ibrahim M. El-Ashmawy, Heba A. Abd El Razik, Mona H. Badr, and Hayam M. A. Ashour. (2009). Design and Synthesis of Some Thiazolyl and Thiadiazolyl Derivatives of Antipyrine as Potential Non-Acidic Anti-Inflammatory, Analgesic and Antimicrobial Agents. Bioorganic & Medicinal Chemistry 17(2):882–895.
34. Taslimi, Parham, Cuneyt Caglayan, Vagif Farzaliyev, Oruj Nabiyev, Afsun Sujayev, Fikret Turkan, Ruya Kaya, and İlhami Gulçin. (2018). Synthesis and Discovery of Potent Carbonic Anhydrase, Acetylcholinesterase, Butyrylcholinesterase, and α-Glycosidase Enzymes Inhibitors: The Novel N,N′-Bis-Cyanomethylamine and Alkoxymethylamine Derivatives. Journal of Biochemical and Molecular Toxicology 32(4):e22042.
35. Tekeli, Tuba, Nebih Lolak, Yener Tekeli, Esra Bozgeyik, Deniz Akın Anakok, Servet Cete, Ilhami Gulcin, and Suleyman Akocak. (2024). Bis-Ureido-Substituted Benzenesulfonamides: Evaluation of Their Antibacterial, Anticholinesterase, and Cytotoxicity Properties. ChemistrySelect. 9(23):e202400485.
36. Tekeli, Yener, Nebih Lolak, Gorkem Deniz Sonmez, Tuba Tekeli, and Suleyman Akocak. (2022). Antibacterial, Antioxidant and DNA Cleavage Activity Evaluation of Substituted Phenylureido Sulfaguanidine and Sulfamethazine Derivatives. Pharmaceutical Chemistry Journal 56(3):345–349.
37. Türkeş, Cüneyt, Suleyman Akocak, Mesut Işık, Nebih Lolak, Parham Taslimi, Mustafa Durgun, İlhami Gülçin, Yakup Budak, and Şükrü Beydemir. (2022). Novel Inhibitors with Sulfamethazine Backbone: Synthesis and Biological Study of Multi-Target Cholinesterases and α-Glucosidase Inhibitors. Journal of Biomolecular Structure and Dynamics 40(19):8752–8764.
38. Walczak-Nowicka, Łucja Justyna, and Mariola Herbet. (2021). Acetylcholinesterase Inhibitors in the Treatment of Neurodegenerative Diseases and the Role of Acetylcholinesterase in Their Pathogenesis. International Journal of Molecular Sciences 22(17):9290.
39. Yang, Zhenqi, Yong Zou, and Lifeng Wang. (2023). Neurotransmitters in Prevention and Treatment of Alzheimer’s Disease. International Journal of Molecular Sciences 24(4):3841. doi: 10.3390/IJMS24043841.
40. Yasar U, Gonul I, Turkes C, Demir Y, Beydemir S. (2021). Transition-Metal Complexes of Bidentate Schiff-Base Ligands: In Vitro and In Silico Evaluation as Non-Classical Carbonic Anhydrase and Potential Acetylcholinesterase Inhibitors. ChemistrySelect. 6(29):7278-7284.
41. Yilmaz A, Koca M, Boga M, Kurt A, Ozturk T. (2023). Synthesis of Novel Oxime and Benzofuran Chemical Frameworks Possessing Potent Anticholinesterase Activity: A SAR Study Related to Alzheimer Disease. ChemistrySelect. 8(30):e202302058.
42. Youssef, Youssef M., Mohammad E. Azab, Galal A. Elsayed, Amira A. El-Sayed, Aya I. Hassaballah, Mounir M. El-Safty, Reem A. Soliman, and Eman A. E. El-Helw. (2023). Synthesis and Antioxidant, Antimicrobial, and Antiviral Activity of Some Pyrazole-Based Heterocycles Using a 2(3H)-Furanone Derivative. Journal of the Iranian Chemical ociety 20(9):2203–2216.