RECENT ADVANCES OF CHOLINESTERASE INHIBITORS PLAYING A CRITICAL ROLE IN THE TREATMENT OF ALZHEIMER’S DISEASE (2020-2022)

Abstract

Alzheimer’s disease (AD) is a common neurodegenerative disorder which has a catastrophic effect on the brain. It significantly affects people’s daily life, especially the population over the age of 65, with problems such as neuron death, memory loss, cognitive disorders, and cholinergic dysfunction. However, despite the drug development studies which have been conducted recently quite intensively, an effective drug molecule that can completely cure people or stop the stage of the disease has not been found yet, unfortunately. One of the reasons for this is the complexity of understanding of how the pathology of the disease arises. The most accepted theory for AD is the cholinergic hypothesis. Acetylcholine (ACh), an important neurotransmitter, is metabolized by two cholinesterase (ChE) enzymes named acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). With AD, ChE activity increases and thus the degradation of acetylcholine is triggered. In addition, it is understood that the peripheral anionic region (PAS) of the AChE also caused the formation of Aβ-peptide fibrils. Therefore, based on this hypothesis, the most effective approach in treatment is the use of cholinesterase inhibitors (ChEI), which try to restore ACh levels by increasing them at cholinergic synapses. Furthermore, it focused on the design of multifunctional molecules. In conclusion, considering the complex nature of the disease and its effects, it is clear that more studies are needed in this area. In this study, important and remarkable studies in recent years have been included and it aimed to contribute to future drug research andv development studies.

Keywords

• Alzheimer’s disease (AD)
• cholinesterase inhibitors (ChEIs)
• acetylcholinesterase inhibitors (AChEIs)
• butyrylcholinesterase inhibitors (BuChEIs)
• multifonctional drugs
• multi-target directed ligands

ALZHEİMER HASTALIĞININ TEDAVİSİNDE KRİTİK BİR ROL OYNAYAN KOLİNESTERAZ İNHİBİTÖRLERİNDEKİ SON GELİŞMELER (2020-2022)

Abstract

Alzheimer hastalığı (AD) oldukça sık rastlanılan ve majör yıkıcı bir etkiye sahip olan nörodejeneratif bir hastalıktır. Özellikle 65 yaş üstü nüfusu büyük oranda tutan, hasta kişinin nöron ölümü, hafıza kaybı, bilişsel ve kolinerjik işlev bozuklukları gibi sıkıntılarla günlük yaşamını önemli derecede etkileyen bir durumdur. Fakat son dönemde yapılan ilaç geliştirme çalışmalarının oldukça yoğun yürütülmesine rağmen, hala kişileri tamamen iyileştirebilecek veya hastalığın evresini tamamen durdurabilecek etkili bir ilaç molekülü maalesef bulunamamıştır. Bunun sebeplerinden biri de hastalığın patolojisinin nasıl ortaya çıktığının anlaşılamaması ve karmaşıklığı ile ilgilidir. Alzheimer hastalığı için kabul gören en önemli teori kolinerjik hipotezdir. Önemli bir nörotransmitter olan asetilkolin (ACh), asetilkolinesteraz (AChE) ve bütirilkolinesteraz (BuChE) isimli iki kolinesteraz enzimi (ChE) tarafından metabolize edilir. AD ile birlikte ise ChE aktivitesi artmış ve dolayısıyla asetilkolinin yıkımı tetiklenmiştir. Ayrıca AChE’in periferal anyonik bölgesi (PAS)’nin Aβ-peptid fibrillerinin oluşmasına da neden olduğu anlaşılmıştır. Bu sebeple bu hipoteze dayanarak tedavideki en etkili yaklaşım, kolinerjik sinapslarda ACh seviyesini arttırarak eski haline döndürmeye çalışan kolinesteraz inhibitörlerinin (ChEI) kullanılmasıdır. Üstelik multifonksiyonel moleküllerin tasarımları üzerine de odaklanılmıştır. Sonuç olarak hastalığın karmaşık yapısı ve etkileri göz önüne alındığında, bu alanda daha fazla çalışma yapılması gerekmektedir. Bu çalışmada son yıllardaki önemli ve dikkat çeken çalışmalar yer almış olup, bundan sonraki ilaç araştırma ve geliştirme çalışmalarına katkı sağlaması amaçlanmıştır.

Keywords

• Alzheimer hastalığı (AD)
• kolinesteraz inhibitörleri (ChEIs)
• asetilkolinesteraz inhibitörleri (AChEIs)
• butirilkolinesteraz inhibitörleri (BuChEIs)
• multifonksiyonel ilaçlar
• çoklu hedefe yönlendirilmiş ligandlar

References

1. Gauthier S, Rosa-Neto P, Morais JA, Webster C. World Alzheimer Report 2021: Journey through the diagnosis of dementia. London, England: Alzheimer's Disease International, McGill University 2021. Available from https://www.alzint.org/resource/world-alzheimer-report-2021/ google scholar
2. Alptüzün V. Jenerik İlaçlar ve Akılcı Kullanım-Alzheimer Hastalığında Asetilkolinesteraz İnhibitörleri [Generic Drugs and Rational Use-Acetylcholinesterase İnhibitors in Alzheimer's Disease]. Turkish Pharmacy Association 8th Pharmacy Congress of Turkey, (28.10.2006; Session one); 2006. google scholar
3. Breijyeh Z, Karaman R. Comprehensive Review on Alzheimer's Disease: Causes and Treatment. Molecules 2020;25(24):5789. google scholar
4. Bhagat K, Singh JV, Sharma A, Kaur A, Kumar N, Gulati HK, et al. Novel series of triazole containing coumarin and isatin based hybrid molecules as acetylcholinesterase inhibitors. J Mol Struct 2021;1245:131085. google scholar
5. Bortolami M, Rocco D, Messore A, Di Santo R, Costi R, Madia VN, et al. Acetylcholinesterase inhibitors for the treatment of Alzheimer's disease - a patent review (2016-present). Expert Opin Ther Pat 2021;31(5):399-420. google scholar
6. Carcak-Yilmaz N, Altuntas M, Akyel YK, Uydes-Dogan BS. Pharmacist's role in pharmacotherapeutic management of Alzheimer's disease. İstanbul J Pharm 2017;47(1):1-4. google scholar
7. El-Khatabi K, El-Mernissi R, Aanouz I, Ajana MA, Lakhlifi T, Shahinozzaman M, et al. Benzimidazole derivatives in identifying novel acetylcholinesterase inhibitors: a combination of 3D-QSAR, docking and molecular dynamics simulation. Phys Chem Res 2021;10(2):237-49. google scholar
8. Nguyen TT, Nguyen TTD, Nguyen TKO, Vo TK, Vo VG. Advances in developing therapeutic strategies for Alzheimer's disease. Biomed Pharmacotherapy 2021;139:111623 google scholar

9. Kabir MT, Uddin MS, Jeandet P, Emran TB, Mitra S, Albadrani GM, et al. Anti-Alzheimer's molecules derived from marine life: understanding molecular mechanisms and therapeutic potential. Mar drugs 2021;19(5):251. google scholar
10. Macha B, Kulkarni R, Garige AK, Pola S, Akkinepally R, Garlapati A. Design and Friedlander Reaction Based Synthesis of New Cycloalkyl Ring Fused Quinolines as Multifunctional Agents for Alzheimer's Treatment: İn Silico Studies. Chemistry Select 2021;6(9):1947-57. google scholar
11. Arslan T. Design, synthesis of novel peripherally tetra-chalcone substituted phthalocyanines and their inhibitory effects on acetylcholinesterase and carbonic anhydrases (hCA I and II). J Organomet Chem 2021;951:122021. google scholar
12. Silva T, Reis J, Teixeira J, Borges F. Alzheimer's disease, enzyme targets and drug discovery struggles: From natural products to drug prototypes. Ageing Res Rev 2014;15:116-45. google scholar
13. Joâo KG, Videira RA, Paiva-Martins F, Valentâo P, Pereira DM, Andrade PM. Homarine Alkyl Ester Derivatives as Promising Acetylcholinesterase Inhibitors. Chem Med Chem 2021;16(21):3315-25. google scholar
14. Miles JA, Ross BP. Recent Advances in Virtual Screening for Cholinesterase Inhibitors. ACS Chem Neurosci 2021;12(1):30-41. google scholar
15. Li Q, He S, Chen Y, Feng F, Qu W, Sun H. Donepezil-based multifunctional cholinesterase inhibitors for treatment of Alzheimer's disease. Eur J Med Chem 2018;158:463-77. google scholar
16. Weinreb O, Amit T, Bar-Am O, Youdim MBH. Ladostigil: A novel multimodal neuroprotective drug with cholinesterase and brain-selective monoamine oxidase inhibitory activities for alzheimer's disease treatment. Curr Drug Targets 2012;13(4):483-94. google scholar
17. Barut B, Sari S, Sabuncuoğlu S, Özel A. Azole antifungal compounds could have dual cholinesterase inhibitory potential according to virtual screening, enzyme kinetics, and toxicity studies of an inhouse library. J Mol Struct 2021;1235:130268. google scholar
18. Sayar-Gümüş G. Potansiyel Anti-Alzheimer Heteroaromatik Hidrazit-Hidrazon Türevi Bileşikler Üzerinde Sentez ve Biyoaktivite Çalışmaları [Synthesis and Bioactivity Studies on Potential Anti-Alzheimer Heteroaromatic Hydrazide-Hydrazone Derivatives]. (Doctoral dissertation): Ege Univ. 2017. URL: https://tez.yok.gov. tr/UlusalTezMerkezi/tezDetay.jsp?id=F9auTkEImHVKDNkQdlw08 A&no=06ntbxASM0baT15BlhaGxA google scholar
19. Soreq H, Seidman S. Acetylcholinesterase-new roles for an old actor. Nat Rev Neurosci 2001;2(4):294-302. google scholar
20. Dantoine T, Auriacombe S, Sarazin M, Becker H, Pere J-J, Bourdeix I. Rivastigmine monotherapy and combination therapy with memantine in patients with moderately severe Alzheimer's disease who failed to benefit from previous cholinesterase inhibitor treatment. Int J Clin Pract 2006;60(1):110-8. google scholar
21. David B, Schneider P, Schafer P, Pietruszka J, Gohlke H. Discovery of new acetylcholinesterase inhibitors for Alzheimer's disease: virtual screening and in vitro characterisation. J Enzyme Inhib and Med Chem 2021;36(1):491-6. google scholar
22. Vignaux PA, Minerali E, Lane TR, Foil DH, Madrid PB, Puhl AC, et al. The Antiviral Drug Tilorone Is a Potent and Selective Inhibitor of Acetylcholinesterase. Chem Res Toxicol 2021;34(5):1296-307. google scholar
23. Ujan R, Channar PA, Bahadur A, Abbas Q, Shahe M, Rashid SG, et al. Synthesis, kinetics and biological assay of some novel aryl bis-thioureas: A potential drug candidates for Alzheimer's disease. J Mol Struct 2021;1246:131136. google scholar
24. Guo Y, Yang H, Huang Z, Tian S, Li Q, Du, C, et al. Design, Synthesis, and Evaluation of Acetylcholinesterase and Butyrylcholinesterase Dual-Target Inhibitors against Alzheimer's Diseases. Molecules 2020;25(3):489. google scholar
25. Lotfi S, Rahmani T, Hatami M, Pouramiri B, Kermani ET, Rezvannejad E et al. Design, synthesis and biological assessment of acridine derivatives containing 1,3,4-thiadiazole moiety as novel selective acetylcholinesterase inhibitors. Bioorg Chem 2020;105:104457. google scholar
26. Liu G, Jiao Y, Lin Y, Hao H, Dou Y, Yang J, et al. Discovery and Biological Evaluation of New Selective Acetylcholinesterase Inhibitors with Anti-AP Aggregation Activity through Molecular Docking-Based Virtual Screening. Chem Pharm Bull 2020;68(2):161-6. google scholar
27. Chakravarty H, Ju Y, Chen W-H, Tam KY. Dual targeting of cholinesterase and amyloid beta with pyridinium/isoquinolium derivatives. Drug Dev Res 2020;81(2):242-55. google scholar
28. Cadez T, Grgi"cevi'c A, Ahmetovi'c R, Bari'c D, Hrvat NM, Kovarik Z, et al. Benzobicyclo[3.2.1]octene Derivatives as a New Class of Cholinesterase Inhibitors. Molecules 2020;25(21):4872. google scholar
29. Xie RR, Su, CL, Li W, Zou XY, Chen YS, Tang H. Synthesis and biological evaluation of novel 8- substituted sampangine derivatives as potent inhibitor of Zn2+-Ap complex mediated toxicity, oxidative stress and inflammation. Bioorg Chem 2021;109:104710. google scholar
30. El-Sayed NF, El-Hussieny M, Ewies EF, Fouad MA, Boulos LS. New phosphazine and phosphazide derivatives as multifunctional ligands targeting acetylcholinesterase and P-Amyloid aggregation for treatment of Alzheimer's disease. Bioorg Chem 2020;95:103499. google scholar
31. Mak S, Li W, Fu H, Luo J, Cui W, Hu S, et al. Promising tacrine/ huperzine A-based dimeric acetylcholinesterase inhibitors for neurodegenerative disorders: From relieving symptoms to modifying diseases through multitarget. J Neurochem 2021;158(6):1381-93. google scholar
32. Lasmari S, Ikhlef S, Boulcinaa R, Mokrani, EH, Bensouici C, Gürbüz N, et al. New silver N-heterocyclic carbenes complexes: Synthesis, molecular docking study and biological activities evaluation as cholinesterase inhibitors and antimicrobials. J Mol Struct 2021;1238:130399. google scholar
33. Mughal EU, Sadiq A, Ayub M, Naeem N, Javid A, Sumrra SH, et al. Exploring 3-Benzyloxyflavones as new lead cholinesterase inhibitors: synthesis, structure-activity relationship and molecular modelling simulations. J Biomol Struct Dyn 2021;39(16):6154-67. google scholar
34. Sharma RK, Singh M, Ghimeray K, Juneja P, Dev G, Pulavarthi S, et al. Imidazopyridazine acetylcholinesterase inhibitors display potent anti-proliferative effects in the human neuroblastoma cell-line, IMR-32. Molecules 2021;26(17):5319. google scholar
35. Guieu B, Lecoutey C, Legay R, Davis A, Sopkova de Oliveira Santos J, Altomare CD, et al. First Synthesis of Racemic Trans Propargylamino-Donepezil, a Pleiotrope Agent Able to Both Inhibit AChE and MAO-B, with Potential Interest against Alzheimer's Disease. Molecules 2021;26(1):80. google scholar
36. Shaikh S, Dhavan P, Ramana MMV, Jadhav BL. Design, synthesis and evaluation of new chromone-derived aminophosphonates as potential acetylcholinesterase inhibitör. Mol Divers 2021;25(2):811-25. google scholar
37. Song M-Q, Min W, Wang J, Si X-X, Wang X-J, Liu Y-W, et al. Design, synthesis and biological evaluation of new carbazole-coumarin hybrids as dual binding site inhibitors of acetylcholinesterase. J Mol Struct 2021;1229:129784. google scholar
38. Skrzypek A, Matysiak J, Karpinska M, Czarnecka K, Krşcisz P, Stary D, et al. Biological evaluation and molecular docking of novel 1, 3, 4-thiadiazole-resorcinol conjugates as multifunctional cholinesterases inhibitors. Bioorg Chem 2021;107:104617. google scholar
39. Liu D, Zhang H, Wang Y, Liu W, Yin G, Wang D, et al. Design, synthesis, and biological evaluation of carbamate derivatives of N-salicyloyl tryptamine as multifunctional agents for the treatment of Alzheimer's disease. Eur J Med Chem 2022;229:114044. google scholar
40. Liu T, Chen S, Du J, Xing S, Li R, Li Z. Design, synthesis, and biological evaluation of novel (4-(1,2,4- oxadiazol-5-yl)phenyl)-2-aminoacetamide derivatives as multifunctional agents for the treatment of Alzheimer's disease. Eur J Med Chem 2022;227:113973. google scholar
41. Kaur Gulati H, Choudhary S, Kumar N, Ahmed A, Bhagat K, Singh JV, et al. Design, Synthesis, biological investigations and molecular interactions of triazole linked tacrine glycoconjugates as Acetylcholinesterase inhibitors with reduced hepatotoxicity. Bioorg Chem 2022;118:105479. google scholar
42. Heise N, Friedrich S, Temml V, Schuster D, Siewert B, Csuk R. N-methylated diazabicyclo[3.2.2]nonane substituted triterpenoic acids are excellent, hyperbolic and selective inhibitors for butyrylcholinesterase. Eur J Med Chem 2022;227:113947. google scholar
43. Lolak N, Akocak S, Durgun M, Duran HE, Necip A, Turkes C, et al. Novel bis-ureido-substituted sulfaguanidines and sulfisoxazoles as carbonic anhydrase and acetylcholinesterase inhibitors. Mol Divers 2022;4(1):1-15. google scholar
44. Gumus M, Babacan SN, Demir Y, Sert Y, Koca I, Gulcin I. Discovery of sulfadrug-pyrrole conjugates as carbonic anhydrase and acetylcholinesterase inhibitors. Arch Pharm 2022 (Weinheim);355(1):e2100242. doi:10.1002/ardp.202100242 google scholar
45. Codony S, Pont C, Grinan-Ferre C, Di Pede-Mattatelli A, Calvo-Tusell C, Feixas F, et al. Discovery and in vivo proof of concept of a highly potent dual inhibitor of soluble epoxide hydrolase and acetylcholinesterase for the treatment of alzheimer's disease. J Med Chem 2022;65(6):4909-25. google scholar
46. Messaad M, Dhouib I, Abdelhedi M, Khemakhem B. Synthesis, bioassay and molecular docking of novel pyrazole and pyrazolone derivatives as acetylcholinesterase inhibitors. J Mol Struct 2022;1263:133105. google scholar
47. Pourtaher H, Hasaninejad A, Iraji A. Design, synthesis, in silico and biological evaluations of novel polysubstituted pyrroles as selective acetylcholinesterase inhibitors against Alzheimer's disease. Sci Rep google scholar
48. Makarian M, Gonzalez M, Salvador SM, Lorzadeh S, Hudson PK, Pecic S. Synthesis, kinetic evaluation and molecular docking studies of donepezil-based acetylcholinesterase inhibitors. J Mol Struct 2022;1247:131425. google scholar
49. Han C, Wei BB, Shang PP, Guo XY, Bai LG, Ma ZY. Design, synthesis and evaluation of 2-(2-oxoethyl)pyrimidine-5-carboxamide derivatives as acetylcholinesterase inhibitors. Bioorg Med Chem Lett 2022;72:128873. google scholar
50. Sağlık BN, Levent S, Osmaniye D, Evren AE, Karaduman AB, Özkay Y, et al. Design, Synthesis, and in Vitro and In Silico Approaches of Novel Indanone Derivatives as Multifunctional Anti-Alzheimer Agents. ACS Omega 2022;7(50):47378-404. google scholar