Design, synthesis, and bio-evaluation of new isoindoline-1,3-dione derivatives as possible inhibitors of acetylcholinesterase

Motahareh Hassanzadeh , Farshid Hassanzadeh , Ghadam Ali khodarahmi, Mahbobe Rostami, Fateme Azimi, Hamid Nadri, Farshad Homayouni Moghadam

Abstract


Background and purpose: Alzheimer’s disease is considered one of the lead causes of elderly death around the world. A significant decrease in acetylcholine level in the brain is common in most patients with Alzheimer’s disease, therefore acetylcholinesterase (AChE) inhibitors such as donepezil and rivastigmine are widely used for patients with limited therapeutic results and major side effects.

Experimental approach: A series of isoindoline-1,3-dione -N-benzyl pyridinium hybrids were designed, synthesized and evaluated as anti-Alzheimer agents with cholinesterase inhibitory activities. The structure of the compounds were confirmed by various methods of analysis such as HNMR, CNMR, and FT-IR. Molecular modeling studies were also performed to identify the possible interactions between neprilysin and synthesized compounds.

Findings/Results: The biological screening results indicated that all synthesized compounds displayed potent inhibitory activity with IC50 values ranging from 2.1 to 7.4 µM. Among synthesized compounds, para-fluoro substituted compounds 7a and 7f exhibited the highest inhibitory potency against AChE (IC50 = 2.1 µM). Molecular modeling studies indicated that the most potent compounds were able to interact with both catalytic and peripheral active sites of the enzyme. Also, some of the most potent compounds (7a, 7c, and 7f) demonstrated a neuroprotective effect against H2O2-induced cell death in PC12 neurons.

Conclusion and implications: The synthesized compounds demonstrated moderate to good AChE inhibitory effect with results higher than rivastigmine.


Keywords


Acetylcholinesterase inhibitors; Alzheimer's disease; Isoindoline-1,3-dione; Molecular docking; N-benzyl pyridinium.

References


Peauger L, Azzouz R, Gembus V, Tintas ML, Sopková-de Oliveira Santos J, Bohn P, et al. Donepezil-based central acetylcholinesterase inhibitors by means of a “bio-oxidizable” prodrug strategy: design, synthesis, and in vitro biological evaluation. J Med Chem. 2017;60(13):5909-5926.

DOI: 10.1021/acs.jmedchem.7b00702.

Zueva I, Dias J, Lushchekina S, Semenov V, Mukhamedyarov M, Pashirova T, et al. New evidence for dual binding site inhibitors of acetylcholinesterase as improved drugs for treatment of Alzheimer's disease. Neuropharmacology. 2019;155:131-141.

DOI: 10.1016/j.neuropharm.2019.05.025.

Alzheimer's Association. 2014 Alzheimer's disease facts and figures. Alzheimers Dement. 2014;10(2):e47-e92.

DOI: 10.1016/j.jalz.2014.02.001.

Bondi MW, Edmonds EC, Salmon DP. Alzheimer’s disease: past, present, and future. J Int Neuropsychol Soc. 2017;23(9-10):818-831.

DOI: 10.1017/S135561771700100X.

Kumar B, Kumar V, Prashar V, Saini S, Dwivedi AR, Bajaj B, et al. Dipropargyl substituted diphenylpyrimidines as dual inhibitors of monoamine oxidase and acetylcholinesterase. Eur J Med Chem. 2019;177:221-234.

DOI: 10.1016/j.ejmech.2019.05.039.

Rodda J, Carter J. Cholinesterase inhibitors and memantine for symptomatic treatment of dementia. BMJ. 2012;344:e2986.

DOI: 10.1136/bmj.e2986.

Bar-On P, Millard CB, Harel M, Dvir H, Enz A, Sussman JL, et al. Kinetic and structural studies on the interaction of cholinesterases with the anti-Alzheimer drug rivastigmine. Biochemistry. 2002;41(11):3555-3564.

DOI: 10.1021/bi020016x.

Cummings JL, Morstorf T, Zhong K. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther. 2014;6(4):37-43.

DOI: 10.1186/alzrt269.

Schneider LS, Mangialasche F, Andreasen N, Feldman H, Giacobini E, Jones R, et al. Clinical trials and late‐stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014. J Intern Med. 2014;275(3):251-283.

DOI: 10.1111/joim.12191.

Kryger G, Silman I, Sussman JL. Structure of acetylcholinesterase complexed with E2020 (Aricept®): implications for the design of new anti-Alzheimer drugs. Structure. 1999;7(3):297-307.

DOI: 10.1016/s0969-2126(99)80040-9.

Castro A, Martinez A. Peripheral and dual binding site acetylcholinesterase inhibitors: implications in treatment of Alzheimer's disease. Mini Rev Med Chem. 2001;1(3):267-272.

DOI: 10.2174/1389557013406864.

Giacobini E. Cholinesterases: new roles in brain function and in Alzheimer's disease. Neurochem Res. 2003;28(3-4):515-522.

DOI: 10.1023/a:1022869222652.

Pera M, Martinez-Otero A, Colombo L, Salmona M, Ruiz-Molina D, Badia A, et al. Acetylcholinesterase as an amyloid enhancing factor in PrP82-146 aggregation process. Mol Cell Neurosci. 2009;40(2):217-224.

DOI: 10.1016/j.mcn.2008.10.008.

Si W, Zhang T, Zhang L, Mei X, Dong M, Zhang K, et al. Design, synthesis and bioactivity of novel phthalimide derivatives as acetylcholinesterase inhibitors. Bioorg Med Chem Lett. 2016;26(9):2380-2382.

DOI: 10.1016/j.bmcl.2015.07.052.

Amanlou M, Asadollahi A, Asadi M, Hosseini F, Ekhtiari Z, Biglar M. Synthesis, molecular docking, and antiepileptic activity of novel phthalimide derivatives bearing amino acid conjugated anilines. Res Pharm Sci. 2019;14(6):534-543.

DOI: 10.4103/1735-5362.272562.

Alonso D, Dorronsoro I, Rubio L, Munoz P, García-Palomero E, Del Monte M, et al. Donepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE. Bioorg Med Chem. 2005;13(24):6588-6597.

DOI: 10.1016/j.bmc.2005.09.029.

Baharloo F, Moslemin MH, Nadri H, Asadipour A, Mahdavi M, Emami S, et al. Benzofuran-derived benzylpyridinium bromides as potent acetylcholinesterase inhibitors. Eur J Med Chem. 2015;93:196-201.

DOI: 10.1016/j.ejmech.2015.02.009.

Mostofi M, Ziarani GM, Mahdavi M, Moradi A, Nadri H, Emami S, et al. Synthesis and structure-activity relationship study of benzofuran-based chalconoids bearing benzylpyridinium moiety as potent acetylcholinesterase inhibitors. Eur J Med Chem. 2015;103:361-369.

DOI: 10.1016/j.ejmech.2015.08.061.

Wang C, Wu Z, Cai H, Xu S, Liu J, Jiang J, et al. Design, synthesis, biological evaluation and docking study of 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors. Bioorg Med Chem Lett. 2015;25(22):5212-5216.

DOI: 10.1016/j.bmcl.2015.09.063.

Bansode TN, Shelke JV, Dongre VG. Synthesis and antimicrobial activity of some new N-acyl substituted phenothiazines. Eur J Med Chem. 2009;44(12):5094-5098.

DOI: 10.1016/j.ejmech.2009.07.006.

Alzheimer's Association. 2013 Alzheimer's disease facts and figures. Alzheimers Dement. 2013;9(2):208-245.

DOI: 10.1016/j.jalz.2013.02.003.

Mohammadi-Farani A, Ahmadi A, Nadri H, Aliabadi A. Synthesis, docking and acetylcholinesterase inhibitory assessment of 2-(2-(4-Benzylpiperazin-1-yl) ethyl) isoindoline-1,3-dione derivatives with potential anti-Alzheimer effects. Daru. 2013;21(1):47-55.

DOI: 10.1186/2008-2231-21-47.

Momany FA, Rone R. Validation of the general purpose QUANTA® 3.2/CHARMm® force field. J Comput Chem. 1992;13(7):888-900.

DOI: 10.1002/jcc.540130714.

Azimi F, Ghasemi JB, Saghaei L, Hassanzadeh F, Mahdavi M, Sadeghi-Aliabadi H, et al. Identification of essential 2D and 3D chemical features for discovery of the novel tubulin polymerization inhibitors. Curr Top Med Chem. 2019;19(13):1092-1120.

DOI: 10.2174/1568026619666190520083655.

Azimi F, Ghasemi JB, Azizian H, Najafi M, Faramarzi MA, Saghaei L, et al. Design and synthesis of novel pyrazole-phenyl semicarbazone derivatives as potential α-glucosidase inhibitor: kinetics and molecular dynamics simulation study. Int J Biol Macromol. 2021;166:1082-1095.

DOI: 10.1016/j.ijbiomac.2020.10.263.

Rostami M, Bidram Z, Sirous H, Khodarahmi G, Hassanzadeh F, Dana N, et al. Monastrol derivatives: in silico and in vitro cytotoxicity assessments. Res Pharm Sci. 2020;15(3):249-262.

DOI: 10.4103/1735-5362.288427.

Mohammadi-Farani A, Abdi N, Moradi A, Aliabadi A. 2-(2-(4-Benzoylpiperazin-1-yl)ethyl)isoindoline-1,3-dione derivatives: synthesis, docking and acetylcholinesterase inhibitory evaluation as anti-alzheimer agents. Iran J Basic Med Sci. 2017;20(1):59-66.

DOI: 10.22038/ijbms.2017.8095.

Lan JS, Ding Y, Liu Y, Kang P, Hou JW, Zhang XY, et al. Design, synthesis and biological evaluation of novel coumarin-N-benzyl pyridinium hybrids as multi-target agents for the treatment of Alzheimer's disease. Eur J Med Chem. 2017;139:48-59.

DOI: 10.1016/j.ejmech.2017.07.055.


Refbacks

  • There are currently no refbacks.


Creative Commons LicenseThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.