Synthesis of some benzothiazole-piperazine derivatives, investigation by in vitro and molecular modelling for hMAO inhibitory activities

Abstract

Monoamine oxidase (MAO) is an enzyme that helps regulate the functions of intracellular amines, as well as chemicals such as dopamine, serotonin and norepinephrine, in the brain and its tissues. Active substances that are inhibitors of monoamine oxidases (MAOs) are used in the treatment of anxiety, depression and Alzheimer’s disease. Previous studies have shown that compounds containing piperazine rings show MAO-A inhibitory activity. Based on these studies, 4 compounds containing piperazine and benzothiazole rings were designed, and the structures of the compounds were elucidated using spectroscopic methods such as HRMS and 1H-NMR. hMAO-A and hMAO-B inhibitory activity was examined by in vitro methods. An in silico procedure was applied to investigate the residues and binding modes that interact with the docking of compounds 3a-d to the active site of the hMAO-A (PDB ID: 2Z5X) enzyme identified in the previous study. Compound 3b was found to be the most effective agent among the synthesized compounds with an IC50 value of 0.104±0.004 µM against the MAO-A enzyme.

Keywords

• Enzyme Inhibition
• MAO-A
• Molecular Docking
• Piperazine

References

1. Xu R, Xiao G, Li Y, Liu H, Song Q, Zhang X, Deng Y. Multifunctional 5, 6-dimethoxybenzo [d] isothiazol-3 (2H)-one-N-alkylbenzylamine derivatives with acetylcholinesterase, monoamine oxidases and β-amyloid aggregation inhibitory activities as potential agents against Alzheimer’s disease. Bioorg Med Chem. (2018); 26(8): 1885-1895. https://doi.org/10.1016/j.bmc.2018.02.037
2. Kaya B, Sağlık BN, Levent S, Özkay Y, Kaplancıklı ZA. Synthesis of some novel 2-substituted benzothiazole derivatives containing benzylamine moiety as monoamine oxidase inhibitory agents. J Enzyme Inhib Med Chem. (2016); 31(6): 1654-1661. https://doi.org/10.3109/14756366.2016.1161621
3. Tripathi RK, Ayyannan SR. Design, Synthesis, and Evaluation of 2‐Amino‐6‐nitrobenzothiazole‐Derived Hydrazones as MAO Inhibitors: Role of the Methylene Spacer Group. ChemMedChem. (2016); 11(14): 1551-1567. https://doi.org/10.1002/cmdc.201600202
4. Hall DWR, Logan BW, Parsons GH. Further studies on the inhibition of monoamine oxidase by M & B 9302 (clorgyline)—I: Substrate specificity in various mammalian species. Biochem Pharmacol. (1969); 18(6): 1447-1454. https://doi.org/10.1016/0006-2952(69)90258-5
5. Youdim MB, Finberg JP. New directions in monoamine oxidase A and B selective inhibitors and substrates. Biochem Pharmacol. (1991); 41(2): 155-162. https://doi.org/10.1016/0006-2952(91)90471-G
6. Finberg JP. Update on the pharmacology of selective inhibitors of MAO-A and MAO-B: focus on modulation of CNS monoamine neurotransmitter release. Pharmacol. & therap. (2014); 143(2): 133-152. https://doi.org/10.1016/j.pharmthera.2014.02.010
7. Youdim MB, Edmondson D, Tipton, KF. The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci. (2006); 7(4): 295-309. https://doi:10.1038/nrn1883
8. Shang J, Wang WM, Li YH, Song HB, Li ZM, Wang JG. Synthesis, crystal structure, in vitro acetohydroxyacid synthase inhibition, in vivo herbicidal activity, and 3D-QSAR of new asymmetric aryl disulfides. J Agric Food Chem. (2012); 60(34): 8286-8293. https://doi.org/10.1021/jf302206x

9. Johnstone AL, Reierson GW, Smith RP, Goldberg JL, Lemmon VP, Bixby JL. A chemical genetic approach identifies piperazine antipsychotics as promoters of CNS neurite growth on inhibitory substrates. Mol Cell Neurosci. (2012); 50(2): 125-135. https://doi.org/10.1016/j.mcn.2012.04.008
10. Kane JM, Dudley MW, Sorensen SM, Miller FP. 2, 4-Dihydro-3H-1,2,4-triazole-3-thiones as potential antidepressant agents. J Med Chem. (1988); 31(6): 1253-1258. https://doi.org/10.1021/jm00401a031
11. Sato G, Asakura S, Hakura A, Tsutsui-Hiyoshi Y, Kobayashi N, Tsukidate K. Assessment of potential mutagenic activities of a novel benzothiazole MAO-A inhibitor E2011 using Salmonella typhimurium YG1029. Mutat Res Genet Toxicol Environ Mutagen (2000); 472(1-2): 163-169. https://doi.org/10.1016/S1383-5718(00)00139-X
12. Uslu H, Osmaniye D, Sağlik BN, Levent S, Özkay Y, Benkli K, Kaplancikli ZA. Design, synthesis, in vitro, and in silico studies of 1,2,4-triazole-piperazine hybrid derivatives as potential MAO inhibitors. Bioorg Chem. (2021); 117: 105430. https://doi.org/10.1016/j.bioorg.2021.105430
13. Pessoa‐Mahana H, Gajardo GR, Araya‐Maturana R, Cárcamo JK, Pessoa‐Mahana CD. Synthesis of 4‐arylpiperazine derivatives of moclobemide: Potential antidepressants with a dual mode of action. Synth Commun (2004); 34(14): 2513-2521. https://doi.org/10.1081/SCC-200025581
14. Huang C, Xiong J, Guan HD, Wang CH, Lei X, Hu JF. Discovery, synthesis, biological evaluation and molecular docking study of (R)-5-methylmellein and its analogs as selective monoamine oxidase A inhibitors. Bioorg Med Chem. (2019); 27(10): 2027-2040. https://doi.org/10.1016/j.bmc.2019.03.060
15. Mohsen UA, Kaplancikli ZA, Özkay Y, Yurttaş L. Synthesis and evaluation of anti-acetylcholinesterase activity of some benzothiazole based new piperazine-dithiocarbamate derivatives. Drug Res. (2014); 176-183. https://doi.org 10.1055/s-0034-1375613
16. Turan-Zitouni G, Ozkay Y, Ozdemir A, Kaplancikli ZA, Altintop MD. Synthesis of some benzothiazole based piperazine-dithiocarbamate derivatives and evaluation of their anticancer activities. Lett Drug Des Discov (2011); 8(9): 830-837. https://doi.org/10.2174/157018011797200786
17. Sağlık BN, Osmaniye D, Acar Çevik U, Levent S, Kaya Çavuşoğlu B, Atlı Eklioğlu, Ö, Kaplancikli ZA. Synthesis, in vitro enzyme activity and molecular docking studies of new benzylamine-sulfonamide derivatives as selective MAO-B inhibitors. J Enzyme Inhib Med Chem (2020); 35(1): 1422-1432. https://doi.org/10.1080/14756366.2020.1784892
18. Can NÖ, Osmaniye D, Levent S, Sağlık BN, Korkut B, Atlı Ö, Kaplancıklı ZA. Design, synthesis and biological assessment of new thiazolylhydrazine derivatives as selective and reversible hMAO-A inhibitors. Eur J Med Chem. (2018); 144: 68-81. https://doi.org/10.1016/j.ejmech.2017.12.013
19. Altintop MD, Sever B, Osmaniye D, Sağlık BN, Özdemir A. Design, synthesis, in vitro and in silico evaluation of new pyrrole derivatives as monoamine oxidase inhibitors. Arch Pharm. (2018); 351(7): 1800082. https://doi.org/10.1002/ardp.201800082
20. Tok F, Sağlık BN, Özkay Y, Ilgın S, Kaplancıklı ZA, Koçyiğit-Kaymakçıoğlu B. Synthesis of new hydrazone derivatives and evaluation of their monoamine oxidase inhibitory activity. Bioorg Chem. (2021); 114: 105038. https://doi.org/10.1016/j.bioorg.2021.105038
21. Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. (2017); 7(1): 42717. https://doi.org/10.1038/srep42717
22. Son SY, Ma J, Kondou Y, Yoshimura M, Yamashita E, Tsukihara T. Structure of human monoamine oxidase A at 2.2-Å resolution: the control of opening the entry for substrates/inhibitors. Proc Natl Acad Sci. (2008); 105(15): 5739-5744. https://doi.org/10.1073/pnas.0710626105
23. Binda C, Wang J, Pisani L, Caccia C, Carotti A, Salvati P, Edmondson DE, Mattevi, A. Structures of human monoamine oxidase B complexes with selective noncovalent inhibitors: safinamide and coumarin analogs. J Med Chem. (2007); 50(23): 5848-5852. https://dx.doi.org/10.1021/jm070677y
24. Uslu H, Sağlık B, Osmaniye D, Benkli K. Novel substituted oxadiazole-piperazine derivatives as potential MAO inhibitors: Design, synthesis, in vitro and in silico studies. J Res Pharm. (2022); 26(1). https://dx.doi.org/10.29228/jrp.99
25. Osmaniye D, Evren AE, Sağlık BN, Levent S, Özkay Y, Kaplancıklı ZA. Design, synthesis, biological activity, molecular docking, and molecular dynamics of novel benzimidazole derivatives as potential AChE/MAO‐B dual inhibitors. Arch Pharm. (2022); 355(3): 2100450. https://doi.org/10.1002/ardp.202100450
26. Al-Sharabi AA, Evren AE, Sağlık BN, Yurttaş L. Synthesis, characterization, molecular docking and molecular dynamics simulations of novel 2, 5-disubstituted-1, 3, 4-thiadiazole derivatives as potential cholinesterase/monoamine oxidase dual inhibitors for Alzheimer’s disease. J Biomol Struct Dyn. (2023); 1-19. https://doi.org/10.1080/07391102.2023.2274967
27. Maestro, Schrödinger, LLC, New York, NY, 2023.
28. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. (2009); 30(16): 2785-2791. https://doi.org/10.1002/jcc.21256
29. Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. (2010); 31(2): 455-461. https://doi.org/10.1002/jcc.21334
30. Turan G, Osmaniye D, Sağlik BN, Çevik UA, Levent S, Çavuşoğlu BK, Kaplancikli ZA. Synthesis and monoamine oxidase A/B inhibitory evaluation of new benzothiazole-thiazolylhydrazine derivatives. Phosphorus Sulfur Silicon Relat Elem (2020); 195(6): 491-497. https://doi.org/10.1080/10426507.2020.1722667
31. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. (2012); 64: 4-17. https://doi.org/10.1016/j.addr.2012.09.019
32. Daina A, Michielin O, Zoete V. iLOGP: a simple, robust, and efficient description of n-octanol/water partition coefficient for drug design using the GB/SA approach. J Chem Inf Model (2014); 54(12): 3284-3301. https://doi.org/10.1021/ci500467k