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Multifunctional quinoxaline-hydrazone derivatives with acetylcholinesterase and monoamine oxidases inhibitory activities as potential agents against Alzheimer’s disease

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Abstract

Multitarget molecules are considered as an effective way for the treatment of AD, instead of the classic one-drug-one-target strategy because of the multifactorial nature of AD. A variety of studies indicate that several enzymes inhibitors can be useful in the treatment of AD, including acetylcholinesterase (AchE), butyrylcholinesterase (BuChE) and monoamine oxidase (MAO). Various substituted quinoxaline-hydrazone derivatives were synthesized, and their activity in vitro were investigated, including AChE/BuChE inhibitory activity and MAOA/B inhibitory activity. Based on the experimental results, compound 5l exhibited good inhibitory potency on both AchE (IC50 = 0.028 ± 0.001 μM) and monoamine oxidase B (IC50 = 0.046 ± 0.002 μM). Molecular modeling studies showed that 5l could bind to the active site of AChE and MAO-B. Taken together, these results suggested that compound 5l might be a potential multifunctional agent for the treatment of AD.

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References

  • Acar Çevik U, Sağlık BN, Levent S, Osmaniye D, Kaya Çavuşoğlu B, Özkay Y, Kaplancıklı ZA (2019) Synthesis and AChE-inhibitory activity of new benzimidazole derivatives. Molecules 24(5):861

    Article  PubMed Central  Google Scholar 

  • Bar-Am O, Amit T, Weinreb O, Youdim MB, Mandel S (2010) Propargylamine containing compounds as modulators of proteolytic cleavage of amyloid-beta protein precursor: involvement of MAPK and PKC activation. J Alzheimer’s Dis 21(2):361–371

    Article  CAS  Google Scholar 

  • Becker I (2008) Preparation of derivatives of 1-(2-pyrimidinyl) piperazine as potetial antianxiety, antideppessant, and antipsycotic agents. J Het Chem 45:1005–1022

    Article  CAS  Google Scholar 

  • Can ÖD, Osmaniye D, Demir Özkay Ü, Sağlık BN, Levent S, Ilgın S, Baysal M, Özkay Y, Kaplancıklı ZA (2017) MAO enzymes inhibitory activity of new benzimidazole derivatives including hydrazone and propargyl side chains. Eur J Med Chem 131:92–106

    Article  CAS  PubMed  Google Scholar 

  • Can NÖ, Osmaniye D, Levent S, Sağlık BN, Korkut B, Atlı Ö, Özkay Y, Kaplancıklı ZA (2018) Design, synthesis and biological assessment of new thiazolylhydrazine derivatives as selective and reversible hMAO-A inhibitors. Eur J Med Chem 144:68–81

    Article  CAS  PubMed  Google Scholar 

  • Chen CY, Lin TP, Chen CK, Lin SC, Tseng MS, Wen YS, Sun SS (2008) New chromogenic and fluorescent probes for anion detection: formation of a [2+2] supramolecular complex on addition of fluoride with positive homotropic cooperativity. J Org Chem 73(3):900–911

    Article  CAS  PubMed  Google Scholar 

  • Cheung J, Rudolph MJ, Burshteyn F, Cassidy MS, Gary EN, Love J, Matthew CF, Height JJ (2012) Structures of human acetylcholinesterase in complex with pharmacologically important ligands. J Med Chem 55:10282–10286

    Article  CAS  PubMed  Google Scholar 

  • Claudia B, Wang J, Pisani L, Caccia C, Carotti A, Salvati P, Edmondson DE, Mattevi A (2007) Structures of human monoamine oxidase B complexes with selective noncovalent inhibitors: safinamide and coumarin analogs. J Med Chem 50:5848–5852

    Article  Google Scholar 

  • D’Ascenzio M, Chimenti P, Gidaro MC, De Monte C, De Vita D, Granese A, Scipione L, Di Santo R, Costa G, Alcaro S, Yáñez M, Carradori S (2015) (Thiazol-2-yl)hydrazone derivatives from acetylpyridines as dual inhibitors of MAO and AChE: synthesis, biological evaluation and molecular modeling studies. J Enzyme Inhib Med Chem 30(6):908–919

    Article  PubMed  Google Scholar 

  • Dias Viegas FP, de Freitas Silva M, Divino da Rocha M, Castelli MR, Riquiel MM, Machado RP, Vaz SM, Simões de Lima LM, Mancini KC, Marques de Oliveira PC, Morais ÉP, Gontijo VS, da Silva FMR, D’Alincourt da Fonseca Peçanha D, Castro NG, Neves GA, Giusti-Paiva A, Vilela FC, Orlandi L, Camps I, Veloso MP, Leomil Coelho LF, Ionta M, Ferreira-Silva GA, Pereira RM, Dardenne LE, Guedes IA, de Oliveira Carneiro Jr W, Quaglio Bellozi PM, Pinheiro de Oliveira AC, Ferreira FF, Pruccoli L, Tarozzi A, Viegas C (2018) Design, synthesis and pharmacological evaluation of N-benzyl-piperidinyl-aryl-acylhydrazone derivatives as donepezil hybrids: discovery of novel multi-target anti-alzheimer prototype drug candidates. Eur J Med Chem 147:48–65

    Article  PubMed  Google Scholar 

  • Edmondson DE, Mattevi A, Binda C, Li M, Hubálek F (2004) Structure and mechanism of monoamineoxidase. Curr Med Chem 11:1983–1993

    Article  CAS  PubMed  Google Scholar 

  • Evranos-Aksöz B, Baysal İ, Yabanoğlu-Çiftçi S, Djikic T, Yelekçi K, Uçar G, Ertan R (2015) Synthesis and screening of human monoamine oxidase-A inhibitor effect of new 2-pyrazoline and hydrazone derivatives. Arch Pharm Chem Life Sci 348(10):743–756

    Article  Google Scholar 

  • Huang W, Tang L, Shi Y, Huang S, Xu L, Sheng R, Wu P, Li J, Zhou N, Hu Y (2011) Searching for the Multi-Target-Directed Ligands against Alzheimer’s disease: discovery of quinoxaline-based hybrid compounds with AChE, H3R and BACE 1 inhibitory activities. Bioorg Med Chem 19(23):7158–7167

    Article  CAS  PubMed  Google Scholar 

  • Hussein W, Saglık BN, Levent S, Korkut B, Ilgın S, Özkay Y, Kaplancıklı ZA (2018) Synthesis and biological evaluation of new cholinesterase inhibitors for Alzheimer’s disease. Molecules 23:2033

    Article  PubMed Central  Google Scholar 

  • Karaman N, Sıcak Y, Taşkın-Tok T, Öztürk M, Karaküçük-İyidoğan A, Dikmen M, Koçyiğit-Kaymakçıoğlu B, Oruç-Emre EE (2016) New piperidine-hydrazone derivatives: synthesis, biological evaluations and molecular docking studies as AChE and BChE inhibitors. Eur J Med Chem 124:270–283

    Article  CAS  PubMed  Google Scholar 

  • Kaya Çavuşoğlu B, Sağlık BN, Osmaniye D, Levent S, Acar Çevik U, Karaduman A, Özkay Y, Kaplancıklı Z (2018a) Synthesis and biological evaluation of new thiosemicarbazone derivative schiff bases as monoamine oxidase inhibitory agents. Molecules 23:60

    Article  Google Scholar 

  • Kaya Çavuşoğlu B, Sağlık BN, Özkay Y, İnci B, Kaplancıklı ZA (2018b) Design, synthesis, monoamine oxidase inhibition and docking studies of new dithiocarbamate derivatives bearing benzylamine moiety. Bioorg Chem 76:177–187

    Article  PubMed  Google Scholar 

  • Khattab SN, Abdel Moneim SA, Bekhit AA, El Massry AM, Hassan SY, El-Faham A, Ali Ahmed HE, Amer A (2015) Exploring new selective 3-benzylquinoxaline-based MAO-A inhibitors: design, synthesis, biological evaluation and docking studies. Eur J Med Chem 93:308–320

    Article  CAS  PubMed  Google Scholar 

  • Khattab SN, Hassan SY, Bekhit AA, El Massry AM, Langer V, Amer A (2010) Synthesis of new series of quinoxaline based MAO-inhibitors and docking studies. Eur J Med Chem 45(10):4479–4489

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Qiang X, Luo L, Yang X, Xiao G, Zheng Y, Cao Z, Sang Z, Su F, Deng Y (2017) Multitarget drug design strategy against Alzheimer’s disease: homoisoflavonoid mannich base derivatives serve as acetylcholinesterase and monoamine oxidase B dual inhibitors with multifunctional properties. Bioorg Med Chem 25(2):714–726

    Article  CAS  PubMed  Google Scholar 

  • Osmaniye D, Sağlık BN, Acar Çevik U, Levent S, Kaya Çavuşoğlu B, Özkay Y, Kaplancıklı ZA, Turan G (2019) Synthesis and AChE inhibitory activity of novel thiazolylhydrazone derivatives. Molecules 24(13):2392

    Article  CAS  PubMed Central  Google Scholar 

  • Özkay ÜD, Can ÖD, Sağlık BN, Cevik UA, Levent S, Özkay Y, Ilgın S, Atlı Ö (2016) Design, synthesis, and AChE inhibitory activity of new benzothiazole–piperazines. Bioorg Med Chem Lett 26:5387–5394

    Article  PubMed  Google Scholar 

  • Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M, Booker L, Oremus M (2008) Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med 148:379–397

    Article  PubMed  Google Scholar 

  • Sağlık BN, Ilgın S, Özkay Y (2016) Synthesis of new donepezil analogues and investigation of their effects on cholinesterase enzymes. Eur J Med Chem 124:1026–1040

    Article  PubMed  Google Scholar 

  • Sağlık BN, Kaya Çavuşoğlu B, Osmaniye D, Levent S, Acar Çevik U, Ilgın S, Özkay Y, Kaplancıklı ZA, Öztürk Y (2019) In vitro and in silico evaluation of new thiazole compounds as monoamine oxidase inhibitors. Bioorg Chem 85:97–108

    Article  PubMed  Google Scholar 

  • Sang Z, Pan W, Wang K, Ma Q, Yu L, Liu W (2017a) Design, synthesis and biological evaluation of 3,4-dihydro-2(1H)-quinoline-O-alkylamine derivatives as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer’s disease. Bioorg Med Chem 25(12):3006–3017

    Article  CAS  PubMed  Google Scholar 

  • Sang Z, Wang K, Wang H, Wang H, Ma Q, Han X, Ye M, Yu L, Liu W (2017b) Design, synthesis and biological evaluation of 2-acetyl-5-O-(aminoalkyl)phenol derivatives as multifunctional agents for the treatment of Alzheimer’s disease. Bioorg Med Chem Lett 27:5046–5052

    Article  CAS  PubMed  Google Scholar 

  • Scarpini E, Scheltens P, Feldman H (2003) Treatment of Alzheimer’s disease: current status and new perspectives. Lancet Neurol 2(9):539–547

    Article  CAS  PubMed  Google Scholar 

  • Sterling J, Herzig Y, Goren T, Finkelstein N, Lerner D, Goldenberg W, Miskolczi I, Molnar S, Rantal F, Tamas T, Toth G, Zagyva A, Zekany A, Finberg J, Lavian G, Gross A, Friedman R, Razin M, Huang W, Krais B, Chorev M, Youdim MB, Weinstock M (2002) Novel dual inhibitors of AChE and MAO derived from hydroxy aminoindan and phenethylamine as potential treatment for Alzheimer’s disease. J Med Chem 45(24):5260–5279

    Article  CAS  PubMed  Google Scholar 

  • Takeda A, Loveman E, Clegg A, Kirby J, Picot J, Payne E, Green C (2006) A systematic review of the clinical effectiveness of donepezil, rivastigmine and galantamine on cognition, quality of life and adverse events in Alzheimer’s disease. Int J Geriatr Psychopharmacol 21(1):17–28

    Article  CAS  Google Scholar 

  • Tripathi RK, Ayyannan SR (2016) Design, synthesis, and evaluation of 2-amino-6- nitrobenzothiazole-derived hydrazones as MAO inhibitors: role of the methylene spacer group. ChemMedChem 11(14):1551–1567

    Article  CAS  PubMed  Google Scholar 

  • Tok F, Koçyigit Kaymakçıoglu B, Saglık BN, Levent S, Özkay Y, Kaplancıklı ZA (2019) Synthesis and biological evaluation of new pyrazolone Schiff bases as monoamine oxidase and cholinesterase inhibitors. Bioorg Chem 84:41–50

    Article  CAS  PubMed  Google Scholar 

  • Wouters J (1998) Structural aspects of monoamine oxidase and its reversible inhibition. Curr Med Chem 5(2):137–162

    CAS  PubMed  Google Scholar 

  • Xiao G, Li Y, Qiang X, Xu R, Zheng Y, Cao Z, Luo L, Yang X, Sang Z, Su F, Deng Y (2017) Design, synthesis and biological evaluation of 4′-aminochalcone-rivastigmine hybrids as multifunctional agents for the treatment of Alzheimer’s disease. Bioorg Med Chem 25(3):1030–1041

    Article  CAS  PubMed  Google Scholar 

  • Xu YX, Wang H, Li XK, Dong SN, Liu WW, Gong Q, Wang TD, Tang Y, Zhu J, Li J, Zhang HY, Mao F (2018) Discovery of novel propargylamine-modified 4-aminoalkyl imidazole substituted pyrimidinylthiourea derivatives as multifunctional agents for the treatment of Alzheimer’s disease. Eur J Med Chem 143:33–47

    Article  CAS  PubMed  Google Scholar 

  • Yan-Yan H (2010) An efficient synthesis of 3-(indol-3-yl)quinoxalin-2-ones with TfOH- Catalyzed Friedel–Crafts type coupling reaction in air. Tetrahedron Lett 51(15):2023–2028

    Article  Google Scholar 

  • Youdim MB, Buccafusco JJ (2005) Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders. Trends Pharm Sci 26(1):27–35

    Article  CAS  PubMed  Google Scholar 

  • Youdim MB, Edmondson D, Tipton KF (2006) The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci 7(4):295–309

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was financially supported by Anadolu University Scientific Projects Fund, Project No: 1805S190 and 1905S033.

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu Universty, Eskişehir, Turkey

    Ulviye Acar Çevik, Derya Osmaniye, Begüm Nurpelin Sağlik, Betül Kaya Çavuşoğlu, Serkan Levent, Ahmet Çağrı Karaburun, Yusuf Özkay, Zafer Asım Kaplancikli & Gülhan Turan

  2. Doping and Narcotic Compounds Analysis Laboratory, Faculty of Pharmacy, Anadolu Universty, Eskişehir, Turkey

    Ulviye Acar Çevik, Derya Osmaniye, Begüm Nurpelin Sağlik, Betül Kaya Çavuşoğlu, Serkan Levent & Yusuf Özkay

  3. Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Anadolu Universty, Eskişehir, Turkey

    Abdullah Burak Karaduman & Sinem Ilgin

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  1. Ulviye Acar Çevik
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  2. Derya Osmaniye
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Correspondence to Ulviye Acar Çevik.

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Çevik, U.A., Osmaniye, D., Sağlik, B.N. et al. Multifunctional quinoxaline-hydrazone derivatives with acetylcholinesterase and monoamine oxidases inhibitory activities as potential agents against Alzheimer’s disease. Med Chem Res 29, 1000–1011 (2020). https://doi.org/10.1007/s00044-020-02541-4

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