A Review on the Arylpiperazine Derivatives as Potential Therapeutics for the Treatment of Various Neurological Disorders

Page: [729 - 751] Pages: 23

  • * (Excluding Mailing and Handling)

Abstract

Neurological disorders are disease conditions related to the neurons and central nervous system (CNS). Any structural, electrical, biochemical, and functional abnormalities in neurons can lead to various types of disorders, like Alzheimer’s disease (AD), depression, Parkinson’s disease (PD), epilepsy, stroke, etc. Currently available medicines are symptomatic and do not treat the disease state. Thus, novel CNS active agents with the potential to completely treat an illness are highly desired. A range of small organic molecules is being explored as potential drug candidates to cure different neurological disorders. In this context, arylpiperazinehas been found to be a versatile scaffold and indispensable pharmacophore in many CNS active agents. Several molecules with arylpiperazine nucleus have been developed as potent leads for the treatment of AD, PD, depression, and other disorders. The arylpiperazine nucleus can be optionally substituted at different chemical structures and offer flexibility for the synthesis of a large number of derivatives. In the current review article, we have explored the role of various arylpiperazine containing scaffolds against different neurological disorders, including AD, PD, and depression. The structure-activity relationship studies were conducted for recognizing potent lead compounds. This review article may provide important insights into the structural requirements for designing and synthesizing effective molecules as curative agents for different neurological disorders.

Keywords: Neurological disorders, arylpiperazines, Alzheimer’s disease, Parkinson’s disease, depression, curative agents.

Graphical Abstract

[1]
Farooqui AA. Neurochemical aspects of neurological disorders.Trace amines and neurological disorders. Tahira F, Akhlaq AF. London: Elsevier 2016; pp. 237-56.
[http://dx.doi.org/10.1016/B978-0-12-803603-7.00016-1]
[2]
Cruz-Haces M, Tang J, Acosta G, Fernandez J, Shi R. Pathological correlations between traumatic brain injury and chronic neurodegenerative diseases. Transl Neurodegener 2017; 6: 20.
[http://dx.doi.org/10.1186/s40035-017-0088-2] [PMID: 28702179]
[3]
Tyagi V. A Review on Image Classification Techniques to classify Neurological Disorders of brain MRI. 2019 International Conference on Issues and Challenges in Intelligent Computing Techniques (ICICT) 2019; 1-4.
[http://dx.doi.org/10.1109/ICICT46931.2019.8977658] [PMID: 28702179]
[4]
Feigin VL, Nichols E, Alam T, et al. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18(5): 459-80.
[5]
Kanwar JR, Sun X, Punj V, et al. Nanoparticles in the treatment and diagnosis of neurological disorders: Untamed dragon with fire power to heal. Nanomedicine 2012; 8(4): 399-414.
[http://dx.doi.org/10.1016/j.nano.2011.08.006] [PMID: 21889479]
[6]
Rocca WA. The burden of Parkinson’s disease: a worldwide perspective. Lancet Neurol 2018; 17(11): 928-9.
[http://dx.doi.org/10.1016/S1474-4422(18)30355-7] [PMID: 30287052]
[7]
Murray CJ, Vos T, Lozano R, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380(9859): 2197-223.
[http://dx.doi.org/10.1016/S0140-6736(12)61689-4] [PMID: 23245608]
[8]
Rathi AK, Syed R, Shin H-S, Patel RV. Piperazine derivatives for therapeutic use: A patent review (2010-present), Expert opinion on therapeutic patents. Expert Opin Ther Pat 2016; 26: 777-97.
[9]
Maia RC, Tesch R, Fraga CAM. Phenylpiperazine derivatives: A patent review (2006-present). Expert Opin Ther Pat 2012; 22(10): 1169.
[10]
Rague A, Tidgewell K. Pharmacophore comparison and development of recently discovered long chain arylpiperazine and sulfonamide based 5-HT7 ligands. Mini Rev Med Chem 2018; 18(7): 552-60.
[http://dx.doi.org/10.2174/1389557517666170913111533] [PMID: 28901854]
[11]
Singh K, Pal R, Khan SA, Kumar B, Akhtar MJ. Insights into the structure activity relationship of Nitrogen-containing heterocyclics for the development of antidepressant compounds: An updated review. J Mol Struct 2021; 1237130369
[http://dx.doi.org/10.1016/j.molstruc.2021.130369]
[12]
Kharb R, Bansal K, Sharma AK. A valuable insight into recent advances on antimicrobial activity of piperazine derivatives. Pharma Chem 2012; 4(6): 2470-88.
[13]
Kumar CA, Swamy SN, Thimmegowda N, Prasad SB, Yip GW, Rangappa K. Synthesis and evaluation of 1-benzhydryl-sulfonyl-piperazine derivatives as inhibitors of MDA-MB-231 human breast cancer cell proliferation. Med Chem Res 2007; 16: 179-87.
[http://dx.doi.org/10.1007/s00044-007-9022-y]
[14]
Hepperle M, Eckert J, Gala D, Shen L, Anderson EC, Goodman A. Mono N-arylation of piperazine(III): Metal-catalyzed N-arylation and its application to the novel preparations of the antifungal posaconazole and its advanced intermediate. Tetrahedron Lett 2002; 43: 3359-63.
[http://dx.doi.org/10.1016/S0040-4039(02)00556-7]
[15]
Rani M, Parthiban P, Ramachandran R, Kabilan S. Design and synthesis of novel piperazine unit condensed 2, 6-diarylpiperidin-4-one derivatives as antituberculosis and antimicrobial agents. Med Chem Res 2012; 21: 653-62.
[http://dx.doi.org/10.1007/s00044-011-9573-9]
[16]
Bali A, Malhotra S, Dhir H, Kumar A, Sharma A. Synthesis and evaluation of 1-(quinoliloxypropyl)-4-aryl piperazines for atypical antipsychotic effect. Bioorg Med Chem Lett 2009; 19(11): 3041-4.
[http://dx.doi.org/10.1016/j.bmcl.2009.04.019] [PMID: 19398330]
[17]
Pai NR, Dubhashi DS, Pusalkar D. Substituted 3, 4-dihydro-1h-quinolin-2-one derivatives as potential antidepressant, sedative and anti-parkinson agents. Int J Pharm Sci Rev Res 2010; 5: 124-31.
[18]
Mendoza A, Pérez-Silanes S, Quiliano M, et al. Aryl piperazine and pyrrolidine as antimalarial agents. Synthesis and investigation of structure-activity relationships. Exp Parasitol 2011; 128(2): 97-103.
[http://dx.doi.org/10.1016/j.exppara.2011.02.025] [PMID: 21354139]
[19]
Wei Z-Y, Chi K-Q, Wang K-S, Wu J, Liu L-P, Piao H-R. Design, synthesis, evaluation, and molecular docking of ursolic acid derivatives containing a nitrogen heterocycle as anti-inflammatory agents. Bioorg Med Chem Lett 2018; 28(10): 1797-803.
[http://dx.doi.org/10.1016/j.bmcl.2018.04.021] [PMID: 29678461]
[20]
Sharma S, Kumar D, Singh G, Monga V, Kumar B. Recent advancements in the development of heterocyclic anti-inflammatory agents. Eur J Med Chem 2020; 200112438
[http://dx.doi.org/10.1016/j.ejmech.2020.112438] [PMID: 32485533]
[21]
Millan MJ, Gobert A, Roux S, et al. The serotonin1A receptor partial agonist S15535 [4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine] enhances cholinergic transmission and cognitive function in rodents: A combined neurochemical and behavioral analysis. J Pharmacol Exp Ther 2004; 311(1): 190-203.
[http://dx.doi.org/10.1124/jpet.104.069625] [PMID: 15146031]
[22]
Abdelsayed S, Duong NT, Bureau C, et al. Piperazine derivatives as iron chelators: a potential application in neurobiology. Biometals 2015; 28(6): 1043-61.
[http://dx.doi.org/10.1007/s10534-015-9889-x] [PMID: 26502356]
[23]
Dong MX, Lu L, Li H, et al. Design, synthesis, and biological activity of novel 1,4-disubstituted piperidine/piperazine derivatives as CCR5 antagonist-based HIV-1 entry inhibitors. Bioorg Med Chem Lett 2012; 22(9): 3284-6.
[http://dx.doi.org/10.1016/j.bmcl.2012.03.019] [PMID: 22464131]
[24]
Arbo MD, Bastos ML, Carmo HF. Piperazine compounds as drugs of abuse. Drug Alcohol Depend 2012; 122(3): 174-85.
[http://dx.doi.org/10.1016/j.drugalcdep.2011.10.007] [PMID: 22071119]
[25]
Johnstone AC, Lea RA, Brennan KA, Schenk S, Kennedy MA, Fitzmaurice PS. Benzylpiperazine: A drug of abuse? J Psychopharmacol 2007; 21(8): 888-94.
[http://dx.doi.org/10.1177/0269881107077260] [PMID: 17606471]
[26]
Monteiro MS, Bastos Mde L, Guedes de Pinho P, Carvalho M. Update on 1-benzylpiperazine (BZP) party pills. Arch Toxicol 2013; 87(6): 929-47.
[http://dx.doi.org/10.1007/s00204-013-1057-x] [PMID: 23685794]
[27]
Gettys KE, Ye Z, Dai M. Recent advances in piperazine synthesis. Synthesis 2017; 49: 2589-604.
[http://dx.doi.org/10.1055/s-0036-1589491]
[28]
López-Rodríguez ML, Ayala D, Benhamú B, Morcillo MJ, Viso A. Arylpiperazine derivatives acting at 5-HT(1A) receptors. Curr Med Chem 2002; 9(4): 443-69.
[http://dx.doi.org/10.2174/0929867023371030] [PMID: 11945120]
[29]
Bielenica A. Kozio322; AE, Struga M. Binding modes of chain arylpiperazines to 5-HT1a, 5-HT2a and 5-HT7 receptors. Mini Rev Med Chem 2013; 13(10): 1516-39.
[http://dx.doi.org/10.2174/1389557511313100012] [PMID: 24568298]
[30]
Kumar B, Kumar V, Prashar V, et al. Dipropargyl substituted diphenylpyrimidines as dual inhibitors of monoamine oxidase and acetylcholinesterase. Eur J Med Chem 2019; 177: 221-34.
[http://dx.doi.org/10.1016/j.ejmech.2019.05.039] [PMID: 31151057]
[31]
Kumar V, Kumar B, Ranjan Dwivedi A, et al. Design, synthesis and evaluation of o8208;pentyne substituted diphenylpyrimidines as monoamine oxidase and acetylcholinesterase inhibitors. ChemistrySelect 2020; 5: 8021-32.
[http://dx.doi.org/10.1002/slct.202002425]
[32]
Kumar B. Sheetal, Mantha AK, Kumar V. Synthesis, biological evaluation and molecular modeling studies of phenyl-/benzhydrylpiperazine derivatives as potential MAO inhibitors. Bioorg Chem 2018; 77: 252-62.
[http://dx.doi.org/10.1016/j.bioorg.2018.01.020] [PMID: 29421700]
[33]
Kumar B, Gupta VP, Kumar V. A perspective on monoamine oxidase enzyme as drug target: challenges and opportunities. Curr Drug Targets 2017; 18(1): 87-97.
[http://dx.doi.org/10.2174/1389450117666151209123402] [PMID: 26648064]
[34]
Kumar B, Mantha AK, Kumar V. Recent developments on the structure-activity relationship studies of MAO inhibitors and their role in different neurological disorders. RSC Advances 2016; 6: 42660-83.
[http://dx.doi.org/10.1039/C6RA00302H]
[35]
Jankovic J. Parkinson’s disease: Clinical features and diagnosis. J Neurol Neurosurg Psychiatry 2008; 79(4): 368-76.
[http://dx.doi.org/10.1136/jnnp.2007.131045] [PMID: 18344392]
[36]
Gaspar A, Reis J, Fonseca A, et al. Chromone 3-phenylcar-boxamides as potent and selective MAO-B inhibitors. Bioorg Med Chem Lett 2011; 21(2): 707-9.
[http://dx.doi.org/10.1016/j.bmcl.2010.11.128] [PMID: 21194943]
[37]
Song B, Xiao T, Qi X, et al. Design and synthesis of 8-substituted benzamido-phenylxanthine derivatives as MAO-B inhibitors. Bioorg Med Chem Lett 2012; 22(4): 1739-42.
[http://dx.doi.org/10.1016/j.bmcl.2011.12.094] [PMID: 22257893]
[38]
Marek K. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002; 287(13): 1653-61.
[http://dx.doi.org/10.1001/jama.287.13.1653] [PMID: 11926889]
[39]
Kumar RR, Sahu B, Pathania S, Singh PK, Akhtar MJ, Kumar B. Piperazine, a key substructure for antidepressants: Its role in developments and structure-activity relationships. ChemMedChem 2021; 16(12): 1878-901.
[http://dx.doi.org/10.1002/cmdc.202100045] [PMID: 33751807]
[40]
Mallajosyula JK, Kaur D, Chinta SJ, et al. MAO-B elevation in mouse brain astrocytes results in Parkinson’s pathology. PLoS One 2008; 3(2)e1616
[http://dx.doi.org/10.1371/journal.pone.0001616] [PMID: 18286173]
[41]
Jenner P, Olanow CW. Oxidative stress and the pathogenesis of Parkinson’s disease. Neurology 1996; 47(6)(Suppl. 3): S161-70.
[http://dx.doi.org/10.1212/WNL.47.6_Suppl_3.161S] [PMID: 8959985]
[42]
Kumar B, Kumar M, Dwivedi AR, Kumar V. Synthesis, biological evaluation and molecular modeling studies of propargyl-containing 2,4,6-trisubstituted pyrimidine derivatives as potential anti-parkinson agents. ChemMedChem 2018; 13(7): 705-12.
[http://dx.doi.org/10.1002/cmdc.201700589] [PMID: 29534334]
[43]
Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: A review. JAMA 2014; 311(16): 1670-83.
[http://dx.doi.org/10.1001/jama.2014.3654] [PMID: 24756517]
[44]
Macleod AD, Counsell CE, Ives N, Stowe R, Stowe R, Counsell C. Monoamine oxidase B inhibitors for early Parkinson’s disease. Cochrane Database Syst Rev 2005; 20(3)CD004898
[PMID: 16034956]
[45]
Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE. Systematic review of levodopa dose equivalency reporting in Parkinson’s disease. Mov Disord 2010; 25(15): 2649-53.
[http://dx.doi.org/10.1002/mds.23429] [PMID: 21069833]
[46]
Jones CA, Johnston LC, Jackson MJ, et al. An in vivo pharmacological evaluation of pardoprunox (SLV308) - a novel combined dopamine D(2)/D(3) receptor partial agonist and 5-HT(1A) receptor agonist with efficacy in experimental models of Parkinson’s disease. Eur Neuropsychopharmacol 2010; 20(8): 582-93.
[http://dx.doi.org/10.1016/j.euroneuro.2010.03.001] [PMID: 20434890]
[47]
Tayarani-Binazir K, Jackson MJ, Rose S, McCreary AC, Jenner P. The partial dopamine agonist pardoprunox (SLV308) administered in combination with l-dopa improves efficacy and decreases dyskinesia in MPTP treated common marmosets. Exp Neurol 2010; 226(2): 320-7.
[http://dx.doi.org/10.1016/j.expneurol.2010.09.007] [PMID: 20843474]
[48]
Dutta AK, Fei X-S, Reith ME. A novel series of hybrid compounds derived by combining 2-aminotetralin and piperazine fragments: Binding activity at D2 and D3 receptors. Bioorg Med Chem Lett 2002; 12(4): 619-22.
[http://dx.doi.org/10.1016/S0960-894X(01)00820-4] [PMID: 11844685]
[49]
Biswas S, Hazeldine S, Ghosh B, et al. Bioisosteric heterocyclic versions of 7-{[2-(4-phenyl-piperazin-1-yl) ethyl] propylamino}-5, 6, 7, 8-tetrahydronaphthalen-2-ol: identification of highly potent and selective agonists for dopamine D3 receptor with potent in vivo activity. J Med Chem 2008; 51: 3005-19.
[http://dx.doi.org/10.1021/jm701524h] [PMID: 18410082]
[50]
Li C, Biswas S, Li X, Dutta AK, Le W. Novel D3 dopamine receptor-preferring agonist D-264: Evidence of neuroprotective property in Parkinson’s disease animal models induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and lactacystin. J Neurosci Res 2010; 88(11): 2513-23.
[http://dx.doi.org/10.1002/jnr.22405] [PMID: 20623619]
[51]
Modi G, Antonio T, Reith M, Dutta A. Structural modifications of neuroprotective anti-Parkinsonian (-)-N6-(2-(4-(biphenyl-4-yl)piperazin-1-yl)-ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (D-264): an effort toward the improvement of in vivo efficacy of the parent molecule. J Med Chem 2014; 57(4): 1557-72.
[http://dx.doi.org/10.1021/jm401883v] [PMID: 24471976]
[52]
Ghosh B, Antonio T, Zhen J, Kharkar P, Reith ME, Dutta AK. Development of (S)-N6-(2-(4-(isoquinolin-1-yl)piperazin-1-yl)ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]-thiazole-2,6-diamine and its analogue as a D3 receptor preferring agonist: Potent in vivo activity in Parkinson’s disease animal models. J Med Chem 2010; 53(3): 1023-37.
[http://dx.doi.org/10.1021/jm901184n] [PMID: 20038106]
[53]
Noureddine O, Gatfaoui S, Brandan SA, Sagaama A, Marouani H, Issaoui N. Experimental and DFT studies on the molecular structure, spectroscopic properties, and molecular docking of 4-arylpiperazine-1-ium dihydrogen phosphate. J Mol Struct 2020; 1207127762
[http://dx.doi.org/10.1016/j.molstruc.2020.127762]
[54]
Corrêa MF, Reiner D, Fernandes GA, et al. Profiling of LINS01 compounds at human dopamine D 2 and D 3 receptors. J Chem Sci 2020; 132: 1-6.
[http://dx.doi.org/10.1007/s12039-019-1694-6]
[55]
Rangel-Barajas C, Malik M, Taylor M, Neve KA, Mach RH, Luedtke RR. Characterization of [(3) H]LS-3-134, a novel arylamide phenylpiperazine D3 dopamine receptor selective radioligand. J Neurochem 2014; 131(4): 418-31.
[http://dx.doi.org/10.1111/jnc.12825] [PMID: 25041389]
[56]
Shao Y-M, Ma X, Paira P, et al. Discovery of indolylpiperazinylpyrimidines with dual-target profiles at adenosine A2A and dopamine D2 receptors for Parkinson’s disease treatment. PLoS One 2018; 13(1)e0188212
[http://dx.doi.org/10.1371/journal.pone.0188212] [PMID: 29304113]
[57]
Cao Y, Sun N, Zhang J, et al. Design, synthesis, and evaluation of bitopic arylpiperazine-phthalimides as selective dopamine D3 receptor agonists. MedChemComm 2018; 9(9): 1457-65.
[http://dx.doi.org/10.1039/C8MD00237A] [PMID: 30288220]
[58]
Stank L, Frank A, Hagenow S, Stark H. Talipexole variations as novel bitopic dopamine D 2 and D 3 receptor ligands. MedChemComm 2019; 10: 1926-9.
[http://dx.doi.org/10.1039/C9MD00379G]
[59]
Schübler M, Sadek B, Kottke T, Weizel L, Stark H. Synthesis, molecular properties estimations, and dual dopamine D2 and D3 receptor activities of benzothiazole-based ligands. Front Chem 2017; 5: 64.
[http://dx.doi.org/10.3389/fchem.2017.00064] [PMID: 28955709]
[60]
Blazer D, Burchett B, Service C, George LK. The association of age and depression among the elderly: an epidemiologic exploration. J Gerontol 1991; 46(6): M210-5.
[http://dx.doi.org/10.1093/geronj/46.6.M210] [PMID: 1834726]
[61]
Chen S-F, Chien Y-H, Chen P-C, Wang I-J. Association of age with risk of major depression among patients with chronic kidney disease over midlife: A nationwide cohort study in Taiwan. Int Psychogeriatr 2019; 31(8): 1171-9.
[http://dx.doi.org/10.1017/S1041610218001576] [PMID: 30398134]
[62]
WHO. Depression and other common mental disorders: Global health estimates in, World Health Organization 2017. Available from. https://apps.who.int/iris/bitstream/handle/10665/254610/WHO-MSD-MER-2017.2-eng.pdf
[63]
Faquih AE, Memon RI, Hafeez H, Zeshan M, Naveed S. A review of novel antidepressants: A guide for clinicians. Cureus 2019; 11(3)e4185
[http://dx.doi.org/10.7759/cureus.4185] [PMID: 31106085]
[64]
sby U, Brandt L, Correia N, Ekbom A, Sparén P. Excess mortality in bipolar and unipolar disorder in Sweden. Arch Gen Psychiatry 2001; 58(9): 844-50.
[http://dx.doi.org/10.1001/archpsyc.58.9.844] [PMID: 11545667]
[65]
Almeida OP, Alfonso H, Hankey GJ, Flicker L. Depression, antidepressant use and mortality in later life: the health in men study. PLoS One 2010; 5(6)e11266
[http://dx.doi.org/10.1371/journal.pone.0011266] [PMID: 20585644]
[66]
Skånland SS. Cie347;lar-Pobuda A. Off-label uses of drugs for depression. Eur J Pharmacol 2019; 865172732
[http://dx.doi.org/10.1016/j.ejphar.2019.172732] [PMID: 31622593]
[67]
Mathew B, Mathew GE, Suresh J, et al. Monoamine oxidase inhibitors: Perspective design for the treatment of depression and neurological disorders. Curr Enzym Inhib 2016; 12: 115-22.
[http://dx.doi.org/10.2174/1573408012666160402001715]
[68]
Gillman PK, Feinberg SS, Fochtmann LJ. Revitalizing monoamine oxidase inhibitors: A call for action. CNS Spectr 2020; 25(4): 452-4.
[PMID: 31272520]
[69]
Joshi A. Selective serotonin re-uptake inhibitors: An overview. Psychiatr Danub 2018; 30(Suppl. 7): 605-9.
[PMID: 30439857]
[70]
Montgomery SA, Nielsen RZ, Poulsen LH, Häggström L. A randomised, double-blind study in adults with major depressive disorder with an inadequate response to a single course of selective serotonin reuptake inhibitor or serotonin-noradrenaline reuptake inhibitor treatment switched to vortioxetine or agomelatine. Hum Psychopharmacol 2014; 29(5): 470-82.
[http://dx.doi.org/10.1002/hup.2424] [PMID: 25087600]
[71]
Heinrich T, Böttcher H, Bartoszyk GD, Greiner HE, Seyfried CA, Van Amsterdam C. Indolebutylamines as selective 5-HT(1A) agonists. J Med Chem 2004; 47(19): 4677-83.
[http://dx.doi.org/10.1021/jm040792y] [PMID: 15341483]
[72]
Siracusa MA, Salerno L, Modica MN, et al. Synthesis of new arylpiperazinylalkylthiobenzimidazole, benzothiazole, or benzoxazole derivatives as potent and selective 5-HT1A serotonin receptor ligands. J Med Chem 2008; 51(15): 4529-38.
[http://dx.doi.org/10.1021/jm800176x] [PMID: 18598015]
[73]
Kumar J, Chawla G, Akhtar M, Sahu K, Rathore V, Sahu S. Design, synthesis and pharmacological evaluation of some novel derivatives of 1-{[3-(furan-2-yl)-5-phenyl-4, 5-dihydro-1, 2-oxazol-4-yl] methyl}-4-methyl piperazine. Arab J Chem 2013; 10: 141-9.
[http://dx.doi.org/10.1016/j.arabjc.2013.04.027]
[74]
Becker OM, Dhanoa DS, Marantz Y, et al. An integrated in silico 3D model-driven discovery of a novel, potent, and selective amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression. J Med Chem 2006; 49(11): 3116-35.
[http://dx.doi.org/10.1021/jm0508641] [PMID: 16722631]
[75]
Kaya B. Yurtta351; L, Sa287;lik BN, Levent S, zkay Y, Kaplancikli ZA. Novel 1-(2-pyrimidin-2-yl)piperazine derivatives as selective monoamine oxidase (MAO)-A inhibitors. J Enzyme Inhib Med Chem 2017; 32(1): 193-202.
[http://dx.doi.org/10.1080/14756366.2016.1247054] [PMID: 28097890]
[76]
Dorsey JM, Miranda MG, Cozzi NV, Pinney KG. Synthesis and biological evaluation of 2-(4-fluorophenoxy)-2-phenyl-ethyl piperazines as serotonin-selective reuptake inhibitors with a potentially improved adverse reaction profile. Bioorg Med Chem 2004; 12(6): 1483-91.
[http://dx.doi.org/10.1016/j.bmc.2003.12.021] [PMID: 15018922]
[77]
Bang-Andersen B, Ruhland T, Jørgensen M, et al. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): A novel multimodal compound for the treatment of major depressive disorder. J Med Chem 2011; 54(9): 3206-21.
[http://dx.doi.org/10.1021/jm101459g] [PMID: 21486038]
[78]
Sapa J, Filipek B, Kulig K, Malawska B. Antidepressant-like activity of the phenylpiperazine pyrrolidin-2-one derivatives in mice. Pharmacol Rep 2011; 63(1): 71-8.
[http://dx.doi.org/10.1016/S1734-1140(11)70400-5] [PMID: 21441613]
[79]
Seo HJ, Park E-J, Kim MJ, et al. Design and synthesis of novel arylpiperazine derivatives containing the imidazole core targeting 5-HT(2A) receptor and 5-HT transporter. J Med Chem 2011; 54(18): 6305-18.
[http://dx.doi.org/10.1021/jm200682b] [PMID: 21823597]
[80]
Kubacka M, Mogilski S, Bednarski M, et al. Antidepressant-like activity of aroxyalkyl derivatives of 2-methoxyphenylpiperazine and evidence for the involvement of serotonin receptor subtypes in their mechanism of action. Pharmacol Biochem Behav 2016; 141: 28-41.
[http://dx.doi.org/10.1016/j.pbb.2015.11.013] [PMID: 26647362]
[81]
Waszkielewicz AM, Pytka K, Rapacz A, et al. Synthesis and evaluation of antidepressant-like activity of some 4-substituted 1-(2-methoxyphenyl) piperazine derivatives. Chem Biol Drug Des 2015; 85(3): 326-35.
[http://dx.doi.org/10.1111/cbdd.12394] [PMID: 25048712]
[82]
Kang SY, Park E-J, Park W-K, et al. Arylpiperazine-containing pyrrole 3-carboxamide derivatives targeting serotonin 5-HT(2A), 5-HT(2C), and the serotonin transporter as a potential antidepressant. Bioorg Med Chem Lett 2010; 20(5): 1705-11.
[http://dx.doi.org/10.1016/j.bmcl.2010.01.093] [PMID: 20149649]
[83]
Zagórska A, Jurczyk S. Pawłowski M, et al. Synthesis and preliminary pharmacological evaluation of imidazo[2,1-f]purine-2,4-dione derivatives. Eur J Med Chem 2009; 44(11): 4288-96.
[http://dx.doi.org/10.1016/j.ejmech.2009.07.014] [PMID: 19679379]
[84]
Zagórska A, Partyka A, Bucki A, et al. Characteristics of metabolic stability and the cell permeability of 2-pyrimidinyl-piperazinyl-alkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione with antidepressant- and anxiolytic-like activities. Chem Biol Drug Des 2019; 93(4): 511-21.
[http://dx.doi.org/10.1111/cbdd.13442] [PMID: 30422400]
[85]
Kim JY, Kim D, Kang SY, et al. Arylpiperazine-containing pyrimidine 4-carboxamide derivatives targeting serotonin 5-HT(2A), 5-HT(2C), and the serotonin transporter as a potential antidepressant. Bioorg Med Chem Lett 2010; 20(22): 6439-42.
[http://dx.doi.org/10.1016/j.bmcl.2010.09.081] [PMID: 20933409]
[86]
Weng Z, Li J. Synthesis and antidepressant activity of optical isomers of 2-(4-benzylpiperazin-1-yl)-1-(5-chloro-6-methoxy-naphthalen-2-yl) propan-1-ol (SIPI5056). Bioorg Med Chem Lett 2010; 20(3): 1256-9.
[http://dx.doi.org/10.1016/j.bmcl.2009.11.108] [PMID: 20022503]
[87]
Pessoa-Mahana H, Recabarren-Gajardo G, Temer JF, et al. Synthesis, docking studies and biological evaluation of benzo[b]thiophen-2-yl-3-(4-arylpiperazin-1-yl)-propan-1-one derivatives on 5-HT1A serotonin receptors. Molecules 2012; 17(2): 1388-407.
[http://dx.doi.org/10.3390/molecules17021388] [PMID: 22306829]
[88]
Czopek A, Byrtus H. Kołaczkowski M, et al Synthesis and pharmacological evaluation of new 5-(cyclo)alkyl-5-phenyl- and 5-spiroimidazolidine-2,4-dione derivatives. Novel 5-HT1A receptor agonist with potential antidepressant and anxiolytic activity. Eur J Med Chem 2010; 45(4): 1295-303.
[http://dx.doi.org/10.1016/j.ejmech.2009.11.053] [PMID: 20060623]
[89]
Czopek A, Bucki A. Kołaczkowski M, et al Novel multitarget 5-arylidenehydantoins with arylpiperazinealkyl fragment: Pharmacological evaluation and investigation of cytotoxicity and metabolic stability. Bioorg Med Chem 2019; 27(18): 4163-73.
[http://dx.doi.org/10.1016/j.bmc.2019.07.046] [PMID: 31383628]
[90]
Lacivita E, Leopoldo M N. N-[ω-[4-(2-methoxyphenyl)-1-piperazinyl] alkyl]-2-quinolinamines as high-affinity fluorescent 5-HT1A receptor ligands. J Med Chem 2008; 51(5): 1492-5.
[http://dx.doi.org/10.1021/jm7013919] [PMID: 18269229]
[91]
Zar281;ba P, Ja347;kowska J, Czekaj I, Sata322;a G. Design, synthesis and molecular modelling of new bulky Fananserin derivatives with altered pharmacological profile as potential antidepressants. Bioorg Med Chem 2019; 27(15): 3396-407.
[http://dx.doi.org/10.1016/j.bmc.2019.06.028] [PMID: 31253535]
[92]
Wróbel MZ, Chodkowski A, Marciniak M, et al. Synthesis of new 4-butyl-arylpiperazine-3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives and evaluation for their 5-HT1A and D2 receptor affinity and serotonin transporter inhibition. Bioorg Chem 2020; 97103662
[http://dx.doi.org/10.1016/j.bioorg.2020.103662] [PMID: 32086055]
[93]
Łażewska D, Kurczab R, Więcek M, et al. The computer-aided discovery of novel family of the 5-HT6 serotonin receptor ligands among derivatives of 4-benzyl-1,3,5-triazine. Eur J Med Chem 2017; 117(24)
[http://dx.doi.org/10.1016/j.ejmech.2017.04.033] [PMID: 28441580]
[94]
Goedert M, Spillantini MG. A century of Alzheimer’s disease. Science 2006; 314(5800): 777-81.
[http://dx.doi.org/10.1126/science.1132814] [PMID: 17082447]
[95]
Kumar B, Dwivedi AR, Sarkar B, et al. 4, 6-Diphenylpyrimidine derivatives as dual inhibitors of monoamine oxidase and acetylcholinesterase for the treatment of Alzheimer’s disease. ACS Chem Neurosci 2019; 10(1): 252-65.
[http://dx.doi.org/10.1021/acschemneuro.8b00220] [PMID: 30296051]
[96]
Alzheimer’s Association. Thies W, Bleiler L. Alzheimer’s disease facts and figures. Alzheimers Dement 2013; 9(2): 208-45.
[http://dx.doi.org/10.1016/j.jalz.2013.02.003] [PMID: 23507120]
[97]
Luo Z, Sheng J, Sun Y, et al. Synthesis and evaluation of multi-target-directed ligands against Alzheimer’s disease based on the fusion of donepezil and ebselen. J Med Chem 2013; 56(22): 9089-99.
[http://dx.doi.org/10.1021/jm401047q] [PMID: 24160297]
[98]
Singh M, Kaur M, Kukreja H, Chugh R, Silakari O, Singh D. Acetylcholinesterase inhibitors as Alzheimer therapy: From nerve toxins to neuroprotection. Eur J Med Chem 2013; 70: 165-88.
[http://dx.doi.org/10.1016/j.ejmech.2013.09.050] [PMID: 24148993]
[99]
Kumar B, Thakur A, Dwivedi AR, Kumar R, Kumar V. Multi-target-directed ligands as an effective strategy for the treatment of alzheimer’s disease. Curr Med Chem 2021.
[http://dx.doi.org/10.2174/0929867328666210512005508] [PMID: 33982650]
[100]
Zheng H, Youdim MB, Fridkin M. Site-activated multifunctional chelator with acetylcholinesterase and neuroprotective-neurorestorative moieties for Alzheimer’s therapy. J Med Chem 2009; 52(14): 4095-8.
[http://dx.doi.org/10.1021/jm900504c] [PMID: 19485411]
[101]
Bolea I, Gella A, Unzeta M. Propargylamine-derived multitarget-directed ligands: fighting Alzheimer’s disease with monoamine oxidase inhibitors. J Neural Transm (Vienna) 2013; 120(6): 893-902.
[http://dx.doi.org/10.1007/s00702-012-0948-y] [PMID: 23238976]
[102]
Zhou X, Wang X-B, Wang T, Kong L-Y. Design, synthesis, and acetylcholinesterase inhibitory activity of novel coumarin analogues. Bioorg Med Chem 2008; 16(17): 8011-21.
[http://dx.doi.org/10.1016/j.bmc.2008.07.068] [PMID: 18701305]
[103]
Zhou X, Li M, Wang X-B, Wang T, Kong L-Y. Synthesis of benzofuran derivatives via rearrangement and their inhibitory activity on acetylcholinesterase. Molecules 2010; 15(12): 8593-601.
[http://dx.doi.org/10.3390/molecules15128593] [PMID: 21116228]
[104]
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.
[http://dx.doi.org/10.1186/2008-2231-21-47] [PMID: 23758724]
[105]
Ismail MM, Kamel MM, Mohamed LW, Faggal SI. Synthesis of new indole derivatives structurally related to donepezil and their biological evaluation as acetylcholinesterase inhibitors. Molecules 2012; 17(5): 4811-23.
[http://dx.doi.org/10.3390/molecules17054811] [PMID: 22534665]
[106]
Ismail MM, Kamel MM, Mohamed LW, Faggal SI, Galal MA. Synthesis and biological evaluation of thiophene derivatives as acetylcholinesterase inhibitors. Molecules 2012; 17(6): 7217-31.
[http://dx.doi.org/10.3390/molecules17067217] [PMID: 22692245]
[107]
Cappelli A, Gallelli A, Manini M, et al. Further studies on the interaction of the 5-hydroxytryptamine3 (5-HT3) receptor with arylpiperazine ligands. development of a new 5-HT3 receptor ligand showing potent acetylcholinesterase inhibitory properties. J Med Chem 2005; 48(10): 3564-75.
[http://dx.doi.org/10.1021/jm0493461] [PMID: 15887964]
[108]
zturan zer E, Tan OU, Ozadali K. Kkk305;l305;n T, Balkan A, Uar G. Synthesis, molecular modeling and evaluation of novel N8242;-2-(4-benzylpiperidin-/piperazin-1-yl) acylhydrazone derivatives as dual inhibitors for cholinesterases and A946; aggregation. Bioorg Med Chem Lett 2013; 23(2): 440-3.
[http://dx.doi.org/10.1016/j.bmcl.2012.11.064] [PMID: 23273219]
[109]
Ozkay UD, Can D, Ozkay Y, Oztürk Y. Effect of benzothiazole/piperazine derivatives on intracerebroventricular streptozotocin-induced cognitive deficits. Pharmacol Rep 2012; 64(4): 834-47.
[http://dx.doi.org/10.1016/S1734-1140(12)70878-2] [PMID: 23087135]
[110]
Manetti D, Ghelardini C, Bartolini A, et al. Design, synthesis, and preliminary pharmacological evaluation of 1, 4-diazabicyclo[4.3.0]nonan-9-ones as a new class of highly potent nootropic agents. J Med Chem 2000; 43(10): 1969-74.
[http://dx.doi.org/10.1021/jm991170t] [PMID: 10821709]
[111]
Manetti D, Ghelardini C, Bartolini A, et al. Molecular simplification of 1,4-diazabicyclo[4.3.0]nonan-9-ones gives piperazine derivatives that maintain high nootropic activity. J Med Chem 2000; 43(23): 4499-507.
[http://dx.doi.org/10.1021/jm000972h] [PMID: 11087574]
[112]
Martini E, Ghelardini C, Dei S, et al. Design, synthesis and preliminary pharmacological evaluation of new piperidine and piperazine derivatives as cognition-enhancers. Bioorg Med Chem 2008; 16(3): 1431-43.
[http://dx.doi.org/10.1016/j.bmc.2007.10.050] [PMID: 17981042]
[113]
Garino C, Tomita T, Pietrancosta N, et al. Naphthyl and coumarinyl biarylpiperazine derivatives as highly potent human 946;-secretase inhibitors. Design, synthesis, and enzymatic BACE-1 and cell assays. J Med Chem 2006; 49(14): 4275-85.
[http://dx.doi.org/10.1021/jm0602864] [PMID: 16821787]
[114]
Yurtta351; L, Kaplanc305;kl305; ZA, zkay Y. Design, synthesis and evaluation of new thiazole-piperazines as acetylcholinesterase inhibitors. J Enzyme Inhib Med Chem 2013; 28(5): 1040-7.
[http://dx.doi.org/10.3109/14756366.2012.709242] [PMID: 22871134]
[115]
Mohamed T, Yeung JC, Rao PP. Development of 2-substituted-N-(naphth-1-ylmethyl) and N-benzhydrylpyrimidin-4-amines as dual cholinesterase and A946;-aggregation inhibitors: Synthesis and biological evaluation. Bioorg Med Chem Lett 2011; 21(19): 5881-7.
[http://dx.doi.org/10.1016/j.bmcl.2011.07.091] [PMID: 21873056]
[116]
zkay Y. Synthesis of new piperazine compounds and investigation of their anticholinesterase effects. Cukurova Med J 2017; 42: 526-32.
[117]
Sameem B, Saeedi M, Mahdavi M, et al. Synthesis, docking study and neuroprotective effects of some novel pyrano[3,2-c]chromene derivatives bearing morpholine/phenylpiperazine moiety. Bioorg Med Chem 2017; 25(15): 3980-8.
[http://dx.doi.org/10.1016/j.bmc.2017.05.043] [PMID: 28587871]
[118]
Saeedi M, Mohtadi-Haghighi D, Mirfazli SS, et al. Design and synthesis of selective acetylcholinesterase inhibitors: Arylisoxazole-phenylpiperazine derivatives. Chem Biodivers 2019; 16(2)e1800433
[http://dx.doi.org/10.1002/cbdv.201800433] [PMID: 30460743]
[119]
Chaves S, Resta S, Rinaldo F, et al. Design, synthesis, and in vitro evaluation of hydroxybenzimidazole-donepezil analogues as multitarget-directed ligands for the treatment of Alzheimer’s disease. Molecules 2020; 25(4): 985.
[http://dx.doi.org/10.3390/molecules25040985] [PMID: 32098407]
[120]
Więckowska A, Kołaczkowski M, Bucki A, et al. Novel multitarget- directed ligands for Alzheimer’s disease: Combining cholinesterase inhibitors and 5-HT6 receptor antagonists. Design, synthesis and biological evaluation. Eur J Med Chem 2016; 124(63): 81.
[http://dx.doi.org/10.1016/j.ejmech.2016.08.016] [PMID: 27560283]
[121]
Del Bello F, Bonifazi A, Giorgioni G, et al. 1-[3-(4-Butylpipe-ridin-1-yl) propyl]-1, 2, 3, 4-tetrahydroquinolin-2-one (77-LH-28-1) as a model for the rational design of a novel class of brain penetrant ligands with high affinity and selectivity for dopamine D4 receptor. J Med Chem 2018; 61(8): 3712-25.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00265] [PMID: 29589445]
[122]
Pańczyk K, Pytka K, Jakubczyk M, et al. Synthesis of N‐ (phenoxyalkyl)‐, N‐{2‐[2‐(phenoxy) ethoxy] ethyl}‐or N‐ (phenoxyacetyl) piperazine derivatives and their activity within the central nervous system. ChemistrySelect 2019; 4(9381): 91.
[http://dx.doi.org/10.1002/slct.201902648]
[123]
PPańczyk K, Pytka K, Jakubczyk M, et al. Synthesis and activity of di- or trisubstituted N-(phenoxyalkyl)- or N-2-[2-(phenoxy) ethoxy]ethylpiperazine derivatives on the central nervous system. Bioorg Med Chem Lett 2018; 28(11): 2039-49.
[http://dx.doi.org/10.1016/j.bmcl.2018.04.059] [PMID: 29730027]
[124]
Wimalasena DS, Perera RP, Heyen BJ, Balasooriya IS, Wimalasena K. Vesicular monoamine transporter substrate/inhibitor activity of MPTP/MPP+ derivatives: a structure-activity study. J Med Chem 2008; 51(4): 760-8.
[http://dx.doi.org/10.1021/jm070875p] [PMID: 18220329]
[125]
Neustadt BR, Hao J, Lindo N, et al. Potent, selective, and orally active adenosine A2A receptor antagonists: arylpiperazine derivatives of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines. Bioorg Med Chem Lett 2007; 17(5): 1376-80.
[http://dx.doi.org/10.1016/j.bmcl.2006.11.083] [PMID: 17236762]
[126]
Silverman LS, Caldwell JP, Greenlee WJ, et al. 3H-[1,2,4]-Triazolo[5,1-i]purin-5-amine derivatives as adenosine A2A antagonists. Bioorg Med Chem Lett 2007; 17(6): 1659-62.
[http://dx.doi.org/10.1016/j.bmcl.2006.12.104] [PMID: 17234414]
[127]
Johnson M, Antonio T, Reith ME, Dutta AK. Structure-Activity Relationship Study of N 6-(2-(4-(1 H-Indol-5-yl) piperazin-1-yl) ethyl)-N 6-propyl-4, 5, 6, 7-tetrahydrobenzo [d] thiazole-2, 6-diamine Analogues: Development of highly selective D3 dopamine receptor agonists along with a highly potent D2/d3 agonist and their pharmacological characterization. J Med Chem 2012; 55: 5826-40.
[http://dx.doi.org/10.1021/jm300268s] [PMID: 22642365]
[128]
Harris JM, Neustadt BR, Zhang H, et al. Potent and selective adenosine A(2A) receptor antagonists: [1,2,4]-triazolo[4,3-c]pyrimidin-3-ones. Bioorg Med Chem Lett 2011; 21(8): 2497-501.
[http://dx.doi.org/10.1016/j.bmcl.2011.02.045] [PMID: 21398125]
[129]
Ehrlich K, Götz A, Bollinger S, et al. Dopamine D2, D3, and D4 selective phenylpiperazines as molecular probes to explore the origins of subtype specific receptor binding. J Med Chem 2009; 52(15): 4923-35.
[http://dx.doi.org/10.1021/jm900690y] [PMID: 19606869]
[130]
Robarge MJ, Husbands SM, Kieltyka A, Brodbeck R, Thurkauf A, Newman AH. Design and synthesis of [(2,3-dichlorophenyl)piperazin-1-yl]alkylfluorenylcarboxamides as novel ligands selective for the dopamine D3 receptor subtype. J Med Chem 2001; 44(19): 3175-86.
[http://dx.doi.org/10.1021/jm010146o] [PMID: 11543687]
[131]
Gyertyán I, Kiss B, Gál K, et al. Effects of RGH-237 [N-{4-[4-(3-aminocarbonyl-phenyl)-piperazin-1-yl]-butyl}-4-bromo-benzamide], an orally active, selective dopamine D3 receptor partial agonist in animal models of cocaine abuse. J Pharmacol Exp Ther 2007; 320: 1268-78.
[http://dx.doi.org/10.1124/jpet.106.107920] [PMID: 17170312]
[132]
Leopoldo M, Berardi F, Colabufo NA, et al. Structure-affinity relationship study on N-[4-(4-arylpiperazin-1-yl)butyl]arylcar-boxamides as potent and selective dopamine D(3) receptor ligands. J Med Chem 2002; 45(26): 5727-35.
[http://dx.doi.org/10.1021/jm020952a] [PMID: 12477356]
[133]
Newman AH, Cao J, Bennett CJ, Robarge MJ, Freeman RA, Luedtke RRN. -(4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl, butenyl and butynyl)arylcarboxamides as novel dopamine D(3) receptor antagonists. Bioorg Med Chem Lett 2003; 13(13): 2179-83.
[http://dx.doi.org/10.1016/S0960-894X(03)00389-5] [PMID: 12798330]
[134]
Newman AH, Grundt P, Cyriac G, et al. N-(4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides with functionalized linking chains as high affinity and enantioselective D3 receptor antagonists. J Med Chem 2009; 52(8): 2559-70.
[http://dx.doi.org/10.1021/jm900095y] [PMID: 19331412]