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
[http://dx.doi.org/10.1016/B978-0-12-803603-7.00016-1]
[http://dx.doi.org/10.1186/s40035-017-0088-2] [PMID: 28702179]
[http://dx.doi.org/10.1109/ICICT46931.2019.8977658] [PMID: 28702179]
[http://dx.doi.org/10.1016/j.nano.2011.08.006] [PMID: 21889479]
[http://dx.doi.org/10.1016/S1474-4422(18)30355-7] [PMID: 30287052]
[http://dx.doi.org/10.1016/S0140-6736(12)61689-4] [PMID: 23245608]
[http://dx.doi.org/10.2174/1389557517666170913111533] [PMID: 28901854]
[http://dx.doi.org/10.1016/j.molstruc.2021.130369]
[http://dx.doi.org/10.1007/s00044-007-9022-y]
[http://dx.doi.org/10.1016/S0040-4039(02)00556-7]
[http://dx.doi.org/10.1007/s00044-011-9573-9]
[http://dx.doi.org/10.1016/j.bmcl.2009.04.019] [PMID: 19398330]
[http://dx.doi.org/10.1016/j.exppara.2011.02.025] [PMID: 21354139]
[http://dx.doi.org/10.1016/j.bmcl.2018.04.021] [PMID: 29678461]
[http://dx.doi.org/10.1016/j.ejmech.2020.112438] [PMID: 32485533]
[http://dx.doi.org/10.1124/jpet.104.069625] [PMID: 15146031]
[http://dx.doi.org/10.1007/s10534-015-9889-x] [PMID: 26502356]
[http://dx.doi.org/10.1016/j.bmcl.2012.03.019] [PMID: 22464131]
[http://dx.doi.org/10.1016/j.drugalcdep.2011.10.007] [PMID: 22071119]
[http://dx.doi.org/10.1177/0269881107077260] [PMID: 17606471]
[http://dx.doi.org/10.1007/s00204-013-1057-x] [PMID: 23685794]
[http://dx.doi.org/10.1055/s-0036-1589491]
[http://dx.doi.org/10.2174/0929867023371030] [PMID: 11945120]
[http://dx.doi.org/10.2174/1389557511313100012] [PMID: 24568298]
[http://dx.doi.org/10.1016/j.ejmech.2019.05.039] [PMID: 31151057]
[http://dx.doi.org/10.1002/slct.202002425]
[http://dx.doi.org/10.1016/j.bioorg.2018.01.020] [PMID: 29421700]
[http://dx.doi.org/10.2174/1389450117666151209123402] [PMID: 26648064]
[http://dx.doi.org/10.1039/C6RA00302H]
[http://dx.doi.org/10.1136/jnnp.2007.131045] [PMID: 18344392]
[http://dx.doi.org/10.1016/j.bmcl.2010.11.128] [PMID: 21194943]
[http://dx.doi.org/10.1016/j.bmcl.2011.12.094] [PMID: 22257893]
[http://dx.doi.org/10.1001/jama.287.13.1653] [PMID: 11926889]
[http://dx.doi.org/10.1002/cmdc.202100045] [PMID: 33751807]
[http://dx.doi.org/10.1371/journal.pone.0001616] [PMID: 18286173]
[http://dx.doi.org/10.1212/WNL.47.6_Suppl_3.161S] [PMID: 8959985]
[http://dx.doi.org/10.1002/cmdc.201700589] [PMID: 29534334]
[http://dx.doi.org/10.1001/jama.2014.3654] [PMID: 24756517]
[PMID: 16034956]
[http://dx.doi.org/10.1002/mds.23429] [PMID: 21069833]
[http://dx.doi.org/10.1016/j.euroneuro.2010.03.001] [PMID: 20434890]
[http://dx.doi.org/10.1016/j.expneurol.2010.09.007] [PMID: 20843474]
[http://dx.doi.org/10.1016/S0960-894X(01)00820-4] [PMID: 11844685]
[http://dx.doi.org/10.1021/jm701524h] [PMID: 18410082]
[http://dx.doi.org/10.1002/jnr.22405] [PMID: 20623619]
[http://dx.doi.org/10.1021/jm401883v] [PMID: 24471976]
[http://dx.doi.org/10.1021/jm901184n] [PMID: 20038106]
[http://dx.doi.org/10.1016/j.molstruc.2020.127762]
[http://dx.doi.org/10.1007/s12039-019-1694-6]
[http://dx.doi.org/10.1111/jnc.12825] [PMID: 25041389]
[http://dx.doi.org/10.1371/journal.pone.0188212] [PMID: 29304113]
[http://dx.doi.org/10.1039/C8MD00237A] [PMID: 30288220]
[http://dx.doi.org/10.1039/C9MD00379G]
[http://dx.doi.org/10.3389/fchem.2017.00064] [PMID: 28955709]
[http://dx.doi.org/10.1093/geronj/46.6.M210] [PMID: 1834726]
[http://dx.doi.org/10.1017/S1041610218001576] [PMID: 30398134]
[http://dx.doi.org/10.7759/cureus.4185] [PMID: 31106085]
[http://dx.doi.org/10.1001/archpsyc.58.9.844] [PMID: 11545667]
[http://dx.doi.org/10.1371/journal.pone.0011266] [PMID: 20585644]
[http://dx.doi.org/10.1016/j.ejphar.2019.172732] [PMID: 31622593]
[http://dx.doi.org/10.2174/1573408012666160402001715]
[PMID: 31272520]
[PMID: 30439857]
[http://dx.doi.org/10.1002/hup.2424] [PMID: 25087600]
[http://dx.doi.org/10.1021/jm040792y] [PMID: 15341483]
[http://dx.doi.org/10.1021/jm800176x] [PMID: 18598015]
[http://dx.doi.org/10.1016/j.arabjc.2013.04.027]
[http://dx.doi.org/10.1021/jm0508641] [PMID: 16722631]
[http://dx.doi.org/10.1080/14756366.2016.1247054] [PMID: 28097890]
[http://dx.doi.org/10.1016/j.bmc.2003.12.021] [PMID: 15018922]
[http://dx.doi.org/10.1021/jm101459g] [PMID: 21486038]
[http://dx.doi.org/10.1016/S1734-1140(11)70400-5] [PMID: 21441613]
[http://dx.doi.org/10.1021/jm200682b] [PMID: 21823597]
[http://dx.doi.org/10.1016/j.pbb.2015.11.013] [PMID: 26647362]
[http://dx.doi.org/10.1111/cbdd.12394] [PMID: 25048712]
[http://dx.doi.org/10.1016/j.bmcl.2010.01.093] [PMID: 20149649]
[http://dx.doi.org/10.1016/j.ejmech.2009.07.014] [PMID: 19679379]
[http://dx.doi.org/10.1111/cbdd.13442] [PMID: 30422400]
[http://dx.doi.org/10.1016/j.bmcl.2010.09.081] [PMID: 20933409]
[http://dx.doi.org/10.1016/j.bmcl.2009.11.108] [PMID: 20022503]
[http://dx.doi.org/10.3390/molecules17021388] [PMID: 22306829]
[http://dx.doi.org/10.1016/j.ejmech.2009.11.053] [PMID: 20060623]
[http://dx.doi.org/10.1016/j.bmc.2019.07.046] [PMID: 31383628]
[http://dx.doi.org/10.1021/jm7013919] [PMID: 18269229]
[http://dx.doi.org/10.1016/j.bmc.2019.06.028] [PMID: 31253535]
[http://dx.doi.org/10.1016/j.bioorg.2020.103662] [PMID: 32086055]
[http://dx.doi.org/10.1016/j.ejmech.2017.04.033] [PMID: 28441580]
[http://dx.doi.org/10.1126/science.1132814] [PMID: 17082447]
[http://dx.doi.org/10.1021/acschemneuro.8b00220] [PMID: 30296051]
[http://dx.doi.org/10.1016/j.jalz.2013.02.003] [PMID: 23507120]
[http://dx.doi.org/10.1021/jm401047q] [PMID: 24160297]
[http://dx.doi.org/10.1016/j.ejmech.2013.09.050] [PMID: 24148993]
[http://dx.doi.org/10.2174/0929867328666210512005508] [PMID: 33982650]
[http://dx.doi.org/10.1021/jm900504c] [PMID: 19485411]
[http://dx.doi.org/10.1007/s00702-012-0948-y] [PMID: 23238976]
[http://dx.doi.org/10.1016/j.bmc.2008.07.068] [PMID: 18701305]
[http://dx.doi.org/10.3390/molecules15128593] [PMID: 21116228]
[http://dx.doi.org/10.1186/2008-2231-21-47] [PMID: 23758724]
[http://dx.doi.org/10.3390/molecules17054811] [PMID: 22534665]
[http://dx.doi.org/10.3390/molecules17067217] [PMID: 22692245]
[http://dx.doi.org/10.1021/jm0493461] [PMID: 15887964]
[http://dx.doi.org/10.1016/j.bmcl.2012.11.064] [PMID: 23273219]
[http://dx.doi.org/10.1016/S1734-1140(12)70878-2] [PMID: 23087135]
[http://dx.doi.org/10.1021/jm991170t] [PMID: 10821709]
[http://dx.doi.org/10.1021/jm000972h] [PMID: 11087574]
[http://dx.doi.org/10.1016/j.bmc.2007.10.050] [PMID: 17981042]
[http://dx.doi.org/10.1021/jm0602864] [PMID: 16821787]
[http://dx.doi.org/10.3109/14756366.2012.709242] [PMID: 22871134]
[http://dx.doi.org/10.1016/j.bmcl.2011.07.091] [PMID: 21873056]
[http://dx.doi.org/10.1016/j.bmc.2017.05.043] [PMID: 28587871]
[http://dx.doi.org/10.1002/cbdv.201800433] [PMID: 30460743]
[http://dx.doi.org/10.3390/molecules25040985] [PMID: 32098407]
[http://dx.doi.org/10.1016/j.ejmech.2016.08.016] [PMID: 27560283]
[http://dx.doi.org/10.1021/acs.jmedchem.8b00265] [PMID: 29589445]
[http://dx.doi.org/10.1002/slct.201902648]
[http://dx.doi.org/10.1016/j.bmcl.2018.04.059] [PMID: 29730027]
[http://dx.doi.org/10.1021/jm070875p] [PMID: 18220329]
[http://dx.doi.org/10.1016/j.bmcl.2006.11.083] [PMID: 17236762]
[http://dx.doi.org/10.1016/j.bmcl.2006.12.104] [PMID: 17234414]
[http://dx.doi.org/10.1021/jm300268s] [PMID: 22642365]
[http://dx.doi.org/10.1016/j.bmcl.2011.02.045] [PMID: 21398125]
[http://dx.doi.org/10.1021/jm900690y] [PMID: 19606869]
[http://dx.doi.org/10.1021/jm010146o] [PMID: 11543687]
[http://dx.doi.org/10.1124/jpet.106.107920] [PMID: 17170312]
[http://dx.doi.org/10.1021/jm020952a] [PMID: 12477356]
[http://dx.doi.org/10.1016/S0960-894X(03)00389-5] [PMID: 12798330]
[http://dx.doi.org/10.1021/jm900095y] [PMID: 19331412]