Generic placeholder image

CNS & Neurological Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Review Article

Structural Activity Relationship based Medicinal Perspectives of Pyrimidine Derivatives as Anti-Alzheimer’s Agents: A Comprehensive Review

Author(s): Subham Das, Saleem Akbar, Bahar Ahmed*, Rikeshwar Prasad Dewangan, Ashif Iqubal, Faheem Hyder Pottoo and Alex Joseph*

Volume 21, Issue 10, 2022

Published on: 31 March, 2022

Page: [926 - 939] Pages: 14

DOI: 10.2174/1871527320666210804161400

Price: $65

Abstract

Pyrimidine is an aromatic and heterocyclic organic compound containing a 6-membered ring consisting of four carbon and two nitrogen atoms on alternative positions. Pyrimidine scaffolds described their existence in the medicinal chemist’s cause for their synthesizing practicability and nonpoisonous nature. However, the reason behind neurological disorders is still an open challenge for scientific research and development organizations. Efficacy voids are widespread before researchers, despite high throughput research in the field of anti-Alzheimer's drugs.Researchers have constantly investigated all the probabilities for restraining the unwanted adverse effects of the anti-Alzheimer’s agents and are focusing more extensively to rehabilitate neurological disorders. The scientific literature on drug development has been an aspiration to medicinal chemists and other researchers to facilitate further research. Therefore, this review emphasizes the structure-activity relationship (SAR) based approach and the pharmacological advancements of pyrimidine moiety in the new era of therapeutics as anti-Alzheimer’s agents.

Keywords: Pyrimidine, anti-Alzheimer’s drugs, medicinal chemistry, SAR, pharmacology, neurological disorder.

Graphical Abstract
[1]
Bajda M, Boryczka S, Wietrzyk J, Malawska B. Investigation of lipophilicity of anticancer-active thioquinoline derivatives. Biomed Chromatogr 2007; 21(2): 123-31.
[http://dx.doi.org/10.1002/bmc.706] [PMID: 17120300]
[2]
Narwal S, Kumar S, Verma PK. Design, synthesis and antimicrobial evaluation of pyrimidin-2-ol/thiol/amine analogues. Chem Cent J 2017; 11(1): 52.
[http://dx.doi.org/10.1186/s13065-017-0284-2] [PMID: 29086852]
[3]
Pyrimidine | C4H4N2 - PubChem. Availavble from: https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine (accessed Dec 9, 2020).
[4]
Panneer ST, Richa JC, Vijaysarathy DP, Karyn VS. A mini review of pyrimidine and fused pyrimidine marketed drugs. Res Pharm 2012; 2(4): 1-9.
[5]
Rauk A. The chemistry of Alzheimer’s disease. Chem Soc Rev 2009; 38(9): 2698-715.
[http://dx.doi.org/10.1039/b807980n] [PMID: 19690748]
[6]
Mir RH, Sawhney G, Pottoo FH, et al. Role of environmental pollutants in Alzheimer’s disease: A review. Environ Sci Pollut Res Int 2020; 27(36): 44724-42.
[http://dx.doi.org/10.1007/s11356-020-09964-x] [PMID: 32715424]
[7]
Mir RH, Shah AJ, Mohi-Ud-Din R, et al. Natural anti-inflammatory compounds as drug candidates in Alzheimer’s disease. Curr Med Chem 2021; 28(23): 4799-825.
[http://dx.doi.org/10.2174/0929867327666200730213215] [PMID: 32744957]
[8]
Bolognesi ML, Gandini A, Prati F, Uliassi E. From companion diagnostics to theranostics: A new avenue for Alzheimer’s disease? J Med Chem 2016; 59(17): 7759-70.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00151] [PMID: 27124551]
[9]
Liang Z, Zhang B, Su WW, Williams PG, Li QX. C-Glycosylflavones alleviate tau phosphorylation and amyloid neurotoxicity through GSK3β inhibition. ACS Chem Neurosci 2016; 7(7): 912-23.
[http://dx.doi.org/10.1021/acschemneuro.6b00059] [PMID: 27213824]
[10]
Ibrahim AM, Pottoo FH, Dahiya ES, Khan FA, Kumar JBS. Neuron-glia interactions: Molecular basis of alzheimer’s disease and applications of neuroproteomics. Eur J Neurosci 2020; 52(2): 2931-43.
[http://dx.doi.org/10.1111/ejn.14838] [PMID: 32463535]
[11]
Sharma P, Sharma A, Fayaz F, Wakode S, Pottoo FH. Biological signatures of Alzheimer’s disease. Curr Top Med Chem 2020; 20(9): 770-81.
[http://dx.doi.org/10.2174/1568026620666200228095553] [PMID: 32108008]
[12]
Nasica-Labouze J, Nguyen PH, Sterpone F, et al. Amyloid β protein and Alzheimer’s disease: When computer simulations complement experimental studies. Chem Rev 2015; 115(9): 3518-63.
[http://dx.doi.org/10.1021/cr500638n] [PMID: 25789869]
[13]
Maqbool M, Mobashir M, Hoda N. Pivotal role of glycogen synthase kinase-3: A therapeutic target for Alzheimer’s disease. Eur J Med Chem 2016; 107: 63-81.
[http://dx.doi.org/10.1016/j.ejmech.2015.10.018] [PMID: 26562543]
[14]
Rahman MR, Islam T, Zaman T, et al. Identification of molecular signatures and pathways to identify novel therapeutic targets in Alzheimer’s disease: Insights from a systems biomedicine perspective. Genomics 2020; 112(2): 1290-9.
[http://dx.doi.org/10.1016/j.ygeno.2019.07.018] [PMID: 31377428]
[15]
Miziak B, Błaszczyk B, Czuczwar SJ. Some candidate drugs for pharmacotherapy of Alzheimer’s disease. Pharmaceuticals (Basel) 2021; 14(5): 458.
[http://dx.doi.org/10.3390/ph14050458] [PMID: 34068096]
[16]
Shafi S, Singh A, Gupta P, et al. Deciphering the role of aberrant protein post translational modification in the pathology of neurodegeneration. CNS Neurol Disord Drug Targets 2021; 20(1): 54-67.
[http://dx.doi.org/10.2174/1871527319666200903162200] [PMID: 32885763]
[17]
Guo T, Zhang D, Zeng Y, Huang TY, Xu H, Zhao Y. Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease. Mol Neurodegener 2020; 15(1): 40.
[http://dx.doi.org/10.1186/s13024-020-00391-7] [PMID: 32677986]
[18]
Iqubal A, Rahman SO, Ahmed M, et al. Current quest in natural bioactive compounds for Alzheimer’s disease: Multi-targeted-designed-ligand based approach with preclinical and clinical based evidence. Curr Drug Targets 2021; 22(6): 685-720.
[http://dx.doi.org/10.2174/1389450121999201209201004] [PMID: 33302832]
[19]
Meena P, Nemaysh V, Khatri M, Manral A, Luthra PM, Tiwari M. Synthesis, biological evaluation and molecular docking study of novel piperidine and piperazine derivatives as multi-targeted agents to treat Alzheimer’s disease. Bioorg Med Chem 2015; 23(5): 1135-48.
[http://dx.doi.org/10.1016/j.bmc.2014.12.057] [PMID: 25624107]
[20]
Rahim F, Javed MT, Ullah H, et al. Synthesis, molecular docking, acetylcholinesterase and butyrylcholinesterase inhibitory potential of thiazole analogs as new inhibitors for Alzheimer disease. Bioorg Chem 2015; 62: 106-16.
[http://dx.doi.org/10.1016/j.bioorg.2015.08.002] [PMID: 26318401]
[21]
Carlier PR, Chow ESH, Han Y, Liu J, El Yazal J, Pang YP. Heterodimeric tacrine-based acetylcholinesterase inhibitors: Investigating ligand-peripheral site interactions. J Med Chem 1999; 42(20): 4225-31.
[http://dx.doi.org/10.1021/jm990224w] [PMID: 10514292]
[22]
Arias E, Gallego-Sandín S, Villarroya M, García AG, López MG. Unequal neuroprotection afforded by the acetylcholinesterase inhibitors galantamine, donepezil, and rivastigmine in SH-SY5Y neuroblastoma cells: Role of nicotinic receptors. J Pharmacol Exp Ther 2005; 315(3): 1346-53.
[http://dx.doi.org/10.1124/jpet.105.090365] [PMID: 16144975]
[23]
Annicchiarico R, Federici A, Pettenati C, Caltagirone C. Rivastigmine in Alzheimer’s disease: Cognitive function and quality of life. Ther Clin Risk Manag 2007; 3(6): 1113-23.
[PMID: 18516265]
[24]
Carolan CG, Dillon GP, Gaynor JM, et al. Isosorbide-2-carbamate esters: Potent and selective butyrylcholinesterase inhibitors. J Med Chem 2008; 51(20): 6400-9.
[http://dx.doi.org/10.1021/jm800564y] [PMID: 18817366]
[25]
Radić Z, Pickering NA, Vellom DC, Camp S, Taylor P. Three distinct domains in the cholinesterase molecule confer selectivity for acetyl- and butyrylcholinesterase inhibitors. Biochemistry 1993; 32(45): 12074-84.
[http://dx.doi.org/10.1021/bi00096a018] [PMID: 8218285]
[26]
Karlsson D, Fallarero A, Brunhofer G, et al. Identification and characterization of diarylimidazoles as hybrid inhibitors of butyrylcholinesterase and amyloid beta fibril formation. Eur J Pharm Sci 2012; 45(1-2): 169-83.
[http://dx.doi.org/10.1016/j.ejps.2011.11.004] [PMID: 22108346]
[27]
Lilienfeld S. Cholinesterase inhibitors for Alzheimer disease. JAMA 2003; 289(18): 2360.
[http://dx.doi.org/10.1001/jama.289.18.2360-a] [PMID: 12746355]
[28]
Yan R, Vassar R. Targeting the β secretase BACE1 for Alzheimer’s disease therapy. Lancet Neurol 2014; 13(3): 319-29.
[http://dx.doi.org/10.1016/S1474-4422(13)70276-X] [PMID: 24556009]
[29]
Das B, Yan R. Role of BACE1 in Alzheimer’s synaptic function. Transl Neurodegener 2017; 6(1): 23.
[http://dx.doi.org/10.1186/s40035-017-0093-5] [PMID: 28855981]
[30]
Cheng CM, Tseng V, Wang J, Wang D, Matyakhina L, Bondy CA. Tau is hyperphosphorylated in the insulin-like growth factor-I null brain. Endocrinology 2005; 146(12): 5086-91.
[http://dx.doi.org/10.1210/en.2005-0063] [PMID: 16123158]
[31]
Boccardi V, Murasecco I, Mecocci P. Diabetes drugs in the fight against Alzheimer’s disease. Ageing Res Rev 2019; 54(June): 100936.
[http://dx.doi.org/10.1016/j.arr.2019.100936] [PMID: 31330313]
[32]
Yamada M, Yasuhara H. Clinical pharmacology of MAO inhibitors: Safety and future. Neurotoxicology 2004; 25(1-2): 215-21.
[http://dx.doi.org/10.1016/S0161-813X(03)00097-4] [PMID: 14697896]
[33]
Knoll J, Magyar K. Some puzzling pharmacological effects of monoamine oxidase inhibitors. Adv Biochem Psychopharmacol 1972; 5: 393-408.
[PMID: 5066229]
[34]
Johnston JP. Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem Pharmacol 1968; 17(7): 1285-97.
[http://dx.doi.org/10.1016/0006-2952(68)90066-X] [PMID: 5659776]
[35]
O’Carroll AM, Fowler CJ, Phillips JP, Tobbia I, Tipton KF. The deamination of dopamine by human brain monoamine oxidase. Specificity for the two enzyme forms in seven brain regions. Naunyn Schmiedebergs Arch Pharmacol 1983; 322(3): 198-202.
[http://dx.doi.org/10.1007/BF00500765] [PMID: 6408492]
[36]
Alzheimer’s Association. Medications for memory loss. Available from: https://www.alz.org/alzheimers-dementia/treatments/medications-for-memory (accessed Mar 8, 2021).
[37]
Association, A.; Alzheimer’s Association. FDA-Approved t Reatments for Alzheimer’s; 2019.
[38]
dos Santos Pisoni D, Sobieski da Costa J, Gamba D, et al. Synthesis and AChE inhibitory activity of new chiral tetrahydroacridine analogues from terpenic cyclanones. Eur J Med Chem 2010; 45(2): 526-35.
[http://dx.doi.org/10.1016/j.ejmech.2009.10.039] [PMID: 19954865]
[39]
Ramachandran AK, Das S, Joseph A, Shenoy GG, Alex AT, Mudgal J. Neurodegenerative pathways in Alzheimer’s disease: A review. Curr Neuropharmacol 2021; 19(5): 679-92.
[http://dx.doi.org/10.2174/1570159X18666200807130637] [PMID: 32851951]
[40]
Ramachandran AK, Das S, Joseph A. Crosstalk between Covid-19 and associated neurological disorders: A review. Curr Neuropharmacol 2021; 19(10): 1688-700.
[http://dx.doi.org/10.2174/1570159X19666210113154342] [PMID: 33441073]
[41]
Das S, Akbar S, Ahmed B, et al. Recent advancement of pyrazole scaffold based neuroprotective agents: A review. CNS Neurol Disord Drug Targets 2021; 20
[http://dx.doi.org/10.2174/1871527320666210602152308] [PMID: 34080970]
[42]
Manoj A, Das S, Kunnath Ramachandran A, Alex AT, Joseph A. SGLT2 inhibitors, an accomplished development in field of medicinal chemistry: An extensive review. Future Med Chem 2020; 12(21): 1961-90.
[http://dx.doi.org/10.4155/fmc-2020-0154] [PMID: 33124462]
[43]
Tets VV, Tets GV, Krutikov VI. Agent for inducing endogenous interferon. US10029990B2, 2018.
[44]
Eva Caroff EM. (R)-2-methyl piperazine derivatives as CXCR3 receptor modulators. US10047080B2, 2018.
[45]
Chun EP, Young KJ. Imidazopyrimidine and imidazotriazine derivative, and pharmaceutical composition comprising the same. US10100057B2, 2018.
[46]
John V, Bredesen DE. Triazolopyridines and triazolopyrimidines that lower stress - induced p - Tau. US2018034646A1, 2018.
[47]
Ramin F, Achim M, Michael O, et al. Substituted pyrazolopyrimidines and method of use. US10155770B2, 2018.
[48]
Dong-Ming S, Michael P, Dwyer CJ, et al. 6-alkyl dihydropyrazolopyrimidinone compounds as PDE2 inhibitors. US10160762B2, 2018.
[49]
Shen DM, Dwyer MP, Sinz CJ, et al. Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors. US010174037B2, 2019.
[50]
Dong-Ming S, Jonathan E, Wilson T M. Heteroaryl - pyrimidinone compounds as PDE2 inhibitors. US10195201B2, 2020.
[51]
Jeffrey PC, Craig WL, Colleen MN, et al. Isoquiniline and napthalene - substituted compounds as MGLUR4 allosteric potentiators , compositions , and methods of treating neurological dysfunction. US10227343B2, 2020.
[52]
Matthew V, Yu J, Elisia V, Benjamin S, Guosheng W, Aijun L. Pyridopyrimidinones and methods of use thereof. US10280165B2, 2020.
[53]
Dong-Ming S, Deping W, Xiaoxia Q, Bart H, Meng Y, Yingjian B. Pyrimidinone amide compounds as PDE2 inhibitors. US10285989B2, 2019.
[54]
Dong-Ming S, Jonathan EW, Meng Y, et al. Pyrazolyl pyrimidinone compounds as PDE2 inhibitors. US10287269B2, 2019.
[55]
Morriello GJ, Lehua C, Ashley F, et al. Substituted triazolo bicyclic compounds as PDE2 inhibitors. US010357481B2, 2019.
[56]
Shen D-M, Sinz C J, Crespo A, Wilson J E. Triazolyl Pyrimidinone compounds as PDE2 inhibitors. US010358435B2, 2019.
[57]
Nishino T, Kato S, Kato M, Suzuki H, Okamoto K. Drug for preventing and / or treating dementia. US10413546B2, 2020.
[58]
Hiroyuki T, Koji M, Masanao I, Mitsuhiro Y, Manami M. Nitrogen - containing condensed ring compounds having dopamine D3 antagonistic effect. EP3495363, 2020.
[59]
Morriello GJ, Chang L, Forster A, Berger R, Nanda KK, Shipe WD. Substituted pyrazolo/imidazolo bicyclic compounds as PDE2 inhibitors. US10647727B2, 2020.
[60]
Li X, Wang H, Lu Z, et al. Development of multifunctional pyrimidinylthiourea derivatives as potential anti-alzheimer agents. J Med Chem 2016; 59(18): 8326-44.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00636] [PMID: 27552582]
[61]
Kovalevich J, Cornec AS, Yao Y, et al. Characterization of brain-penetrant pyrimidine-containing molecules with differential microtubule-stabilizing activities developed as potential therapeutic agents for Alzheimer’s disease and related tauopathies S. J Pharmacol Exp Ther 2016; 357(2): 432-50.
[http://dx.doi.org/10.1124/jpet.115.231175] [PMID: 26980057]
[62]
Li N, Wang Y, Li W, et al. Screening of some sulfonamide and sulfonylurea derivatives as anti-Alzheimer’s agents targeting BACE1 and PPAR γ. J Chem 2020; 2020(i): 1-19.
[http://dx.doi.org/10.1155/2020/1631243]
[63]
Rehman TU, Khan IU, Ashraf M, Tarazi H, Riaz S, Yar M. An efficient synthesis of bi -aryl pyrimidine heterocycles: Potential new drug candidates to treat Alzheimer’s disease. Arch Pharm (Weinheim) 2017; 350(3-4): 1600304.
[http://dx.doi.org/10.1002/ardp.201600304] [PMID: 28220522]
[64]
Jameel E, Meena P, Maqbool M, et al. Rational design, synthesis and biological screening of triazine-triazolopyrimidine hybrids as multitarget anti-Alzheimer agents. Eur J Med Chem 2017; 136(January): 36-51.
[http://dx.doi.org/10.1016/j.ejmech.2017.04.064] [PMID: 28478343]
[65]
Jismy B, Akssira M, Knez D, Gobec S, Abarbri M. Efficient synthesis and preliminary biological evaluations of trifluoromethylated imidazo[1,2-a]pyrimidines and benzimidazo[1,2-a]pyrimidines. New J Chem 2019; 43(25): 9961-8.
[http://dx.doi.org/10.1039/C9NJ01982K]
[66]
Reddy EK, Remya C, Sajith AM, Dileep KV, Sadasivan C, Anwar S. Functionalised dihydroazo pyrimidine derivatives from morita–baylis–hillman acetates: Synthesis and studies against acetylcholinesterase as its inhibitors. RSC Advances 2016; 6(81): 77431-9.
[http://dx.doi.org/10.1039/C6RA12507G]
[67]
Kumar J, Gill A, Shaikh M, et al. Pyrimidine-triazolopyrimidine and pyrimidine-pyridine hybrids as potential acetylcholinesterase inhibitors for Alzheimer’s disease. ChemistrySelect 2018; 3(2): 736-47.
[http://dx.doi.org/10.1002/slct.201702599]
[68]
Mishra CB, Manral A, Kumari S, Saini V, Tiwari M. Design, synthesis and evaluation of novel indandione derivatives as multifunctional agents with cholinesterase inhibition, anti-β-amyloid aggregation, antioxidant and neuroprotection properties against Alzheimer’s disease. Bioorg Med Chem 2016; 24(16): 3829-41.
[http://dx.doi.org/10.1016/j.bmc.2016.06.027] [PMID: 27353888]
[69]
Wang M, Qin HL, Leng J, et al. Synthesis and biological evaluation of new tetramethylpyrazine-based chalcone derivatives as potential anti-Alzheimer agents. Chem Biol Drug Des 2018; 92(5): 1859-66.
[http://dx.doi.org/10.1111/cbdd.13355] [PMID: 29923315]
[70]
Xu YX, Wang H, Li XL, et al. 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 2018; 143: 33-47.
[http://dx.doi.org/10.1016/j.ejmech.2017.08.025] [PMID: 29172081]
[71]
Zribi L, Pachòn-Angona I, Bautista-Aguilera OM, et al. Triazolopyridopyrimidine: A new scaffold for dual-target small molecules for Alzheimer's disease therapy. Molecules 2020; 25(14): 3190.
[http://dx.doi.org/10.3390/molecules25143190] [PMID: 32668671]
[72]
Semenov VE, Zueva IV, Mukhamedyarov MA, et al. Novel acetylcholinesterase inhibitors based on uracil moiety for possible treatment of Alzheimer disease. Molecules 2020; 25(18): 4191.
[http://dx.doi.org/10.3390/molecules25184191] [PMID: 32932702]
[73]
Semenov VE, Zueva IV, Lushchekina SV, et al. 6-Methyluracil derivatives as peripheral site ligand-hydroxamic acid conjugates: Reactivation for paraoxon-inhibited acetylcholinesterase. Eur J Med Chem 2020; 185: 111787.
[http://dx.doi.org/10.1016/j.ejmech.2019.111787] [PMID: 31675511]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy