Document Type: Review Article


Department of Biology, Faculty of Basic Sciences, Islamic Azad University of central Tehran branch, Tehran, Iran



Alzheimer's disease is a neurological disorder in which the death of brain cells causes memory loss and cognitive decline. A neurodegenerative type of dementia, the disease starts mild and gets progressively worse. Like all types of dementia, Alzheimer's is caused by brain cell death. The most common presentation marking Alzheimer's dementia is where symptoms of memory loss are the most prominent, especially in the area of learning and recalling new information.
Alzheimer's disease is not simple to diagnose. There is no single test for it. For this reason, the first thing doctors do is to rule out other problems before confirming whether mental signs and symptoms are severe enough to be a kind of dementia or something else. Genetic test is possible in some settings to indicate the likelihood of someone having or developing the disease but this is controversial and not entirely reliable.
There are no disease-modifying drugs available for Alzheimer's disease but some options may reduce its symptoms and help improve quality of life. A different kind of drug, memantine, an NMDA receptor antagonist, may also be used, alone or in combination with a cholinesterase inhibitor. This review highlights the several reports that attempt to design and synthesis of some classes of selective Alzheimer's disease inhibitors.


Akhter H, Huang W-T, van Groen T, Kuo H-C, Miyata T, Liu R-M. 2018. A Small Molecule Inhibitor of Plasminogen Activator Inhibitor-1 Reduces Brain Amyloid-β Load and Improves Memory in an Animal Model of Alzheimer’s Disease. J Alzheimers Dis 64(2):447-457.

Alkadhi KA, Tran TT. 2015. Chronic Stress Decreases Basal Levels of Memory-Related Signaling Molecules in Area CA1 of At-Risk (Subclinical) Model of Alzheimer’s Disease. Molecular Neurobiology 52(1):93-100.

Alzheimer’s A. 2015. 2015 Alzheimer's disease facts and figures. Alzheimer's & dementia: the journal of the Alzheimer's Association 11(3):332.

Angelucci F, Čechová K, Průša R, Hort J. 2019. Amyloid beta soluble forms and plasminogen activation system in Alzheimer’s disease: Consequences on extracellular maturation of brain‐derived neurotrophic factor and therapeutic implications. CNS Neurosci Ther 25(3):303-313.

Aziz O, Bürli RW, Fischer DF, Frearson J, Wall MD. 2015. Towards small molecules as therapies for alzheimer's disease and other neurodegenerative disorders. Drug Design and Discovery in Alzheimer's Disease. p 199-290.

Bahramikia S, Yazdanparast R, Gheysarzadeh A. 2012. Syntheses and Structure–Activity Relationships of Seven Manganese–Salen Derivatives as Anti‐amyloidogenic and Fibril‐destabilizing Agents Against Hen Egg‐white Lysozyme Aggregation. Chem Biol Drug Des 80(2):227-236.

Bao X, Liu G, Jiang Y, Jiang Q, Liao M, Feng R, Zhang L, Ma G, Zhang S, Chen Z. 2015. Cell adhesion molecule pathway genes are regulated by cis-regulatory SNPs and show significantly altered expression in Alzheimer's disease brains. Neurobiol Aging 36(10):2904. e2901-2904. e2907.

Beck MW, Oh SB, Kerr RA, Lee HJ, Kim SH, Kim S, Jang M, Ruotolo BT, Lee JY, Lim MH. 2015. A rationally designed small molecule for identifying an in vivo link between metal-amyloid-β complexes and the pathogenesis of Alzheimer's disease. Chemical Science 6(3):1879-1886.

Cao Q, Shin WS, Chan H, Vuong CK, Dubois B, Li B, Murray KA, Sawaya MR, Feigon J, Black DL. 2018. Inhibiting amyloid-β cytotoxicity through its interaction with the cell surface receptor LilrB2 by structure-based design. Nature chemistry:1.

Caruana M, Cauchi R, Vassallo N. 2016. Putative role of red wine polyphenols against brain pathology in Alzheimer’s and Parkinson’s disease. Frontiers in nutrition 3:31.

Castello NA, Nguyen MH, Tran JD, Cheng D, Green KN, LaFerla FM. 2014. 7,8-dihydroxyflavone, a small molecule TrkB agonist, improves spatial memory and increases thin spine density in a mouse model of alzheimer disease-like neuronal loss. PLoS ONE 9(3).

Chang P-T, Talekar RS, Kung F-L, Chern T-R, Huang C-W, Ye Q-q, Yang M-Y, Yu C-W, Lai S-Y, Deore RR. 2015. A newly designed molecule J2326 for Alzheimer's disease disaggregates amyloid fibrils and induces neurite outgrowth. Neuropharmacology 92:146-157.

Chen C, Wang Z, Zhang Z, Liu X, Kang SS, Zhang Y, Ye K. 2018. The prodrug of 7, 8-dihydroxyflavone development and therapeutic efficacy for treating Alzheimer’s disease. Proceedings of the National Academy of Sciences 115(3):578-583.

dos Santos TC, Gomes TM, Pinto BAS, Camara AL, de Andrade Paes AM. 2018. Naturally occurring acetylcholinesterase inhibitors and their potential use for Alzheimer's disease therapy. Front Pharmacol 9.

Gheysarzadeh A, Sadeghifard N, Afraidooni L, Pooyan F, Mofid MR, Valadbeigi H, Bakhtiari H, Keikhavani S. 2018. Serum-based microRNA biomarkers for major depression: MiR-16, miR-135a, and miR-1202. Journal of research in medical sciences: the official journal of Isfahan University of Medical Sciences 23.

Gheysarzadeh A, Yazdanparast R. 2012. Inhibition of H2O2-induced cell death through FOXO1 modulation by EUK-172 in SK-N-MC cells. Eur J Pharmacol 697(1-3):47-52.

Gheysarzadeh A, Yazdanparast R. 2015. STAT5 Reactivation by Catechin Modulates H 2 O 2-Induced Apoptosis Through miR-182/FOXO1 Pathway in SK-N-MC Cells. Cell Biochem Biophys 71(2):649-656.

Guo X, Tang P, Liu P, Liu Y, Chong L, Li R. 2016. Dkk1: A promising molecule to connect Alzheimer's disease and osteoporosis. Medical Hypotheses 88:30-32.

Hochstrasser T, Weiss E, Marksteiner J, Humpel C. 2010. Soluble cell adhesion molecules in monocytes of Alzheimer's disease and mild cognitive impairment. Experimental Gerontology 45(1):70-74.

Hossain S, Hashimoto M, Katakura M, Al Mamun A, Shido O. 2015. Medicinal value of asiaticoside for Alzheimer’s disease as assessed using single-molecule-detection fluorescence correlation spectroscopy, laser-scanning microscopy, transmission electron microscopy, and in silico docking. BMC Complement Altern Med 15(1):118.

Kumar A, Nisha CM, Silakari C, Sharma I, Anusha K, Gupta N, Nair P, Tripathi T, Kumar A. 2016. Current and novel therapeutic molecules and targets in Alzheimer's disease. J Formos Med Assoc 115(1):3-10.

Lou K, Yao Y, Hoye AT, James MJ, Cornec A-S, Hyde E, Gay B, Lee VM-Y, Trojanowski JQ, Smith III AB. 2014a. Brain-penetrant, orally bioavailable microtubule-stabilizing small molecules are potential candidate therapeutics for Alzheimer’s disease and related tauopathies. J Med Chem 57(14):6116-6127.

Lou K, Yao Y, Hoye AT, James MJ, Cornec AS, Hyde E, Gay B, Lee VMY, Trojanowski JQ, Smith AB, Brunden KR, Ballatore C. 2014b. Brain-penetrant, orally bioavailable microtubule-stabilizing small molecules are potential candidate therapeutics for Alzheimer's disease and related tauopathies. Journal of Medicinal Chemistry 57(14):6116-6127.

Mao F, Yan J, Li J, Jia X, Miao H, Sun Y, Huang L, Li X. 2014a. New multi-target-directed small molecules against Alzheimer's disease: a combination of resveratrol and clioquinol. Organic & biomolecular chemistry 12(31):5936-5944.

Mao F, Yan J, Li J, Jia X, Miao H, Sun Y, Huang L, Li X. 2014b. New multi-target-directed small molecules against Alzheimer's disease: A combination of resveratrol and clioquinol. Organic and Biomolecular Chemistry 12(31):5936-5944.

Meng F, Dai E, Yu X, Zhang Y, Chen X, Liu X, Wang S, Wang L, Jiang W. 2014. Constructing and characterizing a bioactive small molecule and microRNA association network for Alzheimer's disease. Journal of the Royal Society Interface 11(92).

Nakanishi A, Minami A, Kitagishi Y, Ogura Y, Matsuda S. 2015. BRCA1 and p53 tumor suppressor molecules in Alzheimer’S disease. International Journal of Molecular Sciences 16(2):2879-2892.

Perpetuini AC, Mathoux J, Kennedy BN. 2019. The potential of small molecule brain-derived neurotrophic factor: mimetics to treat inherited retinal degeneration. Neural regeneration research 14(1):85.

Savelieff MG, Liu Y, Senthamarai RRP, Korshavn KJ, Lee HJ, Ramamoorthy A, Lim MH. 2014. A small molecule that displays marked reactivity toward copper-versus zinc-amyloid-β implicated in Alzheimer's disease. Chemical Communications 50(40):5301-5303.

Simmons DA, Knowles JK, Belichenko NP, Banerjee G, Finkle C, Massa SM, Longo FM. 2014. A small molecule p75NTR ligand, LM11A-31, reverses cholinergic neurite dystrophy in Alzheimer's disease mouse models with mid- To late-stage disease progression. PLoS ONE 9(8).

Sun Y, Fan J, Zhu Z, Guo X, Zhou T, Duan W, Shen X. 2015. Small molecule TBTC as a new selective retinoid X receptor α agonist improves behavioral deficit in Alzheimer's disease model mice. European Journal of Pharmacology 762(1):202-213.

Wozniak MA, Frost AL, Itzhaki RF. 2013. The helicase-primase inhibitor BAY 57–1293 reduces the Alzheimer’s disease-related molecules induced by herpes simplex virus type 1. Antiviral Research 99(3):401-404.

Wright JW, Kawas LH, Harding JW. 2014. The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases. Progress in Neurobiology.

Wright JW, Kawas LH, Harding JW. 2015. The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases. Progress in Neurobiology 125:26-46.

Xiang Z, Xu M, Liao M, Jiang Y, Jiang Q, Feng R, Zhang L, Ma G, Wang G, Chen Z. 2015. Integrating genome-wide association study and brain expression data highlights cell adhesion molecules and purine metabolism in Alzheimer’s disease. Mol Neurobiol 52(1):514-521.

Yu Y, Zhang L, Li C, Sun X, Tang D, Shi G. 2014a. A method for evaluating the level of soluble β-amyloid(1-40/1-42) in Alzheimer's disease based on the binding of gelsolin to β-amyloid peptides. Angewandte Chemie - International Edition 53(47):12832-12835.

Yu Y, Zhang L, Li C, Sun X, Tang D, Shi G. 2014b. A Method for Evaluating the Level of Soluble β‐Amyloid (1–40/1–42) in Alzheimer’s Disease Based on the Binding of Gelsolin to β‐Amyloid Peptides. Angewandte Chemie International Edition 53(47):12832-12835.

Zhao H, Zhou S, Zhang M, Feng J, Wang S, Wang D, Geng Y, Wang X. 2016. An in vitro AChE inhibition assay combined with UF-HPLC-ESI-Q-TOF/MS approach for screening and characterizing of AChE inhibitors from roots of Coptis chinensis Franch. J Pharm Biomed Anal 120:235-240.