Multi-Target Directed Drugs: A Modern Approach for Design of New Drugs for the Treatment of Alzheimer's Disease

Overview

Journal Curr Neuropharmacol

Publisher Bentham Science Publishers

Date 2014 May 23

PMID 24851088

Citations 50

Authors

Kris Simone Tranches Dias

Claudio Viegas Jr

Affiliations

Soon will be listed here.

Abstract

Alzheimer's disease (AD) is a complex neurodegenerative disorder with a multi-faceted pathogenesis. So far, the therapeutic paradigm "one-compound-one-target" has failed and despite enormous efforts to elucidate the pathophysiology of AD, the disease is still incurable. The multiple factors involved in AD include amyloid aggregation to form insoluble neurotoxic plaques of Aβ, hyperphosphorylation of tau protein, oxidative stress, calcium imbalance, mitochondrial dysfunction and deterioration of synaptic transmission. These factors together, accentuate changes in the CNS homeostasis, starting a complex process of interconnected physiological damage, leading to cognitive and memory impairment and neuronal death. A recent approach for the rational design of new drug candidates, also called multitarget-directed ligand (MTDL) approach, has gained increasing attention by many research groups, which have developed a variety of hybrid compounds acting simultaneously on diverse biological targets. This review aims to show some recent advances and examples of the exploitation of MTDL approach in the rational design of novel drug candidate prototypes for the treatment of AD.

Citing Articles

New Insights into the Development of Donepezil-Based Hybrid and Natural Molecules as Multi-Target Drug Agents for Alzheimer's Disease Treatment.

Angelova V, Stoyanov B, Simeonova R Molecules. 2024; 29(22).

PMID: 39598703 PMC: 11596391. DOI: 10.3390/molecules29225314.

ZA-II-05, a novel NMDA-receptor antagonist reverses vanadium-induced neurotoxicity in Caenorhabditis elegans (C. elegans).

Ladagu A, Olopade F, Chazot P, Elufioye T, Luong T, Fuller M BMC Neurosci. 2024; 25(1):56.

PMID: 39468459 PMC: 11520585. DOI: 10.1186/s12868-024-00902-y.

Development of Novel Alaninamide Derivatives with Anticonvulsant Activity and Favorable Safety Profiles in Animal Models.

Abram M, Jakubiec M, Koczurkiewicz-Adamczyk P, Doroz-Plonka A, Rapacz A, Kaminski K Int J Mol Sci. 2024; 25(18).

PMID: 39337345 PMC: 11432405. DOI: 10.3390/ijms25189861.

Discovery and Profiling of New Multimodal Phenylglycinamide Derivatives as Potent Antiseizure and Antinociceptive Drug Candidates.

Jakubiec M, Abram M, Zagaja M, Socala K, Panic V, Latacz G ACS Chem Neurosci. 2024; 15(17):3228-3256.

PMID: 39166702 PMC: 11378297. DOI: 10.1021/acschemneuro.4c00438.

Novel Alaninamide Derivatives with Drug-like Potential for Development as Antiseizure and Antinociceptive Therapies─In Vitro and In Vivo Characterization.

Jakubiec M, Abram M, Zagaja M, Andres-Mach M, Szala-Rycaj J, Latacz G ACS Chem Neurosci. 2024; 15(11):2198-2222.

PMID: 38741575 PMC: 11157491. DOI: 10.1021/acschemneuro.4c00013.

References

Zhang H . One-compound-multiple-targets strategy to combat Alzheimer's disease. FEBS Lett. 2005; 579(24):5260-4. DOI: 10.1016/j.febslet.2005.09.006. View

Reddy P, Beal M . Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. Trends Mol Med. 2008; 14(2):45-53. PMC: 3107703. DOI: 10.1016/j.molmed.2007.12.002. View

. 2011 Alzheimer's disease facts and figures. Alzheimers Dement. 2011; 7(2):208-44. DOI: 10.1016/j.jalz.2011.02.004. View

Bolognesi M, Cavalli A, Valgimigli L, Bartolini M, Rosini M, Andrisano V . Multi-target-directed drug design strategy: from a dual binding site acetylcholinesterase inhibitor to a trifunctional compound against Alzheimer's disease. J Med Chem. 2007; 50(26):6446-9. DOI: 10.1021/jm701225u. View

Lu C, Guo Y, Yan J, Luo Z, Luo H, Yan M . Design, synthesis, and evaluation of multitarget-directed resveratrol derivatives for the treatment of Alzheimer's disease. J Med Chem. 2013; 56(14):5843-59. DOI: 10.1021/jm400567s. View

Bolea I, Juarez-Jimenez J, de Los Rios C, Chioua M, Pouplana R, Luque F . Synthesis, biological evaluation, and molecular modeling of donepezil and N-[(5-(benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine hybrids as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of.... J Med Chem. 2011; 54(24):8251-70. DOI: 10.1021/jm200853t. View

Chao X, He X, Yang Y, Zhou X, Jin M, Liu S . Design, synthesis and pharmacological evaluation of novel tacrine-caffeic acid hybrids as multi-targeted compounds against Alzheimer's disease. Bioorg Med Chem Lett. 2012; 22(20):6498-502. DOI: 10.1016/j.bmcl.2012.08.036. View

Cavalli A, Bolognesi M, Capsoni S, Andrisano V, Bartolini M, Margotti E . A small molecule targeting the multifactorial nature of Alzheimer's disease. Angew Chem Int Ed Engl. 2007; 46(20):3689-92. DOI: 10.1002/anie.200700256. View

Cavalli A, Bolognesi M, Minarini A, Rosini M, Tumiatti V, Recanatini M . Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem. 2008; 51(3):347-72. DOI: 10.1021/jm7009364. View

10.

Schmitt B, Bernhardt T, Moeller H, Heuser I, Frolich L . Combination therapy in Alzheimer's disease: a review of current evidence. CNS Drugs. 2004; 18(13):827-44. DOI: 10.2165/00023210-200418130-00001. View

11.

Heneka M, OBanion M . Inflammatory processes in Alzheimer's disease. J Neuroimmunol. 2007; 184(1-2):69-91. DOI: 10.1016/j.jneuroim.2006.11.017. View

12.

Rook Y, Schmidtke K, Gaube F, Schepmann D, Wunsch B, Heilmann J . Bivalent beta-carbolines as potential multitarget anti-Alzheimer agents. J Med Chem. 2010; 53(9):3611-7. DOI: 10.1021/jm1000024. View

13.

Marco-Contelles J, Leon R, Lopez M, Garcia A, Villarroya M . Synthesis and biological evaluation of new 4H-pyrano[2,3-b]quinoline derivatives that block acetylcholinesterase and cell calcium signals, and cause neuroprotection against calcium overload and free radicals. Eur J Med Chem. 2006; 41(12):1464-9. DOI: 10.1016/j.ejmech.2006.06.016. View

14.

Martins C, Carreiras M, Leon R, de Los Rios C, Bartolini M, Andrisano V . Synthesis and biological assessment of diversely substituted furo[2,3-b]quinolin-4-amine and pyrrolo[2,3-b]quinolin-4-amine derivatives, as novel tacrine analogues. Eur J Med Chem. 2011; 46(12):6119-30. DOI: 10.1016/j.ejmech.2011.09.038. View

15.

Piazzi L, Cavalli A, Colizzi F, Belluti F, Bartolini M, Mancini F . Multi-target-directed coumarin derivatives: hAChE and BACE1 inhibitors as potential anti-Alzheimer compounds. Bioorg Med Chem Lett. 2007; 18(1):423-6. DOI: 10.1016/j.bmcl.2007.09.100. View

16.

Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M . Alzheimer's disease: clinical trials and drug development. Lancet Neurol. 2010; 9(7):702-16. DOI: 10.1016/S1474-4422(10)70119-8. View

17.

Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole G . Inflammation and Alzheimer's disease. Neurobiol Aging. 2000; 21(3):383-421. PMC: 3887148. DOI: 10.1016/s0197-4580(00)00124-x. View

18.

Bolognesi M, Cavalli A, Melchiorre C . Memoquin: a multi-target-directed ligand as an innovative therapeutic opportunity for Alzheimer's disease. Neurotherapeutics. 2008; 6(1):152-62. PMC: 5084263. DOI: 10.1016/j.nurt.2008.10.042. View

19.

Rizzo S, Tarozzi A, Bartolini M, Da Costa G, Bisi A, Gobbi S . 2-Arylbenzofuran-based molecules as multipotent Alzheimer's disease modifying agents. Eur J Med Chem. 2012; 58:519-32. DOI: 10.1016/j.ejmech.2012.10.045. View

20.

Wang J, Grundke-Iqbal I, Iqbal K . Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci. 2007; 25(1):59-68. PMC: 3191918. DOI: 10.1111/j.1460-9568.2006.05226.x. View