Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer's Disease

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2021 Apr 8

PMID 33829779

Citations 30

Authors

Michele Rossi

Michela Freschi

Luciana de Camargo Nascente

Alessandra Salerno

Sarah de Melo Viana Teixeira

Florian Nachon

Fabien Chantegreil

Ondrej Soukup

Lukas Prchal

Marco Malaguti

Christian Bergamini

Manuela Bartolini

Cristina Angeloni

Silvana Hrelia

Luiz Antonio Soares Romeiro

Maria Laura Bolognesi

Affiliations

Soon will be listed here.

Abstract

The multifactorial nature of Alzheimer's disease (AD) is a reason for the lack of effective drugs as well as a basis for the development of "multi-target-directed ligands" (MTDLs). As cases increase in developing countries, there is a need of new drugs that are not only effective but also accessible. With this motivation, we report the first sustainable MTDLs, derived from cashew nutshell liquid (CNSL), an inexpensive food waste with anti-inflammatory properties. We applied a framework combination of functionalized CNSL components and well-established acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) tacrine templates. MTDLs were selected based on hepatic, neuronal, and microglial cell toxicity. Enzymatic studies disclosed potent and selective AChE/BChE inhibitors (, , and ), with subnanomolar activities. The X-ray crystal structure of complexed with BChE allowed rationalizing the observed activity (0.0352 nM). Investigation in BV-2 microglial cells revealed antineuroinflammatory and neuroprotective activities for and (already at 0.01 μM), confirming the design rationale.

Citing Articles

Multi-targeted benzylpiperidine-isatin hybrids: Design, synthesis, biological and in silico evaluation as monoamine oxidases and acetylcholinesterase inhibitors for neurodegenerative disease therapies.

Negi N, Ayyannan S, Tripathi R J Comput Aided Mol Des. 2025; 39(1):10.

PMID: 40021503 DOI: 10.1007/s10822-025-00588-2.

Multi-target-directed therapeutic strategies for Alzheimer's disease: controlling amyloid-β aggregation, metal ion homeostasis, and enzyme inhibition.

Yoo J, Lee J, Ahn B, Han J, Lim M Chem Sci. 2025; 16(5):2105-2135.

PMID: 39810997 PMC: 11726323. DOI: 10.1039/d4sc06762b.

Recent Advances in the Search for Effective Anti-Alzheimer's Drugs.

Ogos M, Stary D, Bajda M Int J Mol Sci. 2025; 26(1.

PMID: 39796014 PMC: 11720639. DOI: 10.3390/ijms26010157.

Conjugates of amiridine and salicylic derivatives as promising multifunctional CNS agents for potential treatment of Alzheimer's disease.

Makhaeva G, Grishchenko M, Kovaleva N, Boltneva N, Rudakova E, Astakhova T Arch Pharm (Weinheim). 2024; 358(1):e2400819.

PMID: 39686878 PMC: 11650361. DOI: 10.1002/ardp.202400819.

Identification of Cannabidiolic and Cannabigerolic Acids as MTDL AChE, BuChE, and BACE-1 Inhibitors Against Alzheimer's Disease by In Silico, In Vitro, and In Vivo Studies.

Vitale R, Morace A, dErrico A, Ricciardi F, Fusco A, Boccella S Phytother Res. 2024; 39(1):233-245.

PMID: 39510547 PMC: 11745148. DOI: 10.1002/ptr.8369.

References

Greig N, Lahiri D, Sambamurti K . Butyrylcholinesterase: an important new target in Alzheimer's disease therapy. Int Psychogeriatr. 2003; 14 Suppl 1:77-91. DOI: 10.1017/s1041610203008676. View

Rosenberry T, Brazzolotto X, Macdonald I, Wandhammer M, Trovaslet-Leroy M, Darvesh S . Comparison of the Binding of Reversible Inhibitors to Human Butyrylcholinesterase and Acetylcholinesterase: A Crystallographic, Kinetic and Calorimetric Study. Molecules. 2017; 22(12). PMC: 6149722. DOI: 10.3390/molecules22122098. View

Azrad M, Zeineh N, Weizman A, Veenman L, Gavish M . The TSPO Ligands 2-Cl-MGV-1, MGV-1, and PK11195 Differentially Suppress the Inflammatory Response of BV-2 Microglial Cell to LPS. Int J Mol Sci. 2019; 20(3). PMC: 6387401. DOI: 10.3390/ijms20030594. View

Chen X, Zenger K, Lupp A, Kling B, Heilmann J, Fleck C . Tacrine-silibinin codrug shows neuro- and hepatoprotective effects in vitro and pro-cognitive and hepatoprotective effects in vivo. J Med Chem. 2012; 55(11):5231-42. DOI: 10.1021/jm300246n. View

Morphy R, Rankovic Z . Designed multiple ligands. An emerging drug discovery paradigm. J Med Chem. 2005; 48(21):6523-43. DOI: 10.1021/jm058225d. View

Mollabagher H, Taheri S, Mojtahedi M, Seyedmousavi S . Cu-metal organic frameworks (Cu-MOF) as an environment-friendly and economical catalyst for one pot synthesis of tacrine derivatives. RSC Adv. 2022; 10(4):1995-2003. PMC: 9047972. DOI: 10.1039/c9ra10111j. View

Nachon F, Nicolet Y, Viguie N, Masson P, Fontecilla-Camps J, Lockridge O . Engineering of a monomeric and low-glycosylated form of human butyrylcholinesterase: expression, purification, characterization and crystallization. Eur J Biochem. 2002; 269(2):630-7. DOI: 10.1046/j.0014-2956.2001.02692.x. View

Olajide O, Kumar A, Velagapudi R, Okorji U, Fiebich B . Punicalagin inhibits neuroinflammation in LPS-activated rat primary microglia. Mol Nutr Food Res. 2014; 58(9):1843-51. DOI: 10.1002/mnfr.201400163. View

Elsinghorst P, Gonzalez Tanarro C, Gutschow M . Novel heterobivalent tacrine derivatives as cholinesterase inhibitors with notable selectivity toward butyrylcholinesterase. J Med Chem. 2006; 49(25):7540-4. DOI: 10.1021/jm060742o. View

10.

Cummings J, Lee G, Ritter A, Sabbagh M, Zhong K . Alzheimer's disease drug development pipeline: 2020. Alzheimers Dement (N Y). 2020; 6(1):e12050. PMC: 7364858. DOI: 10.1002/trc2.12050. View

11.

Antognoni F, Potente G, Mandrioli R, Angeloni C, Freschi M, Malaguti M . Fruit Quality Characterization of New Sweet Cherry Cultivars as a Good Source of Bioactive Phenolic Compounds with Antioxidant and Neuroprotective Potential. Antioxidants (Basel). 2020; 9(8). PMC: 7463759. DOI: 10.3390/antiox9080677. View

12.

Zhou J, Jiang X, He S, Jiang H, Feng F, Liu W . Rational Design of Multitarget-Directed Ligands: Strategies and Emerging Paradigms. J Med Chem. 2019; 62(20):8881-8914. DOI: 10.1021/acs.jmedchem.9b00017. View

13.

Hanisch U, Kettenmann H . Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007; 10(11):1387-94. DOI: 10.1038/nn1997. View

14.

Fu W, Wang X, Ip N . Targeting Neuroinflammation as a Therapeutic Strategy for Alzheimer's Disease: Mechanisms, Drug Candidates, and New Opportunities. ACS Chem Neurosci. 2018; 10(2):872-879. DOI: 10.1021/acschemneuro.8b00402. View

15.

de Souza M, Teotonio I, Coutinho de Almeida F, Heyn G, Alves P, Romeiro L . Molecular evaluation of anti-inflammatory activity of phenolic lipid extracted from cashew nut shell liquid (CNSL). BMC Complement Altern Med. 2018; 18(1):181. PMC: 5996561. DOI: 10.1186/s12906-018-2247-0. View

16.

Streit W . Microglial response to brain injury: a brief synopsis. Toxicol Pathol. 2000; 28(1):28-30. DOI: 10.1177/019262330002800104. View

17.

Barabasi A, Gulbahce N, Loscalzo J . Network medicine: a network-based approach to human disease. Nat Rev Genet. 2010; 12(1):56-68. PMC: 3140052. DOI: 10.1038/nrg2918. View

18.

Dighe S, Deora G, De La Mora E, Nachon F, Chan S, Parat M . Discovery and Structure-Activity Relationships of a Highly Selective Butyrylcholinesterase Inhibitor by Structure-Based Virtual Screening. J Med Chem. 2016; 59(16):7683-9. DOI: 10.1021/acs.jmedchem.6b00356. View

19.

Wolf S, Boddeke H, Kettenmann H . Microglia in Physiology and Disease. Annu Rev Physiol. 2016; 79:619-643. DOI: 10.1146/annurev-physiol-022516-034406. View

20.

Sameem B, Saeedi M, Mahdavi M, Shafiee A . A review on tacrine-based scaffolds as multi-target drugs (MTDLs) for Alzheimer's disease. Eur J Med Chem. 2016; 128:332-345. DOI: 10.1016/j.ejmech.2016.10.060. View