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Novel Multifunctional Ligands and Their Application in Alzheimer's Disease

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Bioorganic Chemistry".

Deadline for manuscript submissions: closed (30 November 2018) | Viewed by 26093

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Prof. Dr. Praveen P. Nekkar Rao

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Guest Editor

School of Pharmacy, Health Sciences Campus, University of Waterloo, 200 University Avenue West, Waterloo, ON N2L 3G1, Canada
Interests: medicinal chemistry; Alzheimer’s disease; drug discovery; structure-based design; organic synthesis; protein–protein interactions; protein–small molecule interactions

Special Issue Information

Dear Colleagues,

More than 100 years ago, the German psychiatrist Alois Alzheimer described an unusual disease in one of his patient’s which was later called Alzheimer’s disease (AD). Since then, humanity has seen an exponential growth in both basic and applied sciences, which has led to the successful treatment of a number of diseases. Despite these advances, unfortunately, cholinesterase inhibitors, which only provide symptomatic relief remain the major class of drugs used in the pharmacotherapy of AD. Nearly 47 million people are affected with AD or related dementia (Alzheimer’s Association, USA). These numbers are expected to grow in the coming years, burdening the health, social, and economic landscape of many countries across the globe. These facts mandate an urgent need to discover novel treatment options for AD. On this note, recent focus has been on designing hybrid multifunctional ligands as disease modifying agents capable of providing not only symptomatic relief but more significantly, prevent disease progression and potentially cure AD. This Special Issue is a call for academic and industrial scientists to share their research on their discovery efforts toward multifunctional ligands aimed at AD. The scope of this issue includes natural/synthetic small molecules, peptides, computational design and lead optimization.

Prof. Dr. Praveen P. Nekkar Rao
Guest Editor

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Keywords

Beta amyloid
tau protein
cholinesterase
mitochondrial dysfunction
oxidative stress
inflammation
heterocycles
peptides
computational methods

Published Papers (5 papers)

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Research

15 pages, 1947 KiB

Open AccessArticle

New Multitarget Hybrids Bearing Tacrine and Phenylbenzothiazole Motifs as Potential Drug Candidates for Alzheimer’s Disease

by Rajeshwari Rajeshwari, Karam Chand, Emanuel Candeias, Sandra M. Cardoso, Sílvia Chaves and M. Amélia Santos

Molecules 2019, 24(3), 587; https://doi.org/10.3390/molecules24030587 - 07 Feb 2019

Cited by 20 | Viewed by 4002

Abstract

Research on neurodegenerative brain disorders, namely the age-dependent Alzheimer’s disease (AD), has been intensified in the last decade due to the absence of a cure and the recognized increasing of life expectancy for populations. To address the multifactorial nature and complexity of AD, a multi-target-directed ligand approach was herein employed, by designing a set of six selected hybrids (14–19) that combine in the same entity two pharmacophores: tacrine (TAC) and 2-phenylbenzothiazole (PhBTA). The compounds contain a methoxy substituent at the PhBTA moiety and have a variable length linker between that and the TAC moiety. The docking studies showed that all the compounds assure a dual-binding mode of acetylcholinesterase (AChE) inhibition, establishing π-stacking and H-bond interactions with aminoacid residues at both active binding sites of the enzyme (CAS and PAS). The bioassays revealed that the designed compounds display excellent AChE inhibitory activity in the sub-micromolar range (0.06–0.27 μM) and moderate inhibition values for amyloid-β (Aβ) self-aggregation (27–44.6%), compounds 14 and 15 being the lead compounds. Regarding neuroprotective effects in neuroblastoma cells, compounds 15, 16 and 19 revealed capacity to prevent Aβ-induced toxicity, but compound 16 showed the highest neuroprotective effect. Overall these hybrid compounds, in particular 15 and 16, with promising multitarget anti-AD ability, encourage further pursuing studies on this type of TAC-PhBTA derivatives for potential AD therapy. Full article

(This article belongs to the Special Issue Novel Multifunctional Ligands and Their Application in Alzheimer's Disease)

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19 pages, 2708 KiB

Open AccessArticle

Synthesis and Biological Evaluation of New Cholinesterase Inhibitors for Alzheimer’s Disease

by Weiam Hussein, Begüm Nurpelin Sağlık, Serkan Levent, Büşra Korkut, Sinem Ilgın, Yusuf Özkay and Zafer Asım Kaplancıklı

Molecules 2018, 23(8), 2033; https://doi.org/10.3390/molecules23082033 - 14 Aug 2018

Cited by 45 | Viewed by 5706

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder mostly influencing the elderly, and causes death due to dementia. The main pathogenic feature connected with the progression of this multifactorial disease is the weakening of the cholinergic system in the brain. Cholinesterase (ChE) inhibitors are recognized as one of the choices in the treatment of AD. The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were approved as a therapeutic strategy to reduce the symptoms of AD and prevent its progression. The capacity of BChE is not completely known yet; rather, it is accepted to assume a part in a few disorders such as AD. Thus, BChE inhibitors may have a greater role for the treatment of AD in the future. In the present study, 2-(9-acridinylamino)-2-oxoethyl piperazine/piperidine/morpholinecarbodithioate derivatives were synthesized in order to investigate anticholinesterase activity. Eight derivatives demonstrated a specific and promising action against BChE. Furthermore, compound 4n showed inhibitory activity against both enzymes. It was found that the active compounds were well tolerated in the cytotoxicity test. Possible interactions between the lead compound, 4n, and the BChE enzyme were determined through a docking study. The findings obtained within this paper will contribute to the development of new and effective synthetic anti-Alzheimer compounds, and will ideally encourage future screening against AD. Full article

(This article belongs to the Special Issue Novel Multifunctional Ligands and Their Application in Alzheimer's Disease)

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23 pages, 3866 KiB

Open AccessFeature PaperArticle

Insights into Structure-Activity Relationships of 3-Arylhydrazonoindolin-2-One Derivatives for Their Multitarget Activity on β-Amyloid Aggregation and Neurotoxicity

by Rosa Purgatorio, Modesto De Candia, Annalisa De Palma, Francesco De Santis, Leonardo Pisani, Francesco Campagna, Saverio Cellamare, Cosimo Damiano Altomare and Marco Catto

Molecules 2018, 23(7), 1544; https://doi.org/10.3390/molecules23071544 - 26 Jun 2018

Cited by 21 | Viewed by 4001

Abstract

Despite the controversial outcomes of clinical trials executed so far, the prevention of β-amyloid (Aβ) deposition and neurotoxicity by small molecule inhibitors of Aβ aggregation remains a target intensively pursued in the search of effective drugs for treating Alzheimer’s disease (AD) and related neurodegeneration syndromes. As a continuation of previous studies, a series of new 3-(2-arylhydrazono)indolin-2-one derivatives was synthesized and assayed, investigating the effects of substitutions on both the indole core and arylhydrazone moiety. Compared with the reference compound 1, we disclosed equipotent derivatives bearing alkyl substituents at the indole nitrogen, and fairly tolerated bioisosteric replacements at the arylhydrazone moiety. For most of the investigated compounds, the inhibition of Aβ₄₀ aggregation (expressed as pIC₅₀) was found to be correlated with lipophilicity, as assessed by a reversed-phase HPLC method, through a bilinear relationship. The N¹-cyclopropyl derivative 28 was tested in cell-based assays of Aβ₄₂ oligomer toxicity and oxidative stress induced by hydrogen peroxide, showing significant cytoprotective effects. This study confirmed the versatility of isatin in preparing multitarget small molecules affecting different biochemical pathways involved in AD. Full article

(This article belongs to the Special Issue Novel Multifunctional Ligands and Their Application in Alzheimer's Disease)

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15 pages, 6444 KiB

Open AccessArticle

Design, Synthesis, and Biological Evaluation of 2-(Benzylamino-2-Hydroxyalkyl)Isoindoline-1,3-Diones Derivatives as Potential Disease-Modifying Multifunctional Anti-Alzheimer Agents

by Dawid Panek, Anna Więckowska, Anna Pasieka, Justyna Godyń, Jakub Jończyk, Marek Bajda, Damijan Knez, Stanislav Gobec and Barbara Malawska

Molecules 2018, 23(2), 347; https://doi.org/10.3390/molecules23020347 - 07 Feb 2018

Cited by 24 | Viewed by 5590

Abstract

The complex nature of Alzheimer’s disease calls for multidirectional treatment. Consequently, the search for multi-target-directed ligands may lead to potential drug candidates. The aim of the present study is to seek multifunctional compounds with expected activity against disease-modifying and symptomatic targets. A series of 15 drug-like various substituted derivatives of 2-(benzylamino-2-hydroxyalkyl)isoindoline-1,3-diones was designed by modification of cholinesterase inhibitors toward β-secretase inhibition. All target compounds have been synthesized and tested against eel acetylcholinesterase (eeAChE), equine serum butyrylcholinesterase (eqBuChE), human β-secretase (hBACE-1), and β-amyloid (Aβ-aggregation). The most promising compound, 12 (2-(5-(benzylamino)-4-hydroxypentyl)isoindoline-1,3-dione), displayed inhibitory potency against eeAChE (IC₅₀ = 3.33 μM), hBACE-1 (43.7% at 50 μM), and Aβ-aggregation (24.9% at 10 μM). Molecular modeling studies have revealed possible interaction of compound 12 with the active sites of both enzymes—acetylcholinesterase and β-secretase. In conclusion: modifications of acetylcholinesterase inhibitors led to the discovery of a multipotent anti-Alzheimer’s agent, with moderate and balanced potency, capable of inhibiting acetylcholinesterase, a symptomatic target, and disease-modifying targets: β-secretase and Aβ-aggregation. Full article

(This article belongs to the Special Issue Novel Multifunctional Ligands and Their Application in Alzheimer's Disease)

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13 pages, 3182 KiB

Open AccessArticle

Towards a Novel Class of Multitarget-Directed Ligands: Dual P2X7–NMDA Receptor Antagonists

by Olga Karoutzou, Seung-Hwa Kwak, So-Deok Lee, Daina Martínez-Falguera, Francesc X. Sureda, Santiago Vázquez, Yong-Chul Kim and Marta Barniol-Xicota

Molecules 2018, 23(1), 230; https://doi.org/10.3390/molecules23010230 - 21 Jan 2018

Cited by 17 | Viewed by 5902

Abstract

Multi-target-directed ligands (MTDLs) offer new hope for the treatment of multifactorial complex diseases such as Alzheimer’s Disease (AD). Herein, we present compounds aimed at targeting the NMDA and the P2X7 receptors, which embody a different approach to AD therapy. On one hand, we are seeking to delay neurodegeneration targeting the glutamatergic NMDA receptors; on the other hand, we also aim to reduce neuroinflammation, targeting P2X7 receptors. Although the NMDA receptor is a widely recognized therapeutic target in treating AD, the P2X7 receptor remains largely unexplored for this purpose; therefore, the dual inhibitor presented herein—which is open to further optimization—represents the first member of a new class of MTDLs. Full article

(This article belongs to the Special Issue Novel Multifunctional Ligands and Their Application in Alzheimer's Disease)

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