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Special Issue "Novel Multifunctional Ligands and Their Application in Alzheimer's Disease"

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

Deadline for manuscript submissions: 30 September 2018

Special Issue Editor

Guest Editor
Prof. Dr. Praveen P. Nekkar Rao

School of Pharmacy, Health Sciences Campus, University of Waterloo, 200 University Avenue West, Waterloo N2L 3G1, Canada
Website | E-Mail
Phone: 519-888-4567 ext: 21317
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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

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

Published Papers (2 papers)

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Research

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
Molecules 2018, 23(2), 347; https://doi.org/10.3390/molecules23020347
Received: 17 January 2018 / Revised: 1 February 2018 / Accepted: 3 February 2018 / Published: 7 February 2018
Cited by 1 | PDF Full-text (6444 KB) | HTML Full-text | XML Full-text
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
[...] Read more.
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
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Graphical abstract

Open AccessArticle Towards a Novel Class of Multitarget-Directed Ligands: Dual P2X7–NMDA Receptor Antagonists
Molecules 2018, 23(1), 230; https://doi.org/10.3390/molecules23010230
Received: 2 December 2017 / Revised: 15 January 2018 / Accepted: 16 January 2018 / Published: 21 January 2018
PDF Full-text (3182 KB) | HTML Full-text | XML Full-text | Supplementary Files
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
[...] Read more.
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
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