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Development of Novel Drugs for Alzheimer´s Disease

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

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 15343

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Special Issue Editors

Prof. Dr. Kamil Kuca

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Department of Chemistry, Faculty of Science, University of Hradec Králové, 50003 Hradec Králové, Czech Republic
Interests: toxins; drug design and development; antidotes for pesticide and nerve agent intoxications; Alzheimer’s disease; detergents as disinfectants, decontamination means; nanotechnology; health economics and pharmacoeconomics
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Tanos Celmar Costa Franca

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1. Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense (LMCBD), Military Institute of Engineering, Praça General Tibúrcio 80, Rio de Janeiro, RJ 22290-270, Brazil
2. Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 50003 Hradec Kralové, Czech Republic
Interests: Medicinal Chemistry; Chemical and Biological Defense; Molecular Modeling; Organic Synthesis; Drug Design
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Teodorico C. Ramalho

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Department of Chemistry, Federal University of Lavras, P.O. Box 3037, Lavras 37200-000, MG, Brazil
Interests: computational and medicinal chemistry; nanotechnology; solid state spectroscopy with biological and environmental interest
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is my great honor to invite you to submit your newly prepared manuscripts to our Special Issue of the MDPI journal Molecules, which is dedicated to the development of novel drugs for the treatment of Alzheimer’s disease (AD). It is known that AD represents a health, economic, and social problem that requires the full attention of scientists around the world. On the basis of this fact, every attempt to combat this disease is very important to obtain the right molecules which in the future will be considered as drug candidates for further preclinical and clinical trials. We hope that this Special Issue will encourage you to share your knowledge on this topic. In this regard, all manuscripts focusing on the design, synthesis, and in vitro and in vivo evaluation of novel AD drug candidates are welcome.

Prof. Kamil Kuča
Prof. Tanos Celmar Costa Franca
Prof. Teodorico C. Ramalho
Guest Editors

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 submissions that pass pre-check are 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 semimonthly 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 2700 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

Alzheimer’s disease
Drug design, discovery, and development
Drug target
Disease treatment
New approaches

Published Papers (4 papers)

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Research

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20 pages, 1953 KiB

Open AccessArticle

Design, Synthesis, and Structure–Activity Relationships of Thiazole Analogs as Anticholinesterase Agents for Alzheimer’s Disease

by Begüm Nurpelin Sağlık, Derya Osmaniye, Ulviye Acar Çevik, Serkan Levent, Betül Kaya Çavuşoğlu, Yusuf Özkay and Zafer Asım Kaplancıklı

Molecules 2020, 25(18), 4312; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25184312 - 20 Sep 2020

Cited by 16 | Viewed by 2880

Abstract

Dementia is a neurological condition commonly correlated with Alzheimer’s disease (AD), and it is seen with many other central nervous system (CNS) disorders. The restricted number of medications is not appropriate to offer enough relief to enhance the quality of life of patients suffering from this symptom; thus, all therapeutic choices should be carefully assessed. In this study, new thiazolylhydrazone derivatives (2a–2l) were designed and synthesized based on the cholinergic hypothesis. Their chemical structures were confirmed by ¹H NMR, ¹³C NMR, and HRMS spectrometric techniques. The ADME (absorption, distribution, metabolism, elimination) parameters of the synthesized compounds were predicted by using QikProp 4.8 software. It was concluded that all compounds presented satisfactory drug-like characteristics. Furthermore, their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro were also tested by modified the Ellman spectrophotometric method. According to the results, all compounds showed a weak inhibitory effect on BChE. On the other hand, most of the compounds (2a, 2b, 2d, 2e, 2g, 2i, and 2j) had a certain AChE inhibitory activity, and the IC₅₀ values of them were calculated as 0.063 ± 0.003, 0.056 ± 0.002, 0.147 ± 0.006, 0.040 ± 0.001, 0.031 ± 0.001, 0.028 ± 0.001, and 0.138 ± 0.005 µM, respectively. Among these derivatives, compound 2i was found to be the most active agent in the series with an IC₅₀ value of 0.028 ± 0.001 µM, which indicated an inhibition profile at a similar rate as the reference drug, donepezil. The potential binding modes of compounds 2a, 2b, 2e, 2g, and 2i with AChE were investigated and compared with each other by the molecular docking studies. The results showed that these compounds were strongly bound up with the AChE enzyme active site with the optimal conformations. Full article

(This article belongs to the Special Issue Development of Novel Drugs for Alzheimer´s Disease)

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19 pages, 3170 KiB

Open AccessArticle

Novel Acetylcholinesterase Inhibitors Based on Uracil Moiety for Possible Treatment of Alzheimer Disease

by Vyacheslav E. Semenov, Irina V. Zueva, Marat A. Mukhamedyarov, Sofya V. Lushchekina, Elena O. Petukhova, Lilya M. Gubaidullina, Evgeniya S. Krylova, Lilya F. Saifina, Oksana A. Lenina and Konstantin A. Petrov

Molecules 2020, 25(18), 4191; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25184191 - 12 Sep 2020

Cited by 14 | Viewed by 2894

Abstract

In this study, novel derivatives based on 6-methyluracil and condensed uracil were synthesized, namely, 2,4-quinazoline-2,4-dione with ω-(ortho-nitrilebenzylethylamino) alkyl chains at the N atoms of the pyrimidine ring. In this series of synthesized compounds, the polymethylene chains were varied from having tetra- to hexamethylene chains, and secondary NH, tertiary ethylamino, and quaternary ammonium groups were introduced into the chains. The molecular modeling of the compounds indicated that they could function as dual binding site acetylcholinesterase inhibitors, binding to both the peripheral anionic site and active site. The data from in vitro experiments show that the most active compounds exhibit affinity toward acetylcholinesterase within a nanomolar range, with selectivity for acetylcholinesterase over butyrylcholinesterase reaching four orders of magnitude. In vivo biological assays demonstrated the potency of these compounds in the treatment of memory impairment using an animal model of Alzheimer disease. Full article

(This article belongs to the Special Issue Development of Novel Drugs for Alzheimer´s Disease)

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21 pages, 4960 KiB

Open AccessArticle

Extensive Structure Modification on Luteolin-Cinnamic Acid Conjugates Leading to BACE1 Inhibitors with Optimal Pharmacological Properties

by De-Yang Sun, Chen Cheng, Katrin Moschke, Jian Huang and Wei-Shuo Fang

Molecules 2020, 25(1), 102; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25010102 - 26 Dec 2019

Cited by 5 | Viewed by 3168

Abstract

BACE1 inhibitory conjugates derived from two natural products, luteolin (1) and p-hydroxy-cinnamic acid (2), were subjected to systematic structure modifications, including various positions in luteolin segment for conjugation, different linkers (length, bond variation), as well as various substitutions in cinnamic acid segment (various substituents on benzene, and replacement of benzene by heteroaromatics and cycloalkane). Optimal conjugates such as 7c and 7k were chosen on the basis of a series of bioassay data for further investigation. Full article

(This article belongs to the Special Issue Development of Novel Drugs for Alzheimer´s Disease)

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Review

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17 pages, 1832 KiB

Open AccessReview

Future Therapeutic Perspectives into the Alzheimer’s Disease Targeting the Oxidative Stress Hypothesis

by Jéssika P. Teixeira, Alexandre A. de Castro, Flávia V. Soares, Elaine F. F. da Cunha and Teodorico C. Ramalho

Molecules 2019, 24(23), 4410; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24234410 - 03 Dec 2019

Cited by 69 | Viewed by 5646

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease that is usually accompanied by aging, increasingly being the most common cause of dementia in the elderly. This disorder is characterized by the accumulation of beta amyloid plaques (Aβ) resulting from impaired amyloid precursor protein (APP) metabolism, together with the formation of neurofibrillary tangles and tau protein hyperphosphorylation. The exacerbated production of reactive oxygen species (ROS) triggers the process called oxidative stress, which increases neuronal cell abnormalities, most often followed by apoptosis, leading to cognitive dysfunction and dementia. In this context, the development of new therapies for the AD treatment is necessary. Antioxidants, for instance, are promising species for prevention and treatment because they are capable of disrupting the radical chain reaction, reducing the production of ROS. These species have also proven to be adjunctive to conventional treatments making them more effective. In this sense, several recently published works have focused their attention on oxidative stress and antioxidant species. Therefore, this review seeks to show the most relevant findings of these studies. Full article

(This article belongs to the Special Issue Development of Novel Drugs for Alzheimer´s Disease)

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