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Alzheimer’s Disease: Small-Molecule Modulators of Novel Therapeutic Pathways
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Alzheimer’s Disease: Small-Molecule Modulators of Novel Therapeutic Pathways

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (20 October 2024) | Viewed by 6760

Special Issue Editor

Dr. Sachin P. Patil

E-Mail Website
Guest Editor
School of Engineering, Widener University, Chester, PA 19013, USA
Interests: Alzheimer's disease; cancer; metabolic engineering; interactome engineering
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

After more than a century since Dr. Alois Alzheimer, a German physician, described the first Alzheimer’s disease (AD) case in 1906, AD still remains a daunting medical and socio-economical challenge.

AD is an age-related, progressive neurodegenerative disease, clinically characterized by severe memory loss and impairment of various cognitive functions. Pathologically, AD is characterized by extracellular deposits of amyloid beta (Aβ) protein and intracellular accumulation of neurofibrillary tangles of tau (τ) protein. Accordingly, much of the therapeutic focus has been on the Aβ plaques and τ tangles. Recently, two anti-amyloid antibodies targeting aggregated (Aducanumab) and protofibril (Lecanemab) forms of Aβ have been approved by the FDA, but with only small clinical benefits. On the small-molecule side, four acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine, and tacrine) and one NMDA receptor antagonist (memantine) are in clinical use, providing only limited and symptomatic effects. Thus, there is a significant unmet need for investigating novel disease mechanisms, leading to the discovery and development of disease-modifying drugs against this devastating disease.

This Special Issue is dedicated to gathering such novel AD mechanisms, with a particular emphasis on targeting these mechanisms using small-molecule drugs. These drugs may offer several benefits versus large biotherapeutics, such as low cost and relatively easier delivery to brain. In addition to the de novo drug discovery efforts, the drug repurposing/repositioning studies that involve approved/investigational drugs are also particularly welcome.

We look forward to your contribution to this Special Issue, in the form of original research articles or focused reviews.

Dr. Sachin P. Patil
Guest Editor

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 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
  • dementia
  • neurodegeneration
  • small molecules
  • disease mechanisms
  • drug discovery and design

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Published Papers (4 papers)

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Research

28 pages, 6755 KiB  
Article
Novel Dual Acetyl- and Butyrylcholinesterase Inhibitors Based on the Pyridyl–Pyridazine Moiety for the Potential Treatment of Alzheimer’s Disease
by Mohamed Elsawalhy, Adel A-H Abdel-Rahman, Ebtesam A. Basiony, Salma A. Ellithy, Allam A. Hassan, Eman S. Abou-Amra, Abdelhamid Ismail, Abdulrahman A. Almehizia, Mohamed A. Al-Omar, Ahmed M. Naglah and Nasser A. Hassan
Pharmaceuticals 2024, 17(10), 1407; https://doi.org/10.3390/ph17101407 - 21 Oct 2024
Viewed by 958
Abstract
Background: Alzheimer’s disease (AD) is characterized by cholinergic dysfunction, making the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) critical for improving cholinergic neurotransmission. However, the development of effective dual inhibitors remains challenging. Objective: This study aims to synthesize and evaluate novel [...] Read more.
Background: Alzheimer’s disease (AD) is characterized by cholinergic dysfunction, making the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) critical for improving cholinergic neurotransmission. However, the development of effective dual inhibitors remains challenging. Objective: This study aims to synthesize and evaluate novel pyridazine-containing compounds as potential dual inhibitors of AChE and BuChE for AD treatment. Methods: Ten novel pyridazine-containing compounds were synthesized and characterized using IR, 1H NMR, and 13C NMR. The inhibitory activities against AChE and BuChE were assessed in vitro, and pharmacokinetic properties were explored through in silico ADME studies. Molecular dynamics simulations were performed for the most active compound. Results: Compound 5 was the most potent inhibitor, with IC50 values of 0.26 µM for AChE and 0.19 µM for BuChE, outperforming rivastigmine and tacrine, and showing competitive results with donepezil. Docking studies revealed a binding affinity of −10.21 kcal/mol to AChE and −13.84 kcal/mol to BuChE, with stable interactions confirmed by molecular dynamics simulations. In silico ADME studies identified favorable pharmacokinetic properties for compounds 5, 8, and 9, with Compound 5 showing the best activity. Conclusions: Compound 5 demonstrates strong potential as a dual cholinesterase inhibitor for Alzheimer’s disease, supported by both in vitro and in silico analyses. These findings provide a basis for further optimization and development of these novel inhibitors. Full article
(This article belongs to the Special Issue Alzheimer’s Disease: Small-Molecule Modulators of Novel Therapeutic Pathways)
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15 pages, 2526 KiB  
Article
Discovery of Small Molecule Glycolytic Stimulants for Enhanced ApoE Lipidation in Alzheimer’s Disease Cell Model
by Sachin P. Patil and Bella R. Kuehn
Pharmaceuticals 2024, 17(4), 491; https://doi.org/10.3390/ph17040491 - 12 Apr 2024
Viewed by 2213
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by pathophysiological deposits of extracellular amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles of tau. The central role of Aβ in AD pathology is well-established, with its increased deposition attributed mainly to its decreased [...] Read more.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by pathophysiological deposits of extracellular amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles of tau. The central role of Aβ in AD pathology is well-established, with its increased deposition attributed mainly to its decreased cerebral clearance. Here, it is noteworthy that apolipoprotein E (ApoE), the most significant risk factor for AD, has been shown to play an isoform-specific role in clearing Aβ deposits (ApoE2 > ApoE3 > ApoE4), owing mainly to its lipidation status. In addition to the pathophysiological Aβ deposits, AD is also characterized by abnormal glucose metabolism, which is a distinct event preceding Aβ deposition. The present study established, for the first time, a possible link between these two major AD etiologies, with glucose metabolism directly influencing ApoE lipidation and its secretion by astrocytes expressing human ApoE4. Specifically, glucose dose-dependently activated liver X receptor (LXR), leading to elevated ABCA1 and ABCG1 protein levels and enhanced ApoE lipidation. Moreover, co-treatment with a glycolytic inhibitor significantly inhibited this LXR activation and subsequent ApoE lipidation, further supporting a central role of glucose metabolism in LXR activation leading to enhanced ApoE lipidation, which may help against AD through potential Aβ clearance. Therefore, we hypothesized that pharmacological agents that can target cellular energy metabolism, specifically aerobic glycolysis, may hold significant therapeutic potential against AD. In this context, the present study also led to the discovery of novel, small-molecule stimulants of astrocytic glucose metabolism, leading to significantly enhanced lipidation status of ApoE4 in astrocytic cells. Three such newly discovered compounds (lonidamine, phenformin, and berberine), owing to their promising cellular effect on the glycolysis-ApoE nexus, warrant further investigation in suitable in vivo models of AD. Full article
(This article belongs to the Special Issue Alzheimer’s Disease: Small-Molecule Modulators of Novel Therapeutic Pathways)
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19 pages, 2868 KiB  
Article
Neuroprotective Effects of Davallia mariesii Roots and Its Active Constituents on Scopolamine-Induced Memory Impairment in In Vivo and In Vitro Studies
by Chung Hyeon Lee, Min Sung Ko, Ye Seul Kim, Ju Eon Ham, Jee Yeon Choi, Kwang Woo Hwang and So-Young Park
Pharmaceuticals 2023, 16(11), 1606; https://doi.org/10.3390/ph16111606 - 14 Nov 2023
Cited by 3 | Viewed by 1519
Abstract
Beta-amyloid (Aβ) proteins, major contributors to Alzheimer’s disease (AD), are overproduced and accumulate as oligomers and fibrils. These protein accumulations lead to significant changes in neuronal structure and function, ultimately resulting in the neuronal cell death observed in AD. Consequently, substances that can [...] Read more.
Beta-amyloid (Aβ) proteins, major contributors to Alzheimer’s disease (AD), are overproduced and accumulate as oligomers and fibrils. These protein accumulations lead to significant changes in neuronal structure and function, ultimately resulting in the neuronal cell death observed in AD. Consequently, substances that can inhibit Aβ production and/or accumulation are of great interest for AD prevention and treatment. In the course of an ongoing search for natural products, the roots of Davallia mariesii T. Moore ex Baker were selected as a promising candidate with anti-amyloidogenic effects. The ethanol extract of D. mariesii roots, along with its active constituents, not only markedly reduced Aβ production by decreasing β-secretase expression in APP–CHO cells (Chinese hamster ovary cells which stably express amyloid precursor proteins), but also exhibited the ability to diminish Aβ aggregation while enhancing the disaggregation of Aβ aggregates, as determined through the Thioflavin T (Th T) assay. Furthermore, in an in vivo study, the extract of D. mariesii roots showed potential (a tendency) for mitigating scopolamine-induced memory impairment, as evidenced by results from the Morris water maze test and the passive avoidance test, which correlated with reduced Aβ deposition. Additionally, the levels of acetylcholine were significantly elevated, and acetylcholinesterase levels significantly decreased in the brains of mice (whole brains). The treatment with the extract of D. mariesii roots also led to upregulated brain-derived neurotrophic factor (BDNF) and phospho-cAMP response element-binding protein (p-CREB) in the hippocampal region. These findings suggest that the extract of D. mariesii roots, along with its active constituents, may offer neuroprotective effects against AD. Consequently, there is potential for the development of the extract of D. mariesii roots and its active constituents as effective therapeutic or preventative agents for AD. Full article
(This article belongs to the Special Issue Alzheimer’s Disease: Small-Molecule Modulators of Novel Therapeutic Pathways)
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27 pages, 5529 KiB  
Article
Discovery of Novel Tryptanthrin Derivatives with Benzenesulfonamide Substituents as Multi-Target-Directed Ligands for the Treatment of Alzheimer’s Disease
by Guoxing Wang, Jiyu Du, Jie Ma, Peipei Liu, Siqi Xing, Jucheng Xia, Shuanghong Dong and Zeng Li
Pharmaceuticals 2023, 16(10), 1468; https://doi.org/10.3390/ph16101468 - 16 Oct 2023
Cited by 1 | Viewed by 1323
Abstract
Based on the multi-target-directed ligands (MTDLs) approach, two series of tryptanthrin derivatives with benzenesulfonamide substituents were evaluated as multifunctional agents for the treatment of Alzheimer’s disease (AD). In vitro biological assays indicated most of the derivatives had good cholinesterase inhibitory activity and neuroprotective [...] Read more.
Based on the multi-target-directed ligands (MTDLs) approach, two series of tryptanthrin derivatives with benzenesulfonamide substituents were evaluated as multifunctional agents for the treatment of Alzheimer’s disease (AD). In vitro biological assays indicated most of the derivatives had good cholinesterase inhibitory activity and neuroprotective properties. Among them, the target compound 4h was considered as a mixed reversible dual inhibitor of acetylcholinesterase (AChE, IC50 = 0.13 ± 0.04 μM) and butyrylcholinesterase (BuChE, IC50 = 6.11 ± 0.15 μM). And it could also potentially prevent the generation of amyloid plaques by inhibiting self-induced Aβ aggregation (63.16 ± 2.33%). Molecular docking studies were used to explore the interactions of AChE, BuChE, and Aβ. Furthermore, possessing significant anti-neuroinflammatory potency (NO, IL-1β, TNF-α; IC50 = 0.62 ± 0.07 μM, 1.78 ± 0.21 μM, 1.31 ± 0.28 μM, respectively) reduced ROS production, and chelated biometals were also found in compound 4h. Further studies showed that 4h had proper blood–brain barrier (BBB) permeability and suitable in vitro metabolic stability. In in vivo study, 4h effectively ameliorated the learning and memory impairment of the scopolamine-induced AD mice model. These findings suggested that 4h may be a promising compound for further development as a multifunctional agent for the treatment of AD. Full article
(This article belongs to the Special Issue Alzheimer’s Disease: Small-Molecule Modulators of Novel Therapeutic Pathways)
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