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Development of Novel Drugs for Alzheimer's Disease and Myasthenia Gravis

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (5 April 2020) | Viewed by 85397

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Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic
Interests: antidotes for pesticide and nerve agent poisonings; Alzheimer’s disease treatment; detergents as disinfectants; nanoparticles; decontamination means; toxins; drug design and development; nanotechnology; IT; parallel computing; ANN; project management; scientific management; technology transfer; health economics and pharmacoeconomics
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Neurology Clinic, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
Interests: brain damage; neurology; Alzheimer’s disease
Special Issues, Collections and Topics in MDPI journals

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Guest Editor

Special Issue Information

Dear Colleagues,

Searching for novel drugs for the treatment of Alzheimer’s disease (AD) became a main task of current developed societies. There were/are and will be novel drug candidates designed, synthesized and tested throughout many places of the world. Despite tremendous advances in understanding many aspects of AD pathogenesis, there are no proven disease-modifying therapies and the only available ones are minimally effective symptomatic therapies.

Myasthenia gravis (MG) is a neuromuscular disorder that causes weakness in the skeletal muscles. Myasthenia gravis is caused by a breakdown in the normal communication between nerves and muscles. In the case of this disease, efficacy of currently-available drugs is limited.

Both diseases (AD and MG) are associated with an enzyme acetylcholinesterase (AChE), which is a target for development on novel drug candidates for these diseases.

In this Special Issue of International Journal of Molecular Sciences, we would like to discuss all chemico-biological aspects, which are behind the Alzheimer’s disease, as well as Myasthenia gravis.

Prof. Dr. Kamil Kuca
Assoc. Prof. Martin Valis
Dr. Eugenie Nepovimova
Guest Editors

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Keywords

  • Alzheimer’s Disease
  • Treatment
  • Drug Development
  • Computational Chemistry
  • Molecular Biology
  • Diagnosis
  • In Vitro & In Vivo
  • Biochemistry

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Published Papers (8 papers)

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Research

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26 pages, 2913 KiB  
Article
Benzothiazolyl Ureas are Low Micromolar and Uncompetitive Inhibitors of 17β-HSD10 with Implications to Alzheimer’s Disease Treatment
by Monika Schmidt, Ondrej Benek, Lucie Vinklarova, Martina Hrabinova, Lucie Zemanova, Matej Chribek, Vendula Kralova, Lukas Hroch, Rafael Dolezal, Antonin Lycka, Lukas Prchal, Daniel Jun, Laura Aitken, Frank Gunn-Moore, Kamil Kuca and Kamil Musilek
Int. J. Mol. Sci. 2020, 21(6), 2059; https://doi.org/10.3390/ijms21062059 - 17 Mar 2020
Cited by 15 | Viewed by 4354
Abstract
Human 17β-hydroxysteroid dehydrogenase type 10 is a multifunctional protein involved in many enzymatic and structural processes within mitochondria. This enzyme was suggested to be involved in several neurological diseases, e.g., mental retardation, Parkinson’s disease, or Alzheimer’s disease, in which it was shown to [...] Read more.
Human 17β-hydroxysteroid dehydrogenase type 10 is a multifunctional protein involved in many enzymatic and structural processes within mitochondria. This enzyme was suggested to be involved in several neurological diseases, e.g., mental retardation, Parkinson’s disease, or Alzheimer’s disease, in which it was shown to interact with the amyloid-beta peptide. We prepared approximately 60 new compounds based on a benzothiazolyl scaffold and evaluated their inhibitory ability and mechanism of action. The most potent inhibitors contained 3-chloro and 4-hydroxy substitution on the phenyl ring moiety, a small substituent at position 6 on the benzothiazole moiety, and the two moieties were connected via a urea linker (4at, 4bb, and 4bg). These compounds exhibited IC50 values of 1–2 μM and showed an uncompetitive mechanism of action with respect to the substrate, acetoacetyl-CoA. These uncompetitive benzothiazolyl inhibitors of 17β-hydroxysteroid dehydrogenase type 10 are promising compounds for potential drugs for neurodegenerative diseases that warrant further research and development. Full article
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15 pages, 3109 KiB  
Article
Synthesis of New Quinoline-Piperonal Hybrids as Potential Drugs against Alzheimer’s Disease
by Juliana de Oliveira C. Brum, Denise Cristian F. Neto, Joyce Sobreiro F. D. de Almeida, Josélia Alencar Lima, Kamil Kuca, Tanos Celmar C. França and José D. Figueroa-Villar
Int. J. Mol. Sci. 2019, 20(16), 3944; https://doi.org/10.3390/ijms20163944 - 14 Aug 2019
Cited by 23 | Viewed by 4562
Abstract
Six quinoline-piperonal hybrids were synthesized and evaluated as potential drugs against Alzheimer’s disease (AD). Theoretical analysis of the pharmacokinetic and toxicological properties of the compounds suggest that they present good oral bio-availability and are also capable of penetrating the blood–brain barrier, qualifying as [...] Read more.
Six quinoline-piperonal hybrids were synthesized and evaluated as potential drugs against Alzheimer’s disease (AD). Theoretical analysis of the pharmacokinetic and toxicological properties of the compounds suggest that they present good oral bio-availability and are also capable of penetrating the blood–brain barrier, qualifying as leads for new drugs against AD. Evaluation of their inhibitory capacity against acetyl- and butyrilcholinesterases (AChE and BChE) through Ellmann’s test showed that three compounds present promising results with one of them being capable of inhibiting both enzymes. Further docking studies of the six compounds synthesized helped to elucidate the main interactions that may be responsible for the inhibitory activities observed. Full article
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Review

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38 pages, 1450 KiB  
Review
Overview of Dual-Acting Drug Methotrexate in Different Neurological Diseases, Autoimmune Pathologies and Cancers
by Przemysław Koźmiński, Paweł Krzysztof Halik, Raphael Chesori and Ewa Gniazdowska
Int. J. Mol. Sci. 2020, 21(10), 3483; https://doi.org/10.3390/ijms21103483 - 14 May 2020
Cited by 183 | Viewed by 11498
Abstract
Methotrexate, a structural analogue of folic acid, is one of the most effective and extensively used drugs for treating many kinds of cancer or severe and resistant forms of autoimmune diseases. In this paper, we take an overview of the present state of [...] Read more.
Methotrexate, a structural analogue of folic acid, is one of the most effective and extensively used drugs for treating many kinds of cancer or severe and resistant forms of autoimmune diseases. In this paper, we take an overview of the present state of knowledge with regards to complex mechanisms of methotrexate action and its applications as immunosuppressive drug or chemotherapeutic agent in oncological combination therapy. In addition, the issue of the potential benefits of methotrexate in the development of neurological disorders in Alzheimer’s disease or myasthenia gravis will be discussed. Full article
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23 pages, 2278 KiB  
Review
Combination Drug Therapy for the Management of Alzheimer’s Disease
by Md. Tanvir Kabir, Md. Sahab Uddin, Abdullah Al Mamun, Philippe Jeandet, Lotfi Aleya, Rasha A. Mansouri, Ghulam Md Ashraf, Bijo Mathew, May N. Bin-Jumah and Mohamed M. Abdel-Daim
Int. J. Mol. Sci. 2020, 21(9), 3272; https://doi.org/10.3390/ijms21093272 - 5 May 2020
Cited by 120 | Viewed by 15365
Abstract
Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Even though the number of AD patients is rapidly growing, there is no effective treatment for this neurodegenerative disorder. At present, implementation of effective treatment approaches for AD is vital to meet clinical [...] Read more.
Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Even though the number of AD patients is rapidly growing, there is no effective treatment for this neurodegenerative disorder. At present, implementation of effective treatment approaches for AD is vital to meet clinical needs. In AD research, priorities concern the development of disease-modifying therapeutic agents to be used in the early phases of AD and the optimization of the symptomatic treatments predominantly dedicated to the more advanced AD stages. Until now, available therapeutic agents for AD treatment only provide symptomatic treatment. Since AD pathogenesis is multifactorial, use of a multimodal therapeutic intervention addressing several molecular targets of AD-related pathological processes seems to be the most practical approach to modify the course of AD progression. It has been demonstrated through numerous studies, that the clinical efficacy of combination therapy (CT) is higher than that of monotherapy. In case of AD, CT is more effective, mostly when started early, at slowing the rate of cognitive impairment. In this review, we have covered the major studies regarding CT to combat AD pathogenesis. Moreover, we have also highlighted the safety, tolerability, and efficacy of CT in the treatment of AD. Full article
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13 pages, 734 KiB  
Review
Neuropharmacology of the Neuropsychiatric Symptoms of Dementia and Role of Pain: Essential Oil of Bergamot as a Novel Therapeutic Approach
by Damiana Scuteri, Laura Rombolà, Luigi Antonio Morrone, Giacinto Bagetta, Shinobu Sakurada, Tsukasa Sakurada, Paolo Tonin and Maria Tiziana Corasaniti
Int. J. Mol. Sci. 2019, 20(13), 3327; https://doi.org/10.3390/ijms20133327 - 6 Jul 2019
Cited by 41 | Viewed by 9829
Abstract
Aging of the population makes of dementia a challenge for health systems worldwide. The cognitive disturbance is a serious but not the only issue in dementia; behavioral and psychological syndromes known as neuropsychiatric symptoms of dementia remarkably reduce the quality of life. The [...] Read more.
Aging of the population makes of dementia a challenge for health systems worldwide. The cognitive disturbance is a serious but not the only issue in dementia; behavioral and psychological syndromes known as neuropsychiatric symptoms of dementia remarkably reduce the quality of life. The cluster of symptoms includes anxiety, depression, wandering, delusions, hallucinations, misidentifications, agitation and aggression. The pathophysiology of these symptoms implicates all the neurotransmitter systems, with a pivotal role for the glutamatergic neurotransmission. Imbalanced glutamatergic and GABAergic neurotransmissions, over-activation of the extrasynaptic N-methyl-D-aspartate (NMDA) receptors and alterations of the latter have been linked to the development of neuropsychiatric symptoms experienced by almost the entire demented population. Drugs with efficacy and safety for prevention or long term treatment of these disorders are not available yet. Aromatherapy provides the best evidence for positive outcomes in the control of agitation, the most resistant symptom. Demented patients often cannot verbalize pain, resulting in unrelieved symptoms and contributing to agitation. Bergamot essential oil provides extensive preclinical evidence of analgesic properties. Incidentally, the essential oil of bergamot induces anxyolitic-like effects devoid of sedation, typical of benzodiazepines, with a noteworthy advantage for demented patients. These data, together with the reported safety profile, form the rational basis for bergamot as a neurotherapeutic to be trialed for the control of behavioral and psychological symptoms of dementia. Full article
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43 pages, 11848 KiB  
Review
Approaches to CNS Drug Delivery with a Focus on Transporter-Mediated Transcytosis
by Rana Abdul Razzak, Gordon J. Florence and Frank J. Gunn-Moore
Int. J. Mol. Sci. 2019, 20(12), 3108; https://doi.org/10.3390/ijms20123108 - 25 Jun 2019
Cited by 77 | Viewed by 14884
Abstract
Drug delivery to the central nervous system (CNS) conferred by brain barriers is a major obstacle in the development of effective neurotherapeutics. In this review, a classification of current approaches of clinical or investigational importance for the delivery of therapeutics to the CNS [...] Read more.
Drug delivery to the central nervous system (CNS) conferred by brain barriers is a major obstacle in the development of effective neurotherapeutics. In this review, a classification of current approaches of clinical or investigational importance for the delivery of therapeutics to the CNS is presented. This classification includes the use of formulations administered systemically that can elicit transcytosis-mediated transport by interacting with transporters expressed by transvascular endothelial cells. Neurotherapeutics can also be delivered to the CNS by means of surgical intervention using specialized catheters or implantable reservoirs. Strategies for delivering drugs to the CNS have evolved tremendously during the last two decades, yet, some factors can affect the quality of data generated in preclinical investigation, which can hamper the extension of the applications of these strategies into clinically useful tools. Here, we disclose some of these factors and propose some solutions that may prove valuable at bridging the gap between preclinical findings and clinical trials. Full article
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33 pages, 3817 KiB  
Review
Recent Developments in Metal-Based Drugs and Chelating Agents for Neurodegenerative Diseases Treatments
by Thais A. Sales, Ingrid G. Prandi, Alexandre A. de Castro, Daniel H. S. Leal, Elaine F. F. da Cunha, Kamil Kuca and Teodorico C. Ramalho
Int. J. Mol. Sci. 2019, 20(8), 1829; https://doi.org/10.3390/ijms20081829 - 12 Apr 2019
Cited by 52 | Viewed by 6218
Abstract
The brain has a unique biological complexity and is responsible for important functions in the human body, such as the command of cognitive and motor functions. Disruptive disorders that affect this organ, e.g., neurodegenerative diseases (NDDs), can lead to permanent damage, impairing the [...] Read more.
The brain has a unique biological complexity and is responsible for important functions in the human body, such as the command of cognitive and motor functions. Disruptive disorders that affect this organ, e.g., neurodegenerative diseases (NDDs), can lead to permanent damage, impairing the patients’ quality of life and even causing death. In spite of their clinical diversity, these NDDs share common characteristics, such as the accumulation of specific proteins in the cells, the compromise of the metal ion homeostasis in the brain, among others. Despite considerable advances in understanding the mechanisms of these diseases and advances in the development of treatments, these disorders remain uncured. Considering the diversity of mechanisms that act in NDDs, a wide range of compounds have been developed to act by different means. Thus, promising compounds with contrasting properties, such as chelating agents and metal-based drugs have been proposed to act on different molecular targets as well as to contribute to the same goal, which is the treatment of NDDs. This review seeks to discuss the different roles and recent developments of metal-based drugs, such as metal complexes and metal chelating agents as a proposal for the treatment of NDDs. Full article
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24 pages, 699 KiB  
Review
Drug Development for Alzheimer’s Disease: Microglia Induced Neuroinflammation as a Target?
by Yuan Dong, Xiaoheng Li, Jinbo Cheng and Lin Hou
Int. J. Mol. Sci. 2019, 20(3), 558; https://doi.org/10.3390/ijms20030558 - 28 Jan 2019
Cited by 105 | Viewed by 17040
Abstract
Alzheimer’s disease (AD) is one of the most common causes of dementia. Its pathogenesis is characterized by the aggregation of the amyloid-β (Aβ) protein in senile plaques and the hyperphosphorylated tau protein in neurofibrillary tangles in the brain. Current medications for AD can [...] Read more.
Alzheimer’s disease (AD) is one of the most common causes of dementia. Its pathogenesis is characterized by the aggregation of the amyloid-β (Aβ) protein in senile plaques and the hyperphosphorylated tau protein in neurofibrillary tangles in the brain. Current medications for AD can provide temporary help with the memory symptoms and other cognitive changes of patients, however, they are not able to stop or reverse the progression of AD. New medication discovery and the development of a cure for AD is urgently in need. In this review, we summarized drugs for AD treatments and their recent updates, and discussed the potential of microglia induced neuroinflammation as a target for anti-AD drug development. Full article
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