Neurodegenerative diseases pose a substantial socioeconomic burden on society. Unfortunately, the aging world population and lack of effective cures foreshadow a negative outlook. Although a large amount of research has been dedicated to elucidating the pathologies of neurodegenerative diseases, their principal causes remain elusive. Metal ion dyshomeostasis, proteopathy, oxidative stress, and neurotransmitter deficiencies are pathological features shared across multiple neurodegenerative disorders. In addition, these factors are proposed to be interrelated upon disease progression. Thus, the development of multifunctional compounds capable of simultaneously interacting with several pathological components has been suggested as a solution to undertake the complex pathologies of neurodegenerative diseases. In this review, we outline and discuss possible therapeutic targets in Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis and molecules, previously designed or discovered as pote...

Development of Multifunctional Molecules as Potential Therapeutic Candidates for Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis in the Last Decade

Multi-target design strategies for the improved treatment of Alzheimer's disease

Despite the burgeoning interest in three-dimensional (3D) printing for the manufacture of customizable oral dosage formulations, a U.S. Food and Drug Administration–approved tablet notwithstanding, the full potential of 3D printing in pharmaceutical sciences has not been realized. In particular, 3D-printed drug-eluting devices offer the possibility for personalization in terms of shape, size, and architecture, but their clinical applications have remained relatively unexplored. We used 3D printing to manufacture a tailored oral drug delivery device with customizable design and tunable release rates in the form of a mouthguard and, subsequently, evaluated the performance of this system in the native setting in a first-in-human study. Our proof-of-concept work demonstrates the immense potential of 3D printing as a platform for the development and translation of next-generation drug delivery devices for personalized therapy.

3D printing of a wearable personalized oral delivery device: A first-in-human study

Alzheimer's disease (AD) is characterized by multiple, intertwined pathological features, including amyloid-β (Aβ) aggregation, metal ion dyshomeostasis, and oxidative stress. We report a novel compound (ML) prototype of a rationally designed molecule obtained by integrating structural elements for Aβ aggregation control, metal chelation, reactive oxygen species (ROS) regulation, and antioxidant activity within a single molecule. Chemical, biochemical, ion mobility mass spectrometric, and NMR studies indicate that the compound ML targets metal-free and metal-bound Aβ (metal-Aβ) species, suppresses Aβ aggregation in vitro, and diminishes toxicity induced by Aβ and metal-treated Aβ in living cells. Comparison of ML to its structural moieties (i.e., 4-(dimethylamino)phenol (DAP) and (8-aminoquinolin-2-yl)methanol (1)) for reactivity with Aβ and metal-Aβ suggests the synergy of incorporating structural components for both metal chelation and Aβ interaction. Moreover, ML is water-soluble and potentially brain permeable, as well as regulates the formation and presence of free radicals. Overall, we demonstrate that a rational structure-based design strategy can generate a small molecule that can target and modulate multiple factors, providing a new tool to uncover and address AD complexity.

Rational Design of a Structural Framework with Potential Use to Develop Chemical Reagents that Target and Modulate Multiple Facets of Alzheimer’s Disease

Alzheimer’s disease (AD) is well-known as a severe neurodegeneration disease involving complicated etiologies, and cholinesterase inhibition remain the prevailing mode of clinical intervention in AD management. Although most clinically applied cholinesterase inhibitors (ChEIs) achieve limited clinical outcomes, research on the central cholinergic system is still thriving. Recently, an impressive amount of knowledge regarding novel acetylcholinesterase functions, as well as the close association between the central cholinergic system and other key elements for AD pathogenesis, has accumulated, highlighting that this field still has great potential for future drug development. In contrast to the overwhelmingly disappointing clinical therapeutic effects of various disease-modifying drug candidates, interesting evidence has continued to emerge over the past 20 years from the wealth of preclinical and clinical data on the usage of ChEIs, indicating underestimated clinical benefits due to physician ambivalence,...

Reconsideration of Anticholinesterase Therapeutic Strategies against Alzheimer's Disease.

Starting from a screening-hit compound, via structure modifications and optimizations, a series of nonfused and nonassembly pyrimidinylthiourea derivatives (2–5) was designed, synthesized, and evaluated as novel multifunctional agents against Alzheimer’s disease. Biological activity results demonstrated that compounds 5r and 5t exhibited potent inhibition and excellent selectivity toward acetylcholinesterase (AChE, 5r, IC50 = 0.204 μM, SI > 196; 5t, IC50 = 0.067 μM, SI > 597), specific metal-chelating ability, significant antioxidant effects, modulation of metal-induced Aβ aggregation, inhibition of ROS production by copper redox cycle, low cytotoxicity, and moderate neuroprotection to human neuroblastoma SH-SY5Y cells. Moreover, compound 5r displayed appropriate blood–brain barrier (BBB) permeability both in vitro and in vivo and could improve memory and cognitive function of scopolamine-induced amnesia mice. The multifunctional profiles of 5r and its effectivity in AD mice highlight these structurally d...

Development of Multifunctional Pyrimidinylthiourea Derivatives as Potential Anti-Alzheimer Agents

The invention relates to substituted pyrimidine compounds and an application thereof. The substituted pyrimidine compounds are compounds shown in a formula I (the specific structure is shown in the specification or claims), stereoisomers of the compounds or pharmaceutically acceptable salts of the compounds. An in-vitro activity test proves that the substituted pyrimidine compounds have cholinesterase inhibiting activity, metal ion chelation, inhibition of generation of metal ion induced free radicals, inhibition of metal ion induced Abeta aggregation and the like. Therefore, the substituted pyrimidine compounds are expected to be used for preparing Alzheimer's disease treating and/or preventing drugs.

Substituted pyrimidine compounds and application thereof

The melting point (MP), an easily accessible physical parameter, has considerable potential for the judgment of drug-like properties. However, to the best of our knowledge, there are no useful guidelines for understanding the relationship between the MP and drug-like properties. To this end, we have constructed the largest MP database (experimental value) of globally approved drugs (3164 organic small-molecule drugs) and discontinued drugs (417 organic small-molecule drugs) and subsequently extracted six subdatabases from the whole approved database and two subdatabases from the discontinued database. The MP distribution statistics and analysis of approved drugs reveal five noteworthy observations; moreover, the MP distribution statistics and analysis of discontinued drugs further supplement these criteria. In addition, the comparison of molecular weight (MW) versus MP and Clog P versus MP distributions of different classes of approved drugs indicated that the MWs and Clog P values of most drugs in the optimal MP range were not more than 500 and 5, respectively, implying the MP distribution criterion was in accordance with Lipinski's rule of five.

Melting Point Distribution Analysis of Globally Approved and Discontinued Drugs: A Research for Improving the Chance of Success of Drug Design and Discovery

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Development of Multifunctional Pyrimidinylthiourea Derivatives as Potential Anti-Alzheimer Agents

Substituted pyrimidine compounds and application thereof

Melting Point Distribution Analysis of Globally Approved and Discontinued Drugs: A Research for Improving the Chance of Success of Drug Design and Discovery