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Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Online First
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Thiazolidine-4-one Analogues: Synthesis, In-Silico Molecular Modeling, and In-vivo Estimation for Anticonvulsant Potential
Available online: 22 October 2024More LessBackgroundEpilepsy is a critically deep-rooted CNS disorder affecting above 50 million people all over the world. Thus, a safe and effective treatment that proves its worth in this ailment is urgently needed. Thiazolidine-4-ones possess the molecules to be used as anticonvulsants. The thiazolidinedione is a cyclic analogue of thiosemicarbazides and thioureas as well as a (bio)isostere of hydantoin (imidazolidine-2,4-dione), which are recognized as novel anticonvulsant designs.
AimThis study aimed to develop and evaluate a novel thiazolidine-4-one derivative by three-component condensation in one pot reaction method.
MethodsA novel thiazolidine-4-one derivative was formulated by three-component condensation. The selected OH (Alcohol) derivatives were found to be more potent; hence, a molecular docking study against a selected target LGI1 LRR domain was performed. Various analytical tests like FTIR and H1 NMR were accomplished. The FTIR was used to validate the existence of multiple functional moieties like C-S, O-H, C=O, C-N, N=O, C-NH, C-O in the wave region from 3075 cm-1 – 1236 cm-1 and H1 NMR was employed to ascertain if the synthesized analogues had the complete set of protons. Then, the anti-seizure activity of the selected compound was examined using PTZ models in mice at three successive doses, i.e., 25, 50, and 100mg/kg, and compared with standard ethosuximide.
ResultsThe docking simulations were initiated using PyMOL after the binding site was determined and the receptor and ligand were suitably prepared. It showed higher binding frequency in comparison to the standard marketed drug Ethosuximide. FTIR and H1 NMR spectroscopy were used to characterize the chemical components. Numerous functional groups, including O-H (alcohol), C=O (ketones), N=O, C-NH, C-N, C-S, and C-O bending stretching, were visible in the synthesized molecule accordingly. The synthesized compound was effective in inhibiting the convulsions at the concentration of 100 mg/kg.
ConclusionThe novel thiazolidine-4-one derivative showed promising activity and could be considered for further investigation and dosage form preparation.
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Novel Emerging Targets Identification in Reducing Risk of Alzheimer’s Disease
Authors: Saurabh Sharma, Kalpana Rahate and Rahul KumarAvailable online: 21 October 2024More LessThe accumulation of tau-containing neurofibrillary tangles and beta-amyloid deposits has been identified as the hallmark of Alzheimer's disease. Alzheimer's disease (AD) is a hereditary and neurological condition that can result in non-amnestic cognitive decline in less common forms and amnestic memory loss in its classic form. While Alzheimer's disease is the most prevalent cause of memory loss in middle-aged and older adults, other neurodegenerative and cerebrovascular disorders can have an impact on the disease's clinical course. Designing multi-target-directed ligands (MTDLs) is a very promising modern approach. This methodology was designed specifically for treating disorders with complex pathological mechanisms. Among these disorders is Alzheimer's disease (AD), which is currently the most prevalent multifactorial neurodegenerative illness. Increased amounts of the amyloid βpeptide (Aβ) and hyperphosphorylated tau protein, together with the loss of neurons and synapses, are linked to Alzheimer's disease (AD). Additionally, there is evidence that the pathophysiology of this condition is influenced by oxidative stress, metal ion dysregulation, inflammation, and failure of the cell cycle regulatory system. Since Alzheimer's disease (AD) is a multi-factor illness, there are many attractive targets for the development of anti-AD medications. These molecules can be useful in treating AD since they are multi-target-directed. This review focuses on the discovery of dual and multi-acting anti-AD drug candidates, especially hybrids made by combining chemically active moieties that function against distinct targets. The first group of substances consists of cholinesterase inhibitors with extra properties or those that function as multiple binding site inhibitors. Natural products also provide numerous options for slowing the progression and symptoms of many diseases, including Alzheimer's Meanwhile, Natural chemical structures with the following characteristics: alkaloids, sterols, triterpenes, tannins, flavonoids, polyphenols, and antioxidants as well as anti-inflammatory and anti-amyloidogenic properties. We provide an overview of Alzheimer's disease pathophysiology and therapy targets in this study. We also show several isolated chemicals and medicinal plants that are used to treat and prevent the symptoms of Alzheimer's disease.
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A Brief Review on Caenorhabditis elegans Role in Modelling Neurodegenerative Disease
Authors: Himangi Vig, Priyanka Shukla, Anamika Mishra, Ayushi Pal and Ankita WalAvailable online: 16 October 2024More LessA small, translucent nematode known as Caenorhabditis elegans, or C. elegans, is frequently utilized as a model organism in biomedical studies. These worms, which are around 1 mm long and feed on bacteria, are usually found in soil. For accessible and effective research on genetics, developmental biology, neuroscience, cell biology, and aging, C. elegans provide an ideal model. Its simplicity, which includes a translucent body and a nervous system with only 302 neurons, makes it possible to see cellular and developmental processes in great detail. Because of its special benefits, the worm Caenorhabditis elegans allows for a thorough characterization of the cellular and molecular processes causing age-related neurodegenerative diseases.
This is a general review of the life cycle, experimental methodologies, and the use of C. elegans to model brain diseases, including those related to molecular and genetic factors that cause neurodegenerative diseases. Additionally, we go over how C. elegans is a perfect model organism for studying neurons in instances of prevalent age-related neurodegenerative illnesses due to a combination of its biological traits and new analytical techniques.
The literature review process was carried out step-by-step using online search databases such as Web of Science, PubMED, Embase, Google Scholar, Medline, and Google Patents. In the first searches, keywords like C.elegans, disease modelling, and neuroprotective activity were employed.
Because of C. elegans's physiological transparency, it is possible to track the development of neurodegeneration in aging organisms by using co-expressed fluorescent proteins. Importantly, a fully characterized connectome provides a unique ability to precisely connect cellular death with behavioural instability or phenotypic diversity in vivo, thus permitting a deep knowledge of the detrimental effect of neurodegeneration on wellbeing.
In addition, pharmacological therapies and both forward and reverse gene screening speed up the discovery of modifiers that change neurodegeneration. These chemical-genetic investigations work together to determine important threshold states that either increase or decrease cellular stress in order to unravel related pathways.
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To Explore Nasal-Brain Lymphatic System for Brain-Targeted Drug Delivery and to Treat Neurodegenerative Diseases
Authors: Rohit Sharma, Monika, Bobby Tyagi, Disha Gupta, Rupa Mazumder and Avijit MazumderAvailable online: 15 October 2024More LessBrain-related Neurodegenerative Disorders (NDD) are the leading cause of low life expectancy globally. Brain-targeted drug delivery is required for treating most the NDD via bypassing the blood-brain barrier, and hepatic first-pass metabolism. The nasal-brain drug delivery route has the advantage of locally enhancing drug delivery to the brain, mainly through the olfactory route rather than systemic circulation. To overcome the limitations of nasal-brain drug delivery, a nanocarrier approach and mucoadhesive polymers are needed. Notwithstanding these constraints, various nanotechnology techniques have been created, including polymeric micelles, liposomes, polymeric nanoparticles, solid lipid nanoparticles, & nano-emulsions. This review aims to explore the intranasal pathway for drug delivery through the nasal-brain lymphatic systems, considering brain anatomy and physiology along with a drug formulation design approach.
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Nattokinase Attenuated Excitatory Amino Acids and Cytokines Release and Restored Cerebral Blood Fflow in a Thrombolytic Focal Cerebral Ischemic Rat Model
Authors: M Ramanathan, Mohammed Jamshir KM, Jerin M Jose and Nidhya GanesanAvailable online: 09 October 2024More LessObjectiveNattokinase (NK), a protease enzyme present in traditional fermented Japanese food, has shown fibrinolytic properties in vitro as well as in cardiac ischemia. In the present study, the Neuroprotective effect of standardized NK was evaluated in the thrombolytic focal cerebral ischemic model.
MethodologyThe parameters of behavioural assessment, cerebral blood flow, inflammatory mediators, excitatory amino acids, and immunohistochemistry were measured to support the NK effect. NK was administered at 150 and 300 mg/kg, and its effects were compared with streptokinase (STK) (100µl/rat). Each mg of NK contains 5.5 Units of the enzyme, which can cause lysis of the fibrin.
ResultsThe results indicate that 7 days of treatment of 300 mg NK restored the cerebral blood flow and prevented the release of cytokine and excitatory amino acids. Similarly, neurological scores were reduced, and grip strength increased significantly with NK treatment. The GFAP and synaptophysin staining of the hippocampus (CA1) and cerebrum have shown recovery of neurons from ischemic damage in comparison to vehicle-treated ischemic-reperfused rats. The NK (300 mg/kg) fibrinolytic effect is comparable to STK treatment.
ConclusionTo conclude, NK, a serine protease, protects the brain from ischemic degeneration in thrombolytic cerebral ischemia. Consumption of this Japanese food might exhibit prophylactic activity.
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