Central nervous system agents in medicinal chemistry最新文献

Introduction: Alzheimer's disease (AD) is a neurodegenerative disorder. Obstructing AChE is a remedial strategy to increase ACh levels in the brain and potentially upgrade cognitive function. In the realm of anti-Alzheimer's agents, pyranophenothiazine has been a noteworthy compound that exhibits significant inhibitory activity toward relevant receptors.

Objective: Novel analogs of pyranophenothiazine were intricately crafted, and their inhibitory potential against AChE enzyme (4EY7) and BuChE enzyme (4AQD) was thoroughly investigated through molecular modeling studies.

Methods: In silico ADMET predictions were carried out by using the QikProp module. Docking studies were conducted by using the Glide module for two targets: AChE enzyme (PDB id: 4EY7) and BuChE enzyme(PDB id: 4AQD). Binding free energies were calculated by means of the Prime MM-GBSA module, and molecular dynamics (MD) simulation was performed by using the Desmond module.

Results and discussion: These results of ADMET predictions indicated that the compounds possess drug-likeness properties, making them suitable candidates for further development and also having the ability to cross the BBB. The docking studies revealed the interaction between the designed ligands and cholinesterases. The results indicate that the ligands exhibit significant binding affinities, which was confirmed by MM-GBSA analysis and MD simulation study.

Conclusion: Conclusively, the study findings suggest that derivatives of pyranophenothiazine hold potential as inhibitors of AChE targeting AD.

Introduction: Schiff bases are a well-known class of substances with a variety of pharmacological properties, including skeletal muscle relaxant and anxiolytic effects. They are ideal candidates for the development of CNS-active drugs due to their structural adaptability and ability to interact with a range of biological targets. The purpose of this study was to create, synthesize, and describe new Schiff base hybrids and assess their possible skeletal muscle relaxant and anxiolytic effects using pharmacological and computational techniques.

Methods: By using condensation reactions between primary amines and substituted aromatic aldehydes, several new Schiff base hybrids were created. FT-IR, ¹H NMR, ¹³C NMR, and mass spectrometry were used for structural elucidation. To evaluate binding affinity with GABA-A and NMDA receptor sites, computational investigations involving molecular docking and ADME profiling were carried out. Validated rodent models were utilized for pharmacological evaluations, including the rotarod and traction tests to assess skeletal muscle relaxation, as well as the elevated plus maze and open-field tests to evaluate anxiolytic activity.

Results: The synthesized Schiff base derivatives demonstrated high purity and stability. In accordance with the observed in vivo anxiolytic activity, docking studies demonstrated advantageous binding interactions with the GABA-A receptor.

Discussion: Certain compounds exhibited moderate skeletal muscle relaxant activity, without producing noticeable sedation or motor impairment, as well as significant anxiolytic effects comparable to those of diazepam (p < 0.05). Good drug-likeness and CNS permeability were predicted for the lead compounds by ADME analysis.

Conclusion: Both in silico and in vivo tests support the encouraging skeletal muscle relaxant and anxiolytic properties of the synthesized Schiff base hybrids. These results suggest their potential as top contenders for the development of innovative CNS-active medications.

Alzheimer's disease (AD) is a neurodegenerative disease associated with memory loss and a decline in cognitive behavior. It is a progressive brain disorder where an individual's intelligence and reasoning capabilities are highly affected. The ability to think and process any idea is impaired, which is quite common in elders aged above 60 years. However, the current era has reported an increase in Alzheimer's disease as people gradually lose the ability to analyze things at an early age of 45 years. The main cause of AD is not known yet, due to which a particular target for drug action is not available. The main elements implicated in Alzheimer's disease (AD) include tau protein, amyloid beta protein, and cholinergic receptors, all of which exhibit altered function and expression levels in individuals with the disease. Several studies indicate the disrupted levels of the brain's dopamine and serotonin neurotransmitters. Mitochondrial dysfunction, calcium ions, and inflammation pathways also play a significant role in disease progression. The interplay of a number of genes and proteins is also dysregulated in Alzheimer's disease, which affects processes related to cell signaling and cell division. The link between Alzheimer's disease and diabetes mellitus is a new breakthrough in the research on both diseases. Transcriptomics and proteomics analyses have revealed a number of interconnected genes responsible for AD. The use of natural products as medicines can be a great hallmark in Alzheimer's research, producing promising results in the future, which may lead to amelioration of the disease and its adverse effects.

Epilepsy is a common neurological condition marked by frequent seizures, which often accompanies cognitive and psychological difficulties. With an estimated 65 million sufferers worldwide, epilepsy imposes an enormous burden on individuals, families, and healthcare systems. Seizures are categorized into focal, generalized, and seizures with unknown onset. Of all the focal seizures, temporal lobe epilepsy (TLE) is distinctive as it develops in the temporal lobes and causes altered consciousness as well as emotional difficulties. About 30% of people with TLE continue to have symptoms that do not improve with antiepileptic medications, resulting in further physical and psychological issues. Oxidative stress (OS) plays a pivotal role in the pathophysiology of epilepsy, driven by an overproduction of reactive oxygen species (ROS). Mitochondrial dysfunction and the accumulation of ROS disrupt neuronal calcium homeostasis, increase synaptic excitability, and contribute to neuronal injury and death. Antioxidant enzymes like catalase and superoxide dismutase help to reduce damage caused by ROS; yet, prolonged OS promotes the development of epileptogenesis. Additionally, recent research highlights the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of cellular defense against OS. Activation of the Nrf2-antioxidant response elements (ARE) signaling pathway enhances antioxidant enzyme expression and protects neurons from ROS damage. Studies suggest that targeting Nrf2 could offer novel therapeutic strategies for epilepsy by reducing OS and improving neuronal survival. Exploring Nrf2-activating compounds holds promise for developing more effective antiepileptic therapies, addressing the unmet need for treatments that can modulate the oxidative environment within the brain.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects both motor and non-motor functions, primarily due to the gradual loss of dopaminergic neurons in the substantia nigra. Traditional diagnostic methods largely depend on clinical symptom evaluation, which often leads to delays in detection and treatment. However, in recent years, artificial intelligence (AI), particularly machine learning (ML) and deep learning (DL), have emerged as groundbreaking techniques for the diagnosis and management of PD. This review explores the emergent role of AI-driven techniques in early disease detection, continuous monitoring, and the development of personalized treatment strategies. Advanced AI applications, including medical imaging analysis, speech pattern recognition, gait assessment, and the identification of digital biomarkers, have shown remarkable potential in improving diagnostic accuracy and patient care. Additionally, AI-driven telemedicine solutions enable remote and real-time disease monitoring, addressing challenges related to accessibility and early intervention. Despite these promising advancements, several hurdles remain, such as concerns over data privacy, the interpretability of AI models, and the need for rigorous validation before clinical implementation. With PD cases expected to rise significantly by 2030, further research and interdisciplinary collaboration are crucial to refining AI technologies and ensuring their reliability in medical practice. By bridging the gap between technology and neurology, AI has the potential to revolutionize PD management, paving the way for precision medicine and better patient outcomes.

Background: Epilepsy is a chronic neurological disease that affects around 50 million people globally. To cure this disorder, different antiepileptic drugs have been studied via computational approaches.

Methods: Density functional theory (DFT) and time-dependent-density functional theory (TDDFT) are employed to investigate the optoelectronic, photodynamic, and structural properties of antiepileptic drugs (EP1-EP5). The B3LYP/6-311 G (d, p) was used for the computational simulations study. Further comparisons with reference drug phenobarbital (R) and (EP1-EP5) drugs, several geometrical variables, including frontier molecular orbitals (FMOs), excitation energy, hole-electron overlap, density of states, binding energy, molecular electrostatic potential, transition density matrix, and density of states were performed.

Results: Compared to R with antiepileptic drugs AEDs (EP1-EP5) exhibited a bathochromic shift of the absorption spectrum, lower excitation energies, and comparable binding energies. The findings showed that the antiepileptic drugs had significantly lower HOMO-LUMO energy gaps (Eg = 1.89-1.98 eV), pointing to their higher charge-directing behavior from HOMO to LUMO. The EP5 molecule exhibited excellent HOMO (-7.17 eV), LUMO (-2.80 eV), lowest energy band gap (4.37 eV), and boosted DOS results, which strengthens the drug-protein interaction.

Conclusion: EP5 exhibited the enhanced performance due to the presence of the electron withdrawing group in the acceptor region, extended conjugation, and better charge transference could be the best drug efficiency. During molecular docking, the robust interactions in EP5 with the antiepileptic proteins (4EY7 and 7SK2) showed an excellent structural template among the designed drugs. Among them, EP5 has better structural properties as an antiepileptic drug for future drug discovery.

Recent studies have shown that plant-derived flavonoids may be useful in the treatment of diabetes. Plants in the Moraceae family are commonly known to contain the bioflavonoid morin. Its pharmacological properties include anti-inflammatory, anti-tumor, anti-diabetic, cardioprotective, neuroprotective, and nephroprotective properties. An organic dithiol molecule called alpha-lipoic acid is essential to mitochondrial bioenergetic functions. Its antioxidant properties have led to significant research in the treatment of diabetic conditions. Diabetic neuropathic pain is associated with poor glucose regulation and metabolic abnormalities, specifically oxidative stress (OS) and inflammation. Many mediators and signaling pathways play a crucial role in the development and pathogenesis of diabetic neuropathic pain, including the polyol pathway, advanced glycation end products, glutamate pathway, trophic factors, activation of channels, inflammation, and OS. Morin is useful in controlling blood sugar levels and lowering the problems associated with diabetes, according to studies conducted in a variety of in vitro and in vivo studies. Alpha-lipoic acid (ALA) is a naturally occurring chemical that is necessary for the function of specific enzymes involved in mitochondrial and oxidative metabolism. Dihydrolipoic acid (DHLA), the reduced form of ALA, is thought to have a variety of biological activities, including the reduction of oxidized forms of other agents, including vitamin E and C, metal chelation, and modulation of signal transduction of several pathways (insulin). With its antioxidant properties and ability to scavenge reactive oxygen species, ALA may be able to inhibit the oxidative stress-inflammation pathways that are triggered in diabetic neuropathy. Thus, in this paper, we studied the impact of dietary flavonoid morin and alpha lipoic acid on the molecular mechanism causing major diabetic problems.

Introduction: Chalcone derivatives are known for their diverse biological activities, including anxiolytic and skeletal muscle relaxant properties. Recent studies indicate that structural modifications can enhance their therapeutic effectiveness. This study aimed to synthesize and biologically evaluate novel chalcone derivatives, investigating their structure-activity relationship through computational studies and assessing their pharmacological potential.

Methods: Five chalcone derivatives (P1-P5) were synthesized via Claisen-Schmidt condensation and characterized using infrared spectroscopy (IR) and nuclear magnetic resonance (NMR) spectroscopy. Their physicochemical and pharmacokinetic profiles were analyzed via SWISS ADME, confirming drug-likeness. Biological assessments, including the Elevated Plus Maze (EPM), Open Field Test (OFT), Hole Board Test (HBT), and Rotarod Test, were conducted to evaluate anxiolytic and muscle-relaxant activities.

Results: The synthesized chalcones exhibited yields of 60%-75% and complied with Lipinski's rule, showing no violations. Among the tested compounds, P2 demonstrated the highest anxiolytic activity, as evidenced by increased exploratory behaviour in EPM, OFT, and HBT. P1 exhibited the strongest skeletal muscle relaxant effect in the Rotarod Test, comparable to diazepam.

Discussion: The study findings suggest that these chalcone derivatives may serve as promising candidates for anxiolytic and muscle-relaxant therapy. Computational analysis supports their pharmacokinetic suitability. Further research is necessary to explore their mechanisms and potential clinical applications.

Conclusion: Chalcone derivatives (P1-P5) were successfully synthesized and studied. They showed strong effects for reducing anxiety and relaxing muscles, making them worthy of further research.

Introduction: Epilepsy is a common disorder of the Central Nervous System (CNS). The rational design of small-molecule drugs for disorders of the CNS is a difficult process because the majority of small molecules are unable to cross the Blood-Brain-Barrier. An efficient method for the design of inhibitors that have high permeability through the Blood-Brain-Barrier has the potential for application in drug design for CNS disorders such as Addiction, Alzheimer's disease, Bipolar disorder, Depression, Epilepsy, Gliomas, and Tuberculous meningitis.

Method: Supervised learning was used to model the Blood-Brain-Barrier permeability of drugs like small organic molecules. This information was utilized to guide an evolutionary algorithm for the design of inhibitors with increased affinity for the target as well as higher Blood-Brain-Barrier permeability.

Results: The ligands designed with guided evolution were predicted to have higher binding affinity for the target as well as higher permeability across the Blood-Brain-Barrier compared to an evolutionary algorithm without the guidance. The guided evolutionary method was applied to design a set of drug-like ligands that were predicted to bind to GABA-T with high affinity, to be BBB permeable, and to be chemically synthesizable.

Discussion: Despite the availability of several drugs that are approved for the treatment of epilepsy, there are many cases that do not respond to available drugs or experience adverse effects. The novel ligands designed as part of this work have the potential to address the limitations of available drugs.

Conclusion: Guided evolution is an efficient computational approach for the design of CNS drugs. The de novo design of drugs by application of the guided evolution algorithm, developed as part of this work, has resulted in the generation of ligands that are potential drugs for the cure of epilepsy. However, the effectiveness of these drugs for the cure of epilepsy has to be validated experimentally.

Cognitive enhancement, aimed at improving or preserving memory, attention, and executive functions, has gained significant interest from both the scientific community and the public. This review explores various strategies for enhancing cognitive function, including natural compounds, synthetic enhancers, and behavioural approaches. Natural compounds like curcumin, Ginkgo biloba, Panax ginseng, and Rhodiola rosea are examined for their cognitive benefits, with ongoing research on their mechanisms and potential nanoformulation-based drug delivery. Synthetic enhancers such as Modafinil, Piracetam, Methylphenidate, and Noopept show promise in improving cognitive functions. Additionally, substances influencing brain metabolism, like Creatine and Coenzyme Q10, are discussed. Behavioural interventions, including sleep optimization, meditation, and physical exercise, are evaluated for their cognitive-enhancing effects. Noninvasive brain stimulation techniques, such as TMS and tDCS, along with innovative methods like whole-body vibration and brain-machine interfaces, are also explored. The review emphasizes the complex interplay of these strategies and the need for continued research to fully exploit their potential. By highlighting natural compounds, synthetic drugs, and behavioural approaches, the review advocates for a multifaceted approach to cognitive enhancement and calls for more detailed and longitudinal studies to understand their long-term benefits and mechanisms.