Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Online First

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Epilepsy is a common and frequently devastating disorder affecting millions of people. According to a recent survey, 1-2% of the Indian population suffers from major mental disorders and 5% suffers from minor mental disorders. Epilepsy is among those mental disorders that affect 30 million people worldwide. Currently, the treatment of epilepsy involves agents which modulate sodium-ion channels, enhance GABAergic transmission, and agents with multiple modes of action. Various classes of synthetic drugs are used to treat epilepsy, but these drugs are often challenged due to their unwanted side effects. Medicinal plants have been a part of human society which combating diseases from the dawn of civilization. The plant Cyanthillium cinereum (L.) H. Rob. is mainly found in the Himalayas from Kashmir to Nepal at an altitude of 8000 m. Decoction of this plant is traditionally used as an anti-cancer, anti-malarial, anti-epileptic, and in neurosis and skin diseases.

The present study investigated the anti-epileptic activity of Cyanthillium cinereum leaves against pentylenetetrazole (PTZ)-induced epileptic model in mice.

Plant extracts were prepared using solvents in increasing polarity viz., petroleum ether, chloroform, ethanol, and water, using a Soxhlet apparatus. The bio-active extract was characterized using FTIR and GC techniques. In vivo antioxidants like GSH and SOD level, oxidative stress markers- MDA and hemoglobin and platelet count were also estimated in the animal brain.

Amongst all extracts tested, only ethanol extract of Cyanthillium cinereum significantly (p<0.05) inhibited generalized tonic-clonic seizures in PTZ-induced epilepsy in mice in a dose (100 or 200 mg/kg., p.o.) dependent manner. The dose of 200 mg/kg of extract exhibited the most significant effect. It is also found that treatment with ethanol extract on PTZ-induced epilepsy in mice significantly (p<0.05) reduces the duration of convulsion and delays the onset of clonic convulsion.

The present findings suggest that the high amounts of phenols and flavonoids in the ethanol extract could be responsible for the anti-epileptic effect. Moreover, the ethanol extract also restored GSH, SOD and hemoglobin and platelet level and decreased oxidative marker- MDA content in the mice brain.

In stroke, reperfusion of blood to the cerebral ischemic area following sustained ischemia further exacerbates tissue damage, identified as cerebral ischemia and reperfusion (I/R) insult. Ischemic post-conditioning (IPoC) appears to offer benefits against I/R injury. The cascade of androgen receptors (ARs) has a vital role in cerebral stroke; however, its neurodefensive function in IPoC is unclear. This investigation aimed to explore the involvement of ARs in IPoC in cerebral I/R insult in rats.

Global cerebral ischemia/reperfusion (GCI/R) insult in experimental animals was provoked by 10 minutes of obstruction of the bilateral carotid arteries after reperfusion for 24 hours. IPoC was carried out by providing a triad of I/R insults with a gap of 10 minutes of GCI after 24 hours of reperfusion. Lateral push, inclined beam, rota rod, hanging wire, and Morris-water maze experimentations were conducted on animals to determine motor control and cognitive functions (learning and memory). Cerebral oxidative damage markers (raised lipid peroxidation and reduced glutathione levels), acetylcholinesterase (AChE) activity, inflammatory indicators (interleukin-6, interleukin-10, tumor necrosis factor-α, and myeloperoxidase), infarction, and histopathological alterations were also assessed.

Animals with I/R exhibited reduced motor function and memory along with raised cerebral oxidative damage, AChE activity, inflammation, infarction, and histopathological alterations. IPoC after ischemic events recuperated the damaging outcomes of I/R insult. 60 minutes before cerebral ischemia, pretreatment with testosterone mimicked the neurodefensive outcomes of IPoC. However, neuroprotective outcomes developed by IPoC were diminished by flutamide (ARs antagonist) pretreatment.

IPoC may offer neuroprotective outcomes in I/R insult by modulation of AR-mediated pathway.

The pharmacophoric approach relies on the theory of possessing ubiquitous chemical functionalities, and carrying a uniform spatial conformation that provides a route to enhanced potency on the same target receptor. JNK3, also known as c-Jun N-terminal kinase 3, is a protein kinase that plays a crucial role in various cellular processes, particularly in the central nervous system (CNS). In this study, a kernel-based partial least square (KPLS)-based Two-dimensional Quantitative structural activity relationship (2D QSAR) model to predict pharmacophores responsible for c-Jun-N-terminal kinase 3 (JNK3) inhibition.

A library of small molecule JNK3 inhibitors was created from the literature, and a predictive model was built using Canvas 2.6.

The analysis revealed key structural determinants of activity. Compounds with high pIC50 values (>6) showed numerous favorable contributions, particularly secondary benzamide nitrogen and methylene groups. Steric effects were more influential than inductive effects, with bulkier groups like t-butyl reducing activity. Positive contributions were observed with OH, O-CH3, and -F substituents, while unfavorable effects were linked to tertiary nitrogen, methyl, and primary amino groups. Substituted sulphonamides and benzotriazole moieties enhanced activity unless modified with amino or carbonyl groups. Favorable contributions were noted for terminal heterocyclic rings like pyrimidinyl acetonitrile, whereas phenyl substitutions and certain piperazine configurations were detrimental. Hydrogen in the urea moiety and avoiding bulky substitutions were crucial for activity. These insights guide the design of potent JNK3 inhibitors.

The present study highlights the significant impact of substituents on molecular activity, with steric effects, particularly on the phenyl ring, playing a dominant role. Favorable contributions are linked to substitutions like hydroxyl, methoxy, and fluorine, while bulky and meta substitutions reduce activity. Functional groups like unsubstituted sulfonamide or free hydrogen in urea are crucial for activity. Insights into steric, electronic, and positional factors, combined with analysis of JNK3 inhibitors, will guide the design of more selective molecules.