Central Nervous System Agents in Medicinal Chemistry - Volume 26, Issue 1, 2026

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.

Ischemic stroke remains one of the leading causes of death and physical and mental disability. Oxidative stress, free radicals, and inflammation play critical roles in ischemic brain damage. Free radical scavengers such as edaravone and dimethyl fumarate (DMF), known for their antioxidant and anti-inflammatory properties, are considered promising targets for ischemic stroke treatment. This study aimed to assess the impact of these drugs on brain ischemia.

Forty-nine rats were randomly divided into seven groups: sham, edaravone, and DMF controls, as well as edaravone, DMF 5, 15, and 30 groups. Middle cerebral artery occlusion (MCAO) was induced in all groups except the sham group. The MCAO groups were administered with either the vehicle, edaravone (3 mg/kg), or DMF at doses of 5, 15, and 30 mg/kg twice daily for 14 days. Neurobehavioral assessments were conducted throughout the experiment, and anatomical changes in the brain were evaluated using stereological methods.

Edaravone and three doses of DMF improved neurobehavioral functions. All treated rats showed a reduction in the ischemic volume and cell loss in the brain regions when compared with the control animals. MCAO reduced the total number of neurons and just DMF doses had a significant effect on this factor. Interestingly, MCAO increased the number of non-neurons and only the DMF 30 group significantly decreased this parameter. DMF 30 was more effective in ischemic stroke.

Although edaravone improved neurological functions and reduced the size of brain ischemia and cell loss, DMF, especially at higher doses, exerted a more beneficial effect on these parameters. Therefore, DMF could be proposed as a reinforcement to currently conventional therapies.

Major Depressive Disorder (MDD) is a psychiatric disorder that has a tight connection to stressful experiences, decreased levels of endogenous antioxidants and enhanced levels of oxidative stress. We drafted this research to define the results of combining agmatine and melatonin on stress-induced depression in mice.

Experimental groups included the non-stressed group treated with vehicle (ethanol at a concentration of 0.0005%), stressed vehicle (ethanol at a concentration of 0.0005%)-treated group, group treated with fluoxetine (10 mg/kg/day), group treated with melatonin (10 mg/kg/day), group treated with agmatine (1 mg/kg/day), group receiving a combination of melatonin (10 mg/kg/day) and agmatine (1 mg/kg/day). The animals were subjected to restraint stress for two hours daily for a duration of one week, concurrently with the daily oral administration of agents through drinking water. Open field test and forced swimming test were operated on the 8th day. The oxidative stress markers were measured in the mice hippocampus.

Stress led to the elevation of immobility time. The combination group showed a significant effect in comparison to the agmatine and melatonin groups. The combination of melatonin and agmatine was successful in the elevation of hippocampus catalase activity; and this effect was comparable in the fluoxetine group. We observed enhancement of superoxide dismutase activity in treatment groups and reduction in malondialdehyde levels in melatonin, agmatine and combination groups.

A combination of agmatine and melatonin improves stress-induced depression more effectively than each alone, which may result from suppressing oxidative stress.

The search for effective treatments for neurodegenerative diseases, particularly Alzheimer's disease, has been fraught with challenges. Alzheimer's disease accounts for 60-80% of dementia cases globally, affecting approximately about 50 million people. Currently, drug repurposing has emerged as a promising strategy in new drug development, attracting significant attention from regulatory agencies, such as the US FDA.

This study aimed to investigate the potential therapeutic role of dolutegravir in Alzheimer's disease (AD) treatment using a novel network pharmacology approach. Specifically, it explored the interaction of dolutegravir with key molecular targets involved in AD pathology, predicted its effects on relevant biological pathways, and evaluated its viability as a new therapeutic candidate.

This study employed a network pharmacology framework to evaluate dolutegravir, an antiretroviral drug, as a potential treatment for Alzheimer's disease, shedding light on its possible therapeutic mechanisms.

A network pharmacology approach was used to predict the drug targets of dolutegravir. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to identify interacting pathways. Additionally, protein-protein interaction (PPI) network analysis was conducted to assess key interactions and molecular docking studies were performed to evaluate the binding affinity of dolutegravir to the predicted targets.

PPI network analysis revealed that dolutegravir interacted with several key targets, including BRAF, mTOR, MAPK1, MAPK3, NOS1, BACE1, CAPN1, CASP3, CASP7, CASP8, CHUK, IKBKB, PIK3CA, and PIK3CD. KEGG pathway analysis suggested that dolutegravir could influence amyloid-beta formation, amyloid precursor protein metabolism, and the cellular response to amyloid-beta. Molecular docking results showed the highest binding affinity of dolutegravir for PI3KCD (-8.5 kcal/mol) and MTOR (-8.7 kcal/mol).

The findings indicated that dolutegravir holds significant potential in modulating key pathways involved in Alzheimer's disease pathogenesis. These results provide a strong foundation for further investigations into the therapeutic efficacy and safety of dolutegravir in the treatment of Alzheimer's disease. The use of drug repurposing strategies, leveraging Dolutegravir's established pharmacological profile, offers a promising route for accelerated therapeutic development in AD.

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.