Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 22, Issue 1, 2022

Background: Neuroprotection is preserving neural function in various neurodegenerative diseases like Alzheimer’s, Huntington’s, Parkinson’s, and multiple sclerosis. Hesperidin, a flavanone glycoside in citrus fruits such as sweet oranges and lemons, possesses many biological effects, including neuroprotection. Objective: The study aims to explore the neuropharmacological mechanisms and therapeutic potential of hesperidin in the management of neurodegenerative disorders. Methods: It emphasizes comparative and clinical trial studies with a number of targets reviewed from the data available on PubMed, Science Direct, Clinicaltrails.gov, and from many reputed foundations. Results: Escalating clinical evidence has established the inhibitory effect of hesperidin in the management of neurodegenerative disorders. Neuroprotective potential of hesperidin is characterized by endogenous antioxidant defence functions, improvement of neural growth factors, antineuroinflammatory activity, and apoptotic pathways. Conclusion: The present study highlights the beneficial neuropharmacological potential of hesperidin, including anticonvulsant, antidepressant, antioxidant, anti-inflammatory, memory, and locomotor enhancing activities.

Background: Depressive disorder is one of the most common mental diseases and has become one of the three major causes of disability worldwide. Although some of the pathological mechanisms have been analyzed, the corresponding drug therapy has only achieved about 30% of curative effects. However, the pathological mechanism of depression is very complex, and the relationship between its complicated pathological mechanisms is still elusive. In recent years, more and more evidence shows that environmental stress induces stable changes in gene expression through the epigenetic mechanism which plays a vital role in the pathogenesis of the disease. Neuroinflammation is considered to be a key pathological mechanism of depression. Objective: The aim of the study was to explore the relationship between epigenetic mechanism and neuroinflammation in the pathological process of depression. Methods: In this paper, we review the crucial role of neuroinflammation in complex pathological mechanisms, especially its complex interrelationship with neurotransmitters, neuroendocrine, neurogenesis, and neuronal plasticity, which play a key role in the pathology of depression. Results: The relationship between epigenetic mechanism and neuroinflammation in the pathological process of depression has been discussed, which mainly involves histone acetylation, histone methylation, DNA methylation, and non-coding RNA association. Conclusion: This review will help to understand the role of epigenetic mechanisms in depression and its related inflammatory responses and provide direction and guidance for future research.

Background: Bile duct ligation (BDL) is used for evaluating the protective effects of different agents with anti-inflammatory and antioxidant properties against the liver and brain damages. Naringenin (N) and melatonin (M) are used as protectants in various models of diseases. Aims: In the current research, the combinational effects of these well-known anti-inflammatory and antioxidants agents were investigated against cerebral injuries induced by BDL in male rats. Methods: The animals were distributed into the following groups: Sham, BDL + Vehicle and BDL+ N + M. Neuronal damages were evaluated using biochemical, motor behavioral tasks and morphological assessments. Results: Based on the data, BDL resulted in decreasing locomotor activity, which was reversed by N and M. Morphological study confirmed that BDL led to neurodegeneration in the cortex of the rats, and the N and M treatment preserved cortical neurons. In addition, immunohistochemical (IHC) study of the rat cortex showed that BDL resulted in increasing the activated astrocytes, and the N and M treatment reduced the number of activated cells. Conclusion: These results obviously depicted combinational therapy with N and M to exert positive effects in the BDL rats, probably due to their synergistic anti-inflammatory and antioxidant activities.

Background: Malaria parasite strains are resistant to the therapeutic effect of prophylactics medicines presently available. This resistance now poses a significant challenge to researchers to beat malaria parasitic infections. Strategies such as investigating newer hybrid chemical entities and specified drug targets may help us spot new efficient derivatives that bind to the parasites in a more specific manner and inhibit their growth. Objective: To scientifically perform the experimental, pharmacological, and computational studies of pyrazole-based furanone hybrids as novel antimalarial agents. Methods: A series of new furanone-based pyrazole derivatives were synthesized and investigated as potential antimalarial agents by performing in vitro antimalarial activity. To get further optimization, these synthesized derivatives were virtually screened based on ADME-T filters, and molecular docking studies were also accomplished on the crystal structures of Plasmodium falciparum lactate dehydrogenase (PfLDH). Furthermore, the in-silico prediction was supported by performing an LDH assay. Results: The docking data suggested that the designed hybrid of furanone-pyrazole may act as PfLDH inhibitors. It was found that the results of experimental in vitro antimalarial activity and in silico analysis correlate well to each other to a good extent. The compounds (7d), (7g), and (8e) were found to be the most potent derivatives with IC50 values of 1.968, 1.983, and 2.069 μg/ml, respectively. Conclusion: From the results, it may be concluded that compounds that are active in low doses might be adopted as a lead compound for the development of more active antimalarial agents. The synthesized compounds (7d), (7g), and (8e) exhibited good antimalarial activity with PfLDH inhibition. The best compounds can be explored further in the future for designing the potent inhibitors of PfLDH as new potent antimalarial agents.

Background: The derivatives of Phenytoin conjugated with various anilines were synthesized. The synthesized derivatives were evaluated for different physicochemical parameters along with log P values using different software programs to discover their ability to cross the blood brain barrier. The pharmacological activities such as antianxiety, skeletal muscle relaxant and anticonvulsant were evaluated by using different models. Objective: The new Phenytoin derivatives were synthesized and evaluated for different properties to predict CNS activity. The drugs synthesized by chloroacetylation and then different aniline were added to it. The compounds were evaluated for their different CNS activity by using different methods. Methods: The compounds were synthesized by firstly chloroacetylating the phenytoin and then different substituted anilines were added to it. The compounds were evaluated for antianxiety activity, muscle relaxant activity and anticonvulsant activity by using different models. Results: The number of derivatives of Phenytoin was synthesized and various physicochemical parameters were optimized which revealed that the compound containing chloro groups such as C2 and C5 exhibited significant potential when compared with the standard drug Diazepam. Conclusion: It was portrayed that the synthesis, computational studies and evaluation of anticonvulsant, antianxiety and skeletal muscle relaxant activity of new Phenytoin derivatives were carried out. The compounds were productively synthesized and portrayed by molecular docking studies. The compounds also exhibit mild to moderate similarity with respect to standard drug. The synthesized drugs have the potential to be optimized further to engender new scaffolds to treat various CNS disorders.

Background: A simultaneous administration of an acetylcholinesterase (AChE) inhibitor and a NSAID as a drug cocktail has been documented to exhibit significantly protective effects in AD patients. But it suffers from poor patent compliance, pharmacodynamics and pharmacokinetic issues. Objective: The present study is aimed to design and synthesize a hybrid molecule capable of exhibiting both AChE inhibition and anti-inflammatory activities for de-accelerating the progression of AD. The synthesized molecules will be evaluated for in vitro and in vivo models. Methods: The present study involves the coupling of ibuprofen or naproxen to varied disubstituted amines (AChE inhibitor pharmacophore) through benzimidazole to develop two series of compounds i.e. IB01-IB05 and NP01-NP05. The synthesized compounds were characterized using FTIR, ¹H-NMR, ¹³C-NMR and MS. All compounds were evaluated for in vitro AChE inhibitory and COX inhibitory activities. The most active compound was taken for in vivo evaluation. Results: Compounds of series IB01-IB05 are found more potent as compared to NP01-NP05. The maximally potent compound IB04 in in vitro evaluation is selected for in vivo evaluation of memory restoration activity using scopolamine-induced amnesia model in mice. It significantly reverses the scopolamine-induced changes (i.e., escape latency time, mean time spent in target quadrant, brain AChE activity and oxidative stress) in a dose-dependent manner. IB04 at 8 mg/kg is significantly effective in lowering AD manifestation in comparison to donepezil. Conclusion: The findings indicate that Benzimidazole hybrids utilizing ibuprofen and pyrrolidine moiety may prove a useful template for the development of new chemical moieties against AD with multiple potencies.