Central nervous system agents in medicinal chemistry最新文献

Background: Phenytoin (5,5-diphenyl hydantoin) has poor water solubility, which results in incomplete oral availability. Other problems associated with the oral and intramuscular administration of phenytoin are gastric irritation and inflammation at the site of injection.

Objective: The purpose of this study was to synthesize mutual amide prodrugs of phenytoin by using amino acids like glycine, L-tryptophan, L-lysine and taurine.

Methods: These prodrugs were synthesized and characterized by Fourier Transform Infrared (FTIR), Proton nuclear magnetic resonance (1H NMR) and Mass Spectra. Physical and spectral characterization was performed by determination of solubility, maximum wavelength, partition coefficient (log P), ionization constant (pKa), specific (α) and molar rotation (μ), refractive index (n), specific refraction (RS) and molar refraction (RM).

Results: The results obtained from solubility and log P values determination indicated that phenytoin prodrugs can be administered by oral as well as a parenteral route by minimizing the limitations associated with phenytoin. Anticonvulsant activity of prodrugs (4a-4d) was evaluated by using maximal electroshock (MES) and strychnine induced seizure test on albino mice of either sex weighing 25-30 g in which 4b and 4d were found to have significant anticonvulsant activity for MES and strychnine induced seizure test. In vitro enzymatic hydrolysis study of 4b and 4d was performed on liver, intestinal mucosa and plasma sample of male Sprague Dawley rats weighing 280-300 g in which phenytoin was eluted at 10.13 to 10.68 minutes at 220 nm.

Conclusion: The results obtained from the present work showed that amino acid-based mutual prodrug strategy can be a promising method to increase the solubility and anticonvulsant activity of phenytoin for the development of anticonvulsant agents.

Threats, challenging events, adverse experiences, predictable or unpredictable, namely stressors, characterize life, being unavoidable for humans. The hypothalamus-pituitary-adrenal axis (HPA) and the sympathetic nervous system (SNS) are well-known to underlie adaptation to psychosocial stress in the context of other interacting systems, signals and mediators. However, much more effort is necessary to elucidate these modulatory cues for a better understanding of how and why the "brain-body axis" acts for resilience or, on the contrary, cannot cope with stress from a biochemical and biological point of view. Indeed, failure to adapt increases the risk of developing and/or relapsing mental illnesses such as burnout, post-traumatic stress disorder (PTSD), and at least some types of depression, even favoring/worsening neurodegenerative and somatic comorbidities, especially in the elderly. We will review here the current knowledge on this area, focusing on works presenting the main brain centers responsible for stressor interpretation and processing, together with those underscoring the physiology/biochemistry of endogenous stress responses. Autonomic and HPA patterns, inflammatory cascades and energy/redox metabolic arrays will be presented as allostasis promoters, leading towards adaptation to psychosocial stress and homeostasis, but also as possible vulnerability factors for allostatic overload and non-adaptive reactions. Besides, the existence of allostasis buffering systems will be treated. Finally, we will suggest promising lines of future research, particularly the use of animal and cell culture models together with human studies by means of high-throughput multi-omics technologies, which could entangle the biochemical signature of resilience or stress-related illness, a considerably helpful facet for improving patients' treatment and monitoring.

Background: A series of phenylurea derivatives were designed and synthesized, The target compounds were subjected to pharmacological studies. Various other parameters such as physicochemical properties, computational studies, and % similarity were also calculated.

Materials and methods: The synthesis of the target compounds has been carried out by reaction of Phenylurea with chloroacetyl chloride to afford 1-(2-chloroacetyl)-3-phenylurea, which further reacted with substituted anilines. All the reactions were monitored by TLC. All the target compounds were purified by recrystallization and characterized by spectroscopic methods. Physicochemical parameters and Log P values of the synthesized derivatives were also calculated. It identified compounds that have the prospect to cross the blood-brain barrier (BBB) and are CNS active. Skeletal muscle relaxant activity was also carried out using the Rotarod method.

Results: The data of Log P indicated that the synthesized compounds have the potential to cross the BBB, so they are CNS active. Pharmacological activities of the derivatives showed that the compounds containing chloro group have moderate skeletal muscle relaxant activity. The test compounds possess significant differences between the control group and the treated group.

Conclusion: The synthesized derivatives containing chloro group were found to be more potent when compared to standard drug Diazepam. Various others parameters studied revealed that the drug has the potency to cross the blood-brain barrier.

Background: Alzheimer's disease (AD), an irreversible complex neurodegenerative disorder, is the most common type of dementia, with progressive loss of cholinergic neurons. Based on the multi-factorial etiology of Alzheimer's disease, novel ligands strategy appears as an up-coming approach for the development of newer molecules against AD. This study is envisaged to investigate anti-Alzheimer's potential of 10 synthesized compounds. The screening of compounds (1-10) was carried out using in silico techniques.

Methods: For in silico screening of physicochemical properties of compounds, Molinspiration property engine v.2018.03, Swiss ADME online web-server and pkCSM ADME were used. For pharmacodynamic prediction, PASS software was used, while the toxicity profile of compounds was analyzed through ProTox-II online software. Simultaneously, molecular docking analysis was performed on mouse AChE enzyme (PDB ID:2JGE, obtained from RSCB PDB) using Auto Dock Tools 1.5.6.

Results: Based on in silico studies, compound 9 and 10 have been found to have better druglikeness, LD50 value, better anti-Alzheimer's, and nootropic activities. However, these compounds had poor blood-brain barrier (BBB) permeability. Compounds 4 and 9 were predicted with a better docking score for the AChE enzyme.

Conclusion: The outcome of in silico studies has suggested, out of various substitutions at different positions of pyridoxine-carbamate, compound 9 has shown promising drug-likeness, with better safety and efficacy profile for anti-Alzheimer's activity. However, BBB permeability appears as one of the major limitations of all these compounds. Further studies are required to confirm its biological activities.

Background: AMD is becoming one of the leading causes of blindness in older adults. The prevalence rate of the wet form of AMD has been increasing due to the lack of selective therapeutic modalities. Current therapeutic interventions such as drugs targeting VEGF, and VEGF receptors, laser coagulants delivered unsuccessful clinical outcomes in AMD patients. Hence, the cost-effective anti-oxidant therapeutic interventions like molecular hydrogen to protect retinal pigment epithelium (RPE) by mitigating oxidative stress may deliver effective clinical outcomes in AMD patients.

Methods: Female patients with late-stage AMD of age above 70 years were chosen for this case report. The patients were administered QIAPI1©, a melanin precursor via sublingual route and the photographs were obtained for left and right eye to depict the efficacy of QIAPI1© against the wet form of AMD.

Results: The administration of QIAPI1© extensively mitigated yellow-colored drusen accumulations in the retina, retinal edema, exudates, and hemorrhages in the right eye, but the effect was minimal in the case of left eye; the overall drusen accumulation was lesser than the first consultation.

Conclusion: Current case report has concluded the intrinsic effect of melanin in producing the molecular hydrogen and chemical energy across the retinal tissues by dissociating water molecules and dissipating the drusen accumulations, retinal edema, and hemorrhages in AMD patients. Our preliminary study reported the usage of QIAPI1© as a prospective therapeutic modality to mitigate the oxidative stress-mediated pathophysiology of the wet form of AMD.

Background: Azodicarbonamide is a dough-enhancer used in the process of breadmaking in countries like Nigeria. While there have been suggestions that it is a sensitizer of the respiratory system, there is a dearth of information on its effects on the central nervous system.

Aim: This study assessed the effects of azodicarbonamide on the central nervous system (ADA) in rats.

Objective: The effects of ADA-containing diet on neurobehaviour, brain antioxidant status, and neuromorphology of selected brain regions in rats were examined.

Methods: Forty adult rats were randomly-assigned into four groups of ten rats each, and were given standard diet or diet containing ADA at 1, 2 and 4% respectively. Rats were fed a standard diet or ADA-containing diet for a period of 28 days. Weekly body weight assessment and daily estimation of food intake were done. Behavioural tests {in the Open field, Y-maze, radial-arm maze, and Elevated Plus Maze (EPM)} were conducted on day 29. Twenty-four hours after the last behavioural test, animals were euthanised, whole brains were dissected, weighed, and either homogenised for assessment of lipid peroxidation and antioxidant status; or sectioned and processed for general histology.

Results: Consumption of ADA-containing diet was associated with a significant decrease in weight gain/food intake, and significant suppression of horizontal locomotion and rearing behaviours; however, grooming activity increased significantly. Also, there was a significant reduction of open-arm time in the EPM and a significant increase in Y-maze alternation (at the lowest concentration of ADA). ADA-containing diet was not associated with significant changes in brain oxidative status or neuromorphology.

Conclusion: The study showed that while ADA-containing diet may alter neurobehaviour in rats; this was not associated with evidence of brain oxidative stress or neuro-histomorphological alterations.