Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 17, Issue 3, 2017

Background: Piroxicam has been reported to be convertible to Central Nervous System (CNS) acting agents. It has serious depressant effects at high doses. Objective: In view of this, structures of piroxicam metabolites were assessed for possible conversion to CNS depressants. Methods: Literature search was carried out with intent to identifying piroxicam metabolites and the possibility of converting them to CNS acting depressants. Results: Piroxicam is convertible to hydroxymethylated metabolite which may be converted to barbiturates such as thiopentone and thiamylal. Whereas cyclodehydrated metabolite may be converted to acetylcyclodehydrated compound that may be in turn converted to acetylacetone and cyclohexamide. However, carboxybenzothiazine metabolite may be converted to carboxamide compound, benzolactone which is convertible to phenazone. Carboxybenzothiazine is also convertible to 2-aminopyridine mepyramine and triplenamine. Conversion of carboxybenzothiazine to gamma aminobutyric acid and phenothiazines such as chlorpromazine, thioridazine, fluphenazine and perphenazine is highly possible. Conclusion: Structurally, barbituric compounds, carboxamide, cyclodehydrated, benzothiazine and carboxybenzothiazine metabolites may act via dopamine and adrenergic receptors causing depression of CNS activities. Piroxicam metabolites may also act via histamine, melatonin and potassium channel receptors causing CNS depression.

Introduction: Central Nervous System (CNS) disorders are on increase perhaps due to genetic, enviromental, social and dietetic factors. Unfortunately, a large number of CNS drugs have adverse effects such as addiction, tolerance, psychological and physical dependence. In view of this, literature search was carried out with a view to identify functional chemical groups that may serve as lead molecules for synthesis of compounds that may have CNS activity. Methods: The search revealed that heterocycles that have heteroatoms such as nitrogen (N), sulphur (S) and oxygen (O) form the largest class of organic compounds. They replace carbon in a benzene ring to form pyridine. Compounds with furan, thiophene, pyrrole, pyridine, azole, imidazole, indole, purine, pyrimidine, esters, carboxylic acid, aldehyde, pyrylium, pyrone, pyrodine, barbituric acid, barbiturate, quinoline, quinolone, isoquinolone, coumarin, alkylpyridine, picoline, piperidine, diazine, carboxamide, flavonoid glycoside, oxindole, aminophenol, benzimidazole, benzoxazole, benzothiazole, and chromone chemical groups among others may have CNS effects ranging from depression passing through euphoria to convulsion. Results and Conclusion: Examples of the compounds with the functional groups include but not limited to coal tar, pyridostigmine, pralidoxime, quinine, mefloquine, pyrilamine, pyronaridine, ciprofloxacin and piroxicam. A number of them can undergo keto-enol tautomerism. Chiral amines may be used for derivation of chiral carboxylic acids which are components of tautomers. Some tautomers may cause parkinsonism and Stevens Johnson syndrome

Background: Chronic arsenic-exposure even at a low-dose results in the neural impairment and motor/cognitive dysfunction. However, several preventive approaches are made mainly against hepatic/ gastrointestinal damages. Only a few investigations postulate therapeutic strategies for neural anomalies. Here, the protective role of Green tea (Camellia sinensis or CS; 10mg/ml aqueous) has been evaluated against arsenic-induced (0.6ppm/100g bw/28 days) cerebral/cerebellar tissue degeneration, oxidative-threats and neurotransmitter deregulation in female rats. Methods and Results: The Dunnett's t test and multiple-comparison ANOVA-test suggest that arsenic significantly decreased free thiol level with an increase in lipid-peroxidised product and damages to the tissue-structure. A significant decrease in serum urate accompanied by increases in C-reactive protein and TNF-α, an acute-phase inflammatory cytokine, strongly suggests a possible mechanism of oxidative- inflammatory tissue injury being supported by the increase in lactate-dehydrogenase activity. In addition, suppression in cytosolic superoxide-dismutase (Cu-Zn isoform/SOD1; NBT reduction-test) and an insufficient protection through catalase activity culminate free radical-related damages. In-vitro, H2O2 inactivated partially-purified (dialyzed/concentrated, 6-8kd cutoff-Millipore) rat liver SOD1 and that was markedly protected by 2-mercaptoethanol. Though significant signs of toxicities were noticed at biochemical/cellular level, the present treatment did not affect DNA (DNA-fragmentation assay) in the brain tissues. The CS supplementation significantly protected serum/tissue antioxidant-components, prevented inflammatory-responses and decreased lipid-peroxidation in brain resulting in increased tissue integrity. Moreover, arsenic-induced impairment of neurotransmitters i.e. glycine, glutamate and aspartate levels in cerebral tissue were significantly restored in CS-supplemented group. Conclusion: Taken together, this investigation indicates the potent neuroprotective and antioxidative efficiencies of Camellia sinensis against arsenic-induced oxidative threat.

Background: Elevation in brain levels of aluminium can be neurotoxic and can cause learning and memory deficiencies. In Chinese medicine, Morus alba is used as a neuroprotective herb. The current study was intended to discover the recuperative effect of morusin against aluminium trichloride (AlCl3)-induced memory impairment in rats along with biochemical mechanism of its protective action. Methods: Memory deficiency was produced by AlCl3 (100 mg/kg; p.o.) in experimental animals. Learning and memory activity was measured using Morris water maze (MWM) test model. Central cholinergic activity was evaluated through the measurement of brain acetylcholinesterase (AChE) activity. In addition to the above, oxidative stress was determined through assessment of brain thiobarbituric acid-reactive species (TBARS) and glutathione (GSH) levels. Results: AlCl3 administration prompted significant deficiency of learning and memory in rats, as specified by a noticeable reduction in MWM presentation. AlCl3 administration also produced a significant deterioration in brain AChE action and brain oxidative stress (increase in TBARS and decrease in GSH) levels. Treatment with morusin (5.0 and 10.0 mg/kg, dose orally) significantly overturned AlCl3- induced learning and memory shortages along with diminution of AlCl3-induced rise in brain AChE activity and brain oxidative stress levels. Conclusion: It may be concluded that morusin exerts a memory-preservative outcome in mental discrepancies of rats feasibly through its various activities.

Background: Epilepsy, one of the most frequent neurological afflictions in man characterized by excessive temporary neuronal discharges resulting in uncontrolled convulsion, requires special medical attention. Though several new anticonvulsants are introduced, some types of seizures are still not adequately treated with current therapy. Toxicity, intolerance, and lack of efficacy for certain types of seizure are some of the limitations of the current medications. Methods: Maximal electroshock (MES) seizure model was used in the present study to evaluate the anticonvulsant activity of the drugs. Seizures were induced in ten weeks old male Wistar rats (200-220 g) by delivering electro shock of 150 mA for 0.2 sec by means of a convulsiometer through a pair of ear clip electrodes. The test compounds (1-10, 100 mg/kg) were administered by oral route 30 mins before the maximal electroshock seizure test by suspending in carboxymethylcellulose (1%). The animals were observed closely for 2 mins. The percentage of inhibition of seizure relative to control was recorded and calculated. Phenytoin (100 mg/kg, p.o) was used as a standard drug. The data was analysed by using one way ANOVA followed by dunnett's test. Results: In our present series of compounds the active compounds possess all the requirements essential for anticonvulsant activity as proposed by Dimmock and others. In this study, it reveals that, compounds showing anticonvulsant activity with more lipophilic N-substitution group are more active than hydrophobic substitution in the hydantoin ring. The rapid onset of action is believed to be due to the substitution of more lipophilic propyl group in the N-substitution in the hydantoin moiety. Evidently, this distal hydrophobic centre alters the bioavailability of the molecules. Conclusion: The results are encouraging and show that, the hydantoins are more potential molecules for the treatment of anticonvulsant. Anticonvulsants have greatly improved the lives of people with epilepsy. Approximately 70% of patients can achieve complete freedom from seizures with appropriate treatment. Lipophilicity appears to govern the MES activity. If there is lipophilic moiety, then MES activity is favoured. All the compounds have shown promising and significant protective effect on maximal electroshock induced seizures when compared to vehicle treated control rats.

Background: Amyloid fibrils represent stable form of many misfolded proteins associated with numerous diseases like Parkinson's Disease (PD), Type II diabetes and Alzheimer's disease (AD). α-synuclein protein is the principal constituent of Lewy bodies that are considered to be pathological hallmark of PD. Recently, a high resolution structure of α-synuclein protein that stacks together forming fibrils in brains of PD patients were identified. What structural features drive pathology of PD can now be possibly answered from the fibril structure of protein. Objectives: To understand the molecular interactions those are responsible for the stability of the α- synuclein fibril structure. Methods: To study the molecular interactions stabilizing the α-synuclein fibril, we have used a high resolution amyloid fibril structure (PDB ID 2N0A). The molecular interactions in fibril structure were studied using PDBSum server. We then looked into the destabilization of α-synuclein fibril by disrupting the salt-bridge holding the strands and probable methods to decompose fibril into structurally distinct units using Top-domain web-server. The effect of salt-bridges on the stability of the fibril structure was studied by mutating one of the residues involved in the formation of salt-bridge using molecular dynamics simulation. Results: Our results indicate a finite salt-bridge (E46-K80) is crucial for stability of protofibril. Besides, we observed hydrogen bonds and non-bonded contacts involved in fibril stabilization. We noticed α-synuclein dimer predominantly exists in conformations distinct from fibril. Conclusion: We characterized the salient molecular interactions in α-synuclein fibril and these findings may be useful to design potential inhibitors for the treatment of PD.

Background: Mannich bases are known to be an important pharmacophore or bioactive leads in the synthesis of various potential agents that have a variety of therapeutic activities like anticancer, antipsychotic, anticonvulsant, antimalarial, anti-inflammatory, antibacterial and so forth. Thus, in the present research, conjugation of moieties like 1,5-benzoxazepines and 1,5-benzothiazepines with secondary amines like piperazine, methyl piperazine and morpholine was carried out in a Mannich base with an anticipation of good anticonvulsant activity. Objective: Synthesis, characterization, structure activity relationship and anticonvulsant activity of the Mannich bases of 1,5-benzothiazepine and 1,5-benzoxazepine derivatives. Methods: All the derivatives were synthesized in three steps. In the first step, substituted 4-hydroxy chalconylbenzene was synthesized by the reaction of 4-hydroxyacetophenone and substituted benzaldehyde, in the presence of potassium hydroxide. In the second step, 2,3-dihydro- 1,5- benzothiazepines and 2,3-dihydro-1,5-benzoxazepines were synthesized by the reaction of 2- thio/aminophenol with chalcones in the presence of glacial acetic acid. In the third step, these compounds finally underwent Mannich reaction with different secondary amines to the respective title compounds. All the synthesized derivatives were characterised and evaluated for anticonvulsant activity using MES (Maximal Electroshock Induced Seizure) and INH (Isoniazide Induced Convulsion) models. Results: The synthesized derivatives were found to be more active in the MES model than INH model, with phenytoin and diazepam being the standards respectively. Accordingly, the mode of action of the synthesized compounds may be similar to phenytoin. The methyl piperazine containing compound, at a dose of 30 mg/kg., was found to be the most active and promising compound in the series. Conclusion: The benzothiazepine derivatives showed better anticonvulsant activity than the benzoxazepines derivatives.

Background: A series of new N-(2-benzoyl-4-chlorophenyl)-2-(4-(substituted phenyl) piperazin-1-yl) acetamides (3a-j) have been synthesized by the chloroacetylation of 2-amino-5- chlorbenzophenone which was further reacted with substituted phenylpiperazine. Material: The chemical structures of the compounds were confirmed on the basis of their TLC, IR, 1HNMR, 13CNMR and by elemental analysis. The physicochemical similarity of the target compounds with respect to standard drug diazepam was assessed by calculating from a set of physicochemical properties using software programs. Conclusion: Molecular docking studies revealed that the target compounds correctly dock into the binding pocket of the GABAA receptor, while their bioavailability/drug-likeness was predicted to be acceptable but requires future optimization. The anxiolytic and skeletal muscle relaxant activity of the target compounds (3a-j) were evaluated in albino mice. Among them, compound 3h showed potent anxiolytic and skeletal muscle relaxant activity.

Background: The benzoxazepine JL13 is an analogue of the clozapine family of antipsychotic agents which target the 5-HT2A receptor, and has showed promise as an atypical antipsychotic agent. Based on the dearth of clinically effective anti-psychotic agents available, we sought to design and chemically synthesize additional analogues. Methods: Structure function analysis was conducted using state of art computational methods, which were designed to highlight new candidates for chemical synthesis. Efficient syntheses were then conducted and the products screened for affinity to the receptor. Results: Among many new analogues prepared, an aza analogue demonstrated seventeen times greater affinity for the receptor than JL13. Conclusion: An efficient synthetic route to an aza-analogue of JL13 was developed and will allow rapid modifications of the core and synthesis of related libraries.