Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 16, Issue 1, 2016

Parkinson´s disease (PD) is a high prevalent progressive neurodegenerative disorder characterized by degeneration of dopaminergic neurons and intracytoplasmatic aggregation of α-synuclein called Lewy Bodies. Anomalies in the proteasomal and endosomal ubiquitin related degradation of α-synuclein have been related with PD. Among the different proteins described in ubiquitin pathway, the hypothetical protein CAB55973.1 was identified previously. Here we modeled this hypothetical protein in order to contribute to the understanding of PD pathogenesis that should be served as an input in the future as drug targets. This study predicted a three-dimensional model of the complete sequence of hypothetical protein CAB55973.1 with a high value of identity and a good homology quality. Subcellular localization was found in the cytoplasm, mainly in the endosomal membrane. 36 protein-protein interactions related to PD were found. 11 residues were predicted to interact with target proteins for ubiquitination. Binding site prediction showed that one domain (residues 163 to 238) might be involved in ubiquitination of target proteins. In this ubiquitin domain, residues were distributed similarly to those of the binding site of the ubiquitin interacting with the UIM of Hrs protein (PDB 2D3G). The hypothetical protein was constructed based on the complete sequence alignment, which allowed predicting the structure with a high accuracy. The functional prediction showed that only one domain of the hypothetical protein might be involved in the α- synuclein ubiquitination of the endosomal pathway of the PD.

Antidepressants generally relief human depressive symptoms and help depressed people. Nevertheless, some undesired clinical events, such as suicide have been emerging more recently. In order to improve and promote antidepressant utilizations in clinics, new researches are focusing on reevaluation of the relationship between efficacy and toxicities of antidepressants in China and US. These researches speed up quickly. Many creative ideas and discoveries have been made, including predictions of the efficacies and toxicities of antidepressants under the same evaluating systems (pharmacogenetics and bioinformatics), genome-wide associate study (GWAS) of the relationship between individual genetic factors and therapeutic outcomes of different types of antidepressants and socio-environmental factors. Hopefully, therapeutic efficacies and outcomes by different types of antidepressant treatments for patients can be improved in clinical trials in the near future.

Indole and its derivatives are continuously drawing interest of researchers in the field of medicinal chemistry for development of newer significant moieties due to their wide range of biological activities. In recent years, indole nucleus has been used to a greater extent for the development of agents acting on central nervous system (CNS) disorders like epilepsy. Binedaline, Amedalin, Pindolol, Siramesine and Oxypertine are the marketed drugs used in CNS disorders having indole moiety. So, keeping this point in mind, the review is specially focused on pharmacological activities of indole derivatives acting on central nervous system like anticonvulsant, antidepressant and sedative-hypnotic activities. The present study covers updated information on the most potent indole derivatives during the past years and also its recent developments. These results may help the researchers to develop novel ideas for future molecular modifications of indole derivatives with potent pharmacological activities and least side effects may be derived.

In the present study a series of new N4-(4-substituted benzylidene)-N1-([1,3,4]thiadiazino [6,5-b]indol-3-yl)semicarbazide (1-6), N4-([1,3,4]thiadiazino[6,5-b]indol-3-yl)-N1-(1-(4—substituted phenyl)ethylidene)semicarbazide (7-10), N4-([1,3,4]thiadiazino[6,5-b]indol-3-yl)-N1-((4-substituted phenyl)(phenyl)methylene) semicarbazide. (11-14) have been synthesized from isatin and thiosemicarbazide through multiple steps to meet structural necessities for the anticonvulsant activity. All the newly prepared compounds were characterized by spectral techniques like FT-IR, 1H and 13C NMR, EI-MS and elemental analysis. All the newly synthesized compounds were investigated for the anticonvulsant activity against maximal electroshock induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ) models and their neurotoxicity were also evaluated by rotarod test. The results obtained showed that 64% of the compounds showed protection in the MES test and 36% of the compounds showed protection in ScPTZ test. Some of the compounds also showed good activity after oral administration. Among the synthesized compounds, compound 14 was shown to be the most active compound showing activity at 100 and 300 mg/kg in MES and ScPTZ test with prolonged duration of action. In the present study, semicarbazones of hydroxy containing carbonyl compounds were depicted to be the potent molecule with low neurotoxicity and prolong duration of action on oral administration. The result of the present study may be used for the future development of novel anticonvulsants with broad spectrum of anticonvulsant activity.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder of aging. It is a multifactorial disease with several overlapping pathways. Therefore, successful therapy should target several pathological features simultaneously. In this regard, cumulative data have demonstrated that polyphenols can display neuroprotective effects through different mechanisms. In this study, we tested the hypothesis that a mixture of anthocyanins/anthocyanidins presents in the formulation MAF14001 may mitigate the amyloid-β peptide (Aβ) toxicity. Anthocyanins are a class of polyphenols capable to cross the blood brain barrier and their intake is associated to a reduced risk of some several chronic diseases. Our results showed that the formulation MAF14001 can protect SK-N-SH cells against Aβ-induced toxicity. From 5 μM, MAF14001 protected SK-N-SH cells against Aβ toxicity by preventing oxidative stress, mitochondrial dysfunction and apoptosis. Furthermore, MAF14001 might directly interact with Aβ to prevent its aggregation process, a key process on Aβ-induced oxidative stress. Indeed, in the presence of MAF14001, Aβ was less susceptible to fibrillation. Finally, MAF14001 decreased the tau phosphorylation (Ser-202) induced by Aβ. Altogether, these results demonstrated that MAF14001 could target multiple mechanisms involved in the etiology of AD and could be useful in preventing and treating AD.

Alzheimer’s disease is an age related disorder and is defined to be progressive, irreversible neurodegenerative disease. The potential targets which are associated with the Alzheimer’s disease are cholinesterases, N-methyl-D-aspartate receptor, Beta secretase 1, Pregnane X receptor (PXR) and P-glycoprotein (Pgp). P-glycoprotein is a member of the ATP binding cassette (ABC) transporter family, which is an important integral of the blood-brain, blood-cerebrospinal fluid and the blood–testis barrier. Reports from the literature provide evidences that the up-regulation of the efflux pump is liable for a decrease in β-amyloid intracellular accumulation and is an important hallmark in Alzheimer’s disease (AD). Thus, targeting β-amyloid clearance by stimulating Pgp could be a useful strategy to prevent Alzheimer’s advancement. Currently available drugs provide limited effectiveness and do not assure to cure Alzheimer’s disease completely. On the other hand, the current research is now directed towards the development of synthetic or natural based therapeutics which can delay the onset or progression of Alzheimer's disease. Since ancient time medicinal plants such as Withania somnifera, Bacopa monieri, Nerium indicum have been used to prevent neurological disorders including Alzheimer’s disease. Till today around 125 Indian medicinal plants have been screened on the basis of ethnopharmacology for their activity against neurological disorders. In this paper, we report bioactives from natural sources which show binding affinity towards the Pgp receptor using ligand based pharmacophore development, virtual screening, molecular docking and molecular dynamics simulation studies for the bioactives possessing acceptable ADME properties. These bioactives can thus be useful to treat Alzheimer’s disease.

A series of piperamides (PA) 8a-j were designed, synthesized and evaluated for their antimicrobial and anticonvulsant activity. Compounds 8a and 8h showed considerable antibacterial activity against B. subtilis with minimum inhibitory concentration (MIC) of 8 and 10 μg/mL, respectively. Compounds 8a and 8h showed advanced anticonvulsant activity as well as lower neurotoxicity than the reference drugs. The interaction between bovine serum albumin (BSA) and PA was investigated using fluorescence quenching and UV-vis absorption spectroscopy. Results showed that PA could strongly quinch the intrensic fluorescence of BSA through a static quencing procedure. The binding constant and number of binding sites of PA with BSA were obtained. The binding distance was calculated based on Forster non-radiative energy transfer theory.

Medulloblastoma (MB) treatment is continuously evolving. Better treatment approaches, focused on particular molecular pathways involved in MB development and progression support new treatment strategies. This article explores the antiproliferative, proapoptotic and radiosensitizing effects of Methoxyamine (MX), a base excision repair (BER) inhibitor that has shown anticancer potential by sensitizing tumor cells to ionizing radiation and chemotherapy. The DAOY (a desmoplastic cerebellar-derived MB) and ONS-76 (classical MB) cell lines were treated with MX at different concentrations, either alone or combined with various chemotherapeutic compounds: cisplatin (CDDP), temozolomide (TMZ) and thiotepa (THIO). Additionally, cell lines were exposed to MX and treated at different ionizing radiation fractions. Measurement of cell growth by XTT assay, clonogenic assay and detection of apoptotic cell death through caspase activity was obtained. Exposure to MX significantly decreased cell proliferation (p<0.05) while increasing cell apoptosis (p<0.05). Growth reduction was concentration-dependent for both DAOY and ONS-76 cells lines. Conversely, MX failed to enhance the cytotoxicity of CDDP, TMZ, and THIO. Moreover, MX treatment radiosensitized both cell lines, with ONS-76 cells being more prone to radiation effects at higher doses of exposure. These data support the role of MX as a direct cytotoxic compound for pediatric MB cells by inhibiting the BER pathway. Nevertheless, an antagonism, rather than a synergic or additive effect of MX with different concentrations of CDDP, TMZ and THIO was observed. Likewise, the radiosensitizing effect on MB cell lines seems to depend on radiation doses and MB subtype. This information may be relevant for clinical study designs employing BER inhibitors for MB.