Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 16, Issue 2, 2016

Previously we have reported 5-substituted phenyl-3-(thiophen-2-yl)-4, 5-dihydro-1hpyrazole- 1-carboxamides as a novel class of antidepressants. The aim of the current study is to proposing the reason for such biological activities of the molecules by using molecular docking studies using AutoDock4.2. Using molecular docking studies, we propose that most of the antidepressant molecules showed good binding affinity towards MAO-A than MAO-B which is an effective target for the treatment of depression. The R and S form of thiophene based pyrazolines-carboxamides showed a binding energy and inhibition constant between 7.93 to -8.76 and 1.54 to 0.38 μM toward MAO-A and -6.39 to -8.51 and 20.84 to 0.57 μM toward MAO-B respectively.

Monoamine oxidases A and B (MAO-A and B) play a critical role in the metabolism of intracellular neurotransmitters of the central nervous system. For decades, MAO inhibitors have proven their clinical efficacy as potential drug targets for several neurological and neurodegenerative diseases. Use of first generation non selective MAO inhibitors as neuropsychiatric drugs elicited several side effects like hypertensive crisis and cheese reaction. Therefore their use is now limited due to non-selectivity towards MAO isoforms and inhibition of metabolizing enzymes like cytochrome P450. Development of selective and specific MAO inhibitors like moclobemide, toloxatone improves their efficacy as disease-modifying effects in monotherapy as well as adjunctive therapy. Recently a lot of research has been done to elucidate the pharmacological potential of medicinal plants and their isolated bioactive constituents having MAO inhibitory activity. Herbs containing MAO inhibitors are extensively used for the development of potent synthetic drugs and as safe and effective alternatives to the available synthetic drugs in the treatment of neurodegenerative diseases such as depression, Parkinson and Alzheimer’s. In several diseases like Parkinson natural MAO inhibitors prevented the neuron denaturalization by their dual action via enhancing neurotransmission of dopamine as well as lowering the generation of free radicals and toxins. Currently development of selective MAO inhibitors is still under study to achieve more effective therapies by using Computer Aided Drug Designing, Ligand-based models and structure-activity hypothesis. These approaches also facilitate understanding the interaction of newly designed molecule with MAO enzymes and the rationalization of probable mechanisms of action.

Despite the considerable interest in the search of new and potent human MAO inhibitors, an increasing number of research works deal with new therapeutic and analytical approaches regarding these molecules. Our interest was focused on the detailed analysis of (i) new pharmacological options for selective hMAO inhibitors; (ii) innovative analytical procedures to discover/screen hMAO inhibitors, and (iii) the recent possibility of using labeled hMAO inhibitors to unravel neurodegenerative diseases and drug distribution. All these three aspects could open new scenarios stimulating the interest of researchers in this field.

Monoamine oxidase B inhibitors are of particular importance in the treatment of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. Herein described is pharmacophore generation and atom-based 3D-QSAR analysis of previously reported furan based MAO-B inhibitors in order to get insight into their structural requirements responsible for high affinity. The best pharmacophore model generated with the five-point hypotheses of ADHRR: hydrogen bond acceptor (A), hydrogen bond donor (D), hydrophobic (H) and two aromatic rings (R1 & R2). On the basis of generated model, a statistically valid 3D-QSAR with good predictability was developed. Molecular docking of lead compound showed binding energy of -8.66 kcal/mol with a predicted inhibition constant of 0.448 μM towards MAO-B.

A screening study aimed at identifying inhibitors of the enzyme, monoamine oxidase (MAO), among clinically used drugs have indicated that the antirheumatic drug, leflunomide, is an inhibitor of both MAO isoforms. Leflunomide inhibits human MAO-A and MAO-B and exhibits IC50 values of 19.1 μM and 13.7 μM, respectively. The corresponding Ki values are 17.7 μM (MAO-A) and 10.1 μM (MAO-B). Dialyses of mixtures of the MAO enzymes and leflunomide show that inhibition of the MAOs by leflunomide is reversible. The principal metabolite of leflunomide, teriflunomide (A77 1726), in contrast is not an MAO inhibitor. This study concludes that, although leflunomide is only moderately potent as an MAO inhibitor, isoxazole derivatives may represent a general class of MAO inhibitors and this heterocycle may find application in MAO inhibitor design. In this respect, MAO inhibitors are used in the clinic for the treatment of depressive illness and Parkinson’s disease, and are under investigation as therapy for certain types of cancer, Alzheimer’s disease and age-related impairment of cardiac function.

Introduction: Chalcones are one of the major classes of naturally occurring compounds and have a vast significance in medicinal chemistry, presenting with a wide scope of pharmacological actions. Discussion: The present review focused our attention onto the monoamine oxidase inhibitory activity of natural and synthetic chalcones. The review also emphasises the structure-activity relationship studies and molecular recognition of chalcones towards MAO-A and B inhibition. Conclusion: Many of the studies clearly revealed that most of the chalcones showed selective, reversible and potent MAO-B inhibition compared to MAO-A. Recent studies also showed that heteroaryl-based chalcones are potent MAO-A inhibitors.

Background: Smoking is the world’s leading cause of preventable death among populations. Cigarette smoking increases the risk of numerous health problems, including heart diseases, stroke, atherosclerosis and many types of cancer, including lung, stomach and bladder cancers. Outcomes: Many individuals find it difficult to stop smoking because of the addictive effects of nicotine and the presence of several monoamine oxidase (MAO) inhibitors in the tobacco smoke extract. Objective: The development of novel, safe and effective medications for smoking cessation is a high public health priority. Results: The role of mesocorticolimbic dopaminergic pathways in withdrawal symptoms and general reinforcement processes clearly recommends dopaminergic system as a potential target for the treatment of nicotine addiction. Conclusion: This review article discusses the new pharmacological treatments of nicotine dependence, which are targeting dopaminergic neurotransmission. This includes blockade of dopamine transporter and inhibition of MAO as pharmacotherapy for the treatment of nicotine dependence.

Background: A quantitative structure-activity relationship (QSAR) study of novel Acetamide derivatives as specific Mono amino oxidase (MAO) A inhibitory agents was performed with 28 compounds to derive QSAR models for better activity and lesser side effects. Methods: Various thermodynamic, electronic and steric parameters were calculated using Chem 3D package of molecular modeling software Chemoffice 7.0. QSAR models were generated employing sequential multiple regression method using in–house statistical program VALSTAT. The best models were selected from the various statistically significant equations. Results: The study revealed that an increase in the bulkiness of the substituent’s and molecular solvent accessible surface area is beneficial to the biological activity and the substitution of two interacting groups should be separated by more than three atoms will give better biological activity. Model also suggests that the presence of the comparatively less lipophilic group may increase MAO-A inhibitory activity and substituent that decrease the flexibility and increase rigidity of the nucleus will enhance the activity. The best QSAR model was selected, having a correlation coefficient (r) = 0.93271, coefficient of determination (r2) = 0.8509 with a standard deviation of predictivity (SDEP) = 0.31287 and cross validated squared correlation coefficient (Q2) = 0.92. The predictive ability of the selected model was also confirmed by leave one out cross validation and r2 predicted (r2 pred) was 0.764. Conclusion: This study may be useful in the designing of more potent substituted acetamide derivatives as specific MAOA inhibitors.

A newer series of 1-(4-substitutedphenyl)-3-(4-((2,4-dioxothiazolidin-5-lidene)methyl)phenyl sulfonyl)urea/thiourea (4a-l) were synthesized for their anticonvulsant activity. The activity is attributed to its potential to restrain astrocytic Na+, 2HCl, and K+ co-transport similar to torasemide which has sulfonylurea in its structure. Torasemide having the similar action as the furosemide that obstructs kainic acid-induced electrical discharges observed from cortex and it has neuroprotective agents, for instance antagonizing the N-methyl-D-aspartate (NMDA) and non-NMDA receptors for evaluating antiepileptic activity. The structures of new derivatives were established by elemental analysis and spectroscopic techniques viz. FTIR, 1H NMR and LC-MS. The all twelve derivatives were assessed for anticonvulsant activity at three different doses at 30, 100 and 300 mg/kg body weight into maximal electroshock (MES) and subcutaneous pentylenetetrazole (sports) models. Compounds 4c and 4e were formed to be most active among all the derivatives for both the models of anticonvulsant activity. Beside these compounds 4g, 4i and 4k also possessed the prominent anticonvulsant activity devoid of any neurotoxicity. The sulfonylurea and sulfonylthiourea both were proved to be effective anticonvulsant pharmacophore. Other structure activity relationships were established by considering the aspect of substitution in the lead.

Background: Heterocyclic compounds are extensively dispersed in nature and are vital for life. Various investigational approaches towards Structural Activity Relationship that focus upon the exploration of optimized candidates have become vastly important. Method: Literature studies tell that for a series of compounds that are imperative in industrial and medicinal chemistry, thiophene acts as parent. Among various classes of heterocyclic compounds that have potential central nervous system activity, thiophene is the most important one. In the largely escalating chemical world of heterocyclic compounds showing potential pharmacological character, thiophene nucleus has been recognized as the budding entity. Result: Seventeen Papers were included in this review article to define the central nervous system potential of thiophene. This review article enlightens the rationalized use and scope of thiophene scaffold as novel central nervous system activity such as anticonvulsant, acetylcholinesterase inhibitor, cyclin-dependent kinase 5 (cdk5/p25) inhibitors, CNS depressant, capability to block norepinephrine, serotonin and dopamine reuptake by their respective transporters etc. Conclusion: The Finding of this review confirm the importance of thiophene scaffold as potential central nervous system agents. From this outcome, ideas for future molecular modifications leading to the novel derivatives with better constructive pharmacological potential may be derived.