Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Current Issue

Seizures are a common presenting symptom of the central nervous system (CNS) and could occur from infections (such as toxins) or drugs.

The aim of this study was to present a systematic review of the association between infections, seizures, and drugs.

From their inception to 18 February 2024 relevant in-depth consequent guide approach and the evidence-based choice were selected associated with a knowledgeable collection of current, high-quality manuscripts.

Imbalance between inhibitory and excitatory neurotransmitters due to infections, drugs such as ticarcillin, amoxicillin, oxacillin, penicillin G, ampicillin, tramadol, venlafaxine, cyclosporine, tacrolimus, acyclovir, cellcept, the old generation of antiepileptic drugs, such as carbamazepine, phenytoin, and many other drugs could cause different stages of CNS disturbances ranging from seizure to encephalopathy. Infections could cause life-threatening status epilepticus by continuous unremitting seizures lasting longer than 5 minutes or recurrent seizures. Meningitis, tuberculosis, herpes simplex, cerebral toxoplasmosis, and many others could lead to status epilepticus. In fact, confusion, encephalopathy, and myoclonus were reported with drugs, such as ticarcillin, amoxicillin, oxacillin, penicillin G, ampicillin, and others. Penicillin G was reported as having the greatest epileptogenic potential. A high dose, in addition to prolonged use of metronidazole, was reported with seizure infection. Meropenem could decrease the concentration of valproic acid. Due to the inhibition of cytochrome P450 3A4, the combination of clarithromycin and erythromycin with carbamazepine needs vigilant monitoring.

Due to changes in drug metabolism, co-administration of antiseizure drugs and antibiotics may lead to an enhanced risk of seizures. In patients with neurocysticercosis, cerebral malaria, viral encephalitis, bacterial meningitis, tuberculosis, and human immunodeficiency virus, the evidence-based study recommended different mechanisms mediating epileptogenic properties of toxins and drugs.

The purpose of the current study was to explore the virtual library for the screening against Monoamine oxidase (MAO) isoforms. An in-house library of natural based ligands was docked within the active sites of MAO isoforms and their in vitro study was also conducted.

The prime objective of the current study was to screen and validate the natural-based derivatives for MAO inhibitory action with the least adverse effects and get molecular aspects about further structural modifications on the most active leads.

The importance of MAOs in controlling the activity of the central nervous system has been extensively studied. Our goal in this work is to identify a prospective natural lead molecule that has a stronger affinity for the MAO enzyme in order to produce a more effective natural candidate for a neurological agent.

In order to get insight into how different categories of natural compounds interact with the targeted protein, we virtually screened the numerous natural compound categories in the current study. Rhamnetin, quercetin, piperine, eugenol, and umbelliferone showed the highest dock scores in the case of MAO-B, with scores of -10.57, -9.938, -9.445, and 7.821, respectively. For MAO-A, umbelliferone, curcumin, caffeic acid, and quercetin, the corresponding dock scores were -8.001, -7.941, -7.357, and -6.658. Additionally, an in vitro MAO inhibitory experiment was utilized to assess the top-ranked compounds with the best docking scores. The most potent Human Monoamine oxidase (hMAO-A) inhibitor, with an IC50 of 10.98±0.006 M and a selectivity index (SI) of 0.607, was discovered to be the compound umbelliferone. Rhamnetin, the lead chemical, has demonstrated hMAO-B activity with a value of 10.32±0.044 M (SI value of 3.096).

These natural potential ligands have been found remarkable to the standard compounds against MAO-A and MAO-B, and they could be used as a lead chemical in the development of novel therapeutic candidates. The in silico screening results and in vitro hMAO inhibitory efficacy exhibited strong correlations.

Alzheimer’s disease is a neurodegenerative disorder that affects learning, memory and behavioral turbulence in elderly patients. Acetylcholinesterase (AChE) inhibitors act as anti-Alzheimer’s agents. Phenothiazine derivatives are considered momentous anti-Alzheimer’s agents because of their AChE inhibitory activity. The elevated levels and increased expression of this protein have been associated with Alzheimer's disease. Coumarin-fused phenothiazines have emerged as significant anti-Alzheimer's agents due to their notable receptor inhibitory activity.

Some unique phenothiazine analogs were designed, and computational studies were conducted to explore their inhibitory activity against the AChE enzyme (PDB id: 4EY7) by using the Schrodinger suite-2019-4.

Docking studies were conducted by using the Glide module; binding free energies were calculated by means of the Prime MM-GBSA module, and Molecular dynamics (MD) simulation was performed by using the Desmond module of the Schrodinger suite. Glide scores were used to find out the binding affinity of the ligands with the target 4EY7.

The compounds exhibited enhanced hydrophobic interactions and formed hydrogen bonds, effectively impeding Acetylcholinesterase. The Glide scores for the compounds ranged from -13.4237 to -8.43439, surpassing the standard (Donepezil) with a score of -16.9898. Interestingly, a positive value was obtained for the MM-GBSA binding of the potent inhibitor. To gain insights into the dynamic behavior of the protein A8, molecular dynamics (MD) simulations were employed.

Based on the results, the study concludes that phenothiazine derivatives show promise as acetylcholinesterase inhibitors. Compounds with notable Glide scores are poised to exhibit significant anti-Alzheimer's activity, suggesting their potential therapeutic efficacy. Further in vitro and in vivo investigations are warranted to validate and explore the therapeutic potentials of these compounds.