Medicinal Chemistry - Volume 21, Issue 9, 2025

Oxidative stress is strongly linked to neurodegeneration through the activation of c-Abl kinase, which arrests α-synuclein proteolysis by interacting with parkin interacting substrate (PARIS) and aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2). This activation, triggered by ataxia-telangiectasia mutated (ATM) kinase, leads to dopaminergic neuron loss and α-synuclein aggregation, a critical pathophysiological aspect of Parkinson’s disease (PD). To halt PD progression, pharmacological inhibition of c-Abl kinase is essential. Despite three generations of tyrosine kinase inhibitors (TKIs) being explored for PD treatment, they present significant concerns including poor blood-brain barrier penetration, off-target effects, and severe side effects. Notably, there are currently no FDA-approved c-Abl kinase inhibitors in clinical usage for PD treatment, highlighting the urgent need for potent, safe, and cost-effective alternatives.

This study aims to identify potential c-Abl kinase inhibitors from plant-derived compounds with reported anti-Parkinson's potential and their derivatives using molecular docking, molecular dynamics simulations (MDS), and in silico pharmacokinetics and toxicity profiling.

Seventy-eight compounds sourced from literature were docked against c-Abl kinase using Maestro 12.5. The top three hit compounds, along with nilotinib (control drug), were subjected to drug-likeness, ADMET profiling using the AI Drug Lab server and 100 ns MDS using Desmond.

Amburoside A, diarylheptanoid MS13, and dimethylaminomethyl-substituted-curcumin showed binding affinities close to nilotinib, with values of -12.615, -12.556, and -11.895 kcal/mol respectively, compared to nilotinib's -16.826 kcal/mol. The three plant-derived compounds exhibited excellent structural stability and favorable ADMET profiles, including optimal blood-brain barrier permeation.

The three hit compounds identified in this study show potential as c-Abl kinase inhibitors. Given the absence of FDA-approved c-Abl kinase inhibitors for PD, these findings are significant as they could contribute new therapeutic options for the treatment and management of PD. However, further in vitro and in vivo experiments are necessary to validate these findings.

The marine habitat is a plentiful source of diverse, active compounds that are extensively utilised for their medicinal properties. Pharmaceutical trends have currently changed towards utilising a diverse range of goods derived from the marine environment.

This study aimed to examine the inhibitory effects of bioactive chemicals derived from marine algae and bacteria. The identification of these compounds was carried out through the process of Gas Chromatography-Mass Spectrometry (GC-MS) profiling. Subsequently, these compounds were subjected to docking simulations against a specific set of target proteins that are known to be frequently overexpressed in three distinct types of cancer.

From the docking results, the ligand 1,4:3,6:5,7-Tribenzal-beta-mannoheptitol was found to be effective against the proteins mTOR (PDB ID: 4JSV) and FGFR2 (PDB ID:6V6Q). The findings of molecular simulation highlight that the investigated compound gets integrated with the target proteins effectively.

These marine derived compounds hold significant potential for further development and exploration in the field of cancer therapeutics.

Epilepsy encompasses numerous syndromes characterized by spontaneous, intermittent, and abnormal electrical activity in the brain. Affecting about 1-2% of the population, it is estimated that approximately 30-40% of patients experience refractory epilepsy, which does not respond to traditional anticonvulsant drugs.

Therefore, developing novel, safe, and effective antiepileptic drugs remains a medical need. In this study, we synthesized a series of isoindoline-1,3-dione derivatives and evaluated their anticonvulsant effects.

Compounds (2a-j) and (5) were obtained with yields ranging from 52-97%. These compounds were assessed for their protective effects on the following parameters: a) time to first seizure (seizure latency), b) seizure duration, and c) mortality rate post-seizure. The most active compound, (2a), increased seizure latency, reduced seizure duration, and lowered the mortality rate.

These findings indicate that compound (2a) is a promising new anticonvulsant prototype, offering an alternative to current anticonvulsant drugs.

Neurodegenerative diseases are a group of disorders characterized by progressive neuronal degeneration and death, of which Alzheimer's disease and Parkinson's disease are the most common. These diseases are closely associated with increased expression of monoamine oxidase B (MAO-B), an important enzyme that regulates neurotransmitter concentration, and its overactivity leads to oxidative stress and neurotoxicity, accelerating the progression of neurodegenerative diseases. Therefore, the development of effective MAO-B inhibitors is important for the treatment of neurodegenerative diseases.

This study aims to improve the prediction of the efficacy of novel 6-hydroxy-benzothiazole-2-carboxamide compounds in inhibiting MAO-B by improving the quantitative constitutive effect relationship (QSAR) modeling and to provide a theoretical basis for the discovery of novel neuroprotective drugs.

The study first optimized the structures of 36 compounds using the heuristic method (HM) in CODESSA software to construct linear QSAR models. Subsequently, key descriptors were screened by using the gene expression programming (GEP) technique to generate nonlinear QSAR models and validate them.

The R², F-value, and R²cv of the linear model were 0.5724, 10.3752, and 0.4557, respectively, whereas the nonlinear model constructed by the GEP algorithm showed higher prediction accuracies by achieving R² values of 0.89 and 0.82, and mean squared errors (MSE) of 0.0799 and 0.1215 for the training and test sets, respectively. In addition, molecular docking experiments confirmed that the novel compound 31 was tightly bound to the MAO-B active site with significant inhibitory activity.

In this study, we successfully improved the prediction ability of the efficacy of novel 6-hydroxybenzothiazole-2-carboxamide compounds to inhibit MAO-B by improving the QSAR model. This not only provides new drug candidates for the treatment of neurodegenerative diseases, but also provides important theoretical guidance for subsequent drug design and development, which can help accelerate the process of new drug discovery and reduce the disease burden of patients.

A series of novel 2-((3,5-diphenylpyrazin-2-yl)amino)-1-(piperidin-1-yl/pyrrolidin-1-yl)ethanone derivatives (5a-5l) were synthesized and evaluated for their tuberculosis activity using the standard strain H37Rv and two other clinically isolated multidrug-resistant strains with different resistances.

All compounds 5a-5l showed promising results in tuberculosis activity. Among them, 5g and 5i demonstrated remarkable activity at 5 μg/mL against H37Rv and three other MDR strains. The compounds 5c, 5d, and 5f were sensitive, showing inhibition between 15-25 μg/mL against M. tuberculosis growth. In-silico docking studies were conducted for 5a-5l using the 2FUM protein of M. tuberculosis.

These studies revealed that compounds 5g and 5i exhibited strong interactions with the MTB protein, with binding energies of -9.85 kcal/mol and -10.74 kcal/mol, respectively, and inhibitory concentrations of 0.38 µM and 0.77 µM.

Moreover, these motifs also displayed good binding energy coupled with favorable minimum inhibitory concentrations (MIC).