Alzheimer’s disease (AD) is the predominant form of age-related dementia and a major neurodegenerative disorder. Its progression is associated with multiple pathological processes, including amyloid-beta (Aβ) deposition, Tau hyperphosphorylation, iron accumulation, mitochondrial dysfunction, and heightened oxidative stress, among other contributing factors [1]. The decline in acetylcholine (ACh) levels due to cholinergic neuron loss further contributes to the cognitive and memory impairments characteristic of AD [2]. With AD cases projected to more than triple by 2050 due to aging populations, and therapeutic options still limited [3], the search for new treatments that directly target these pathological mechanisms is critical. In this context, fiscalins, a class of valine-derived alkaloids with an indolyl moiety and a tricyclic anthranilic acid core, have shown neuroprotective, anticancer, and antimicrobial activities, highlighting their potential therapeutic relevance in AD [4].

This study investigated the in vitro cytotoxicity, neuroprotective potential, and acetylcholinesterase (AChE) inhibitory activity of six synthetic fiscalin derivatives using SH-SY5Y cells differentiated into a cholinergic phenotype. Cytotoxicity was assessed after 24 h of exposure to the compounds (0–50 μM) using the neutral red uptake and MTT reduction assays to define non-cytotoxic concentrations. Neuroprotection against Aβ (50 μM)- and iron(III) (500 or 1000 μM)-induced cytotoxicity was subsequently evaluated following 24 h of co-incubation with the derivatives (10 and 25 μM). Additionally, AChE inhibition was determined using the Ellman’s method.

None of the tested fiscalin derivatives exhibited cytotoxicity at concentrations up to 25 μM. Notably, three compounds significantly reduced Aβ-induced cell death, while five mitigated iron(III)-mediated cytotoxicity. Additionally, five derivatives significantly inhibited AChE activity. Taken together, these findings indicate that fiscalin-based compounds exert multitarget neuroprotective effects relevant to AD pathology, although further studies are needed to elucidate their underlying mechanisms.

Automated and user-friendly interfaces are essential in drug discovery, as they expand access to in silico tools for professionals without programming expertise and enable more laboratories to adopt virtual screening strategies. Advances in software and hardware have significantly improved the performance and accuracy of in silico methods applied to small molecule screening. Ligand-based drug discovery (LBDD), which explores structure–activity relationships (SAR) across large datasets, has increasingly incorporated machine learning (ML) and deep learning (DL) models, including artificial neural networks (ANNs). However, applying data science tools remains challenging for researchers in small laboratories, as it often requires programming expertise, integrated development environments (IDEs), or access to proprietary software. To address this gap, we developed CODRUG, an open-source, intuitive and flexible graphical user interface (GUI) designed to support ligand-based drug discovery. Together with CODOC (molecular docking interface) and CODYN (molecular dynamics interface), CODRUG forms a comprehensive softwares suite. The tool integrates into a screening pipeline that combines structure-based approaches (molecular docking and dynamics) with ligand-based methods (3D-QSAR), generating ranked compound lists for in vitro and in vivo validation. CODRUG was implemented in Python version 3.10.12 using PyQt5 and the Qt framework version 5.15.14. Its design uses sequential tabs covering the workflow: home, general settings, dataset preparation, preprocessing, exploratory analysis, descriptor generation, models screening, validation and hyperparameter tuning, prediction and result interpretation. This layout guides users through complex processes, reducing the need for coding expertise. By providing an accessible, open-source platform that incorporates advances in ML and DL, CODRUG lowers technical barriers and enhances efficiency of in silico screening. This contribution is expected to facilitate the identification of promising compounds and accelerate the development of novel therapeutic candidates. Next steps, CODRUG will be validated through case studies and integrated into collaborative pipelines, expanding its applicability in drug discovery.

The strategic incorporation of silicon into bioactive molecules has emerged as an effective approach to enhance drug properties, including metabolic stability and target specificity. However, no secosteroidal vitamin D receptor (VDR) ligands containing silicon have been reported to date. Here, we describe the rational design, synthesis, and biological evaluation of six novel analogues of 1,25-dihydroxyvitamin D₃ (1,25D₃), in which a silicon atom is introduced as an isosteric replacement at the C25 side chain position.

The sila-derivatives were synthesised via a Wittig-Horner approach starting from the Inhoffen-Lythgoe diol, enabling precise silicon incorporation at the C25 position of the side chain, while preserving the stereochemistry of the secosteroidal structure. X-ray crystallographic analysis of VDR ligand-binding domain complexes (PDB codes 9GY8, 9GYJ, 9GYC, 9GYA, and 9GYK, available at Protein Data Bank) revealed additional stabilising interactions mediated by the silicon-containing side chains, supporting the receptor’s active conformation.

Functional assays showed that these analogues maintain VDR binding and transcriptional activity comparable to 1,25D₃, while exhibiting markedly lower hypercalcaemic effects in cellular models. Notably, in combination with conventional chemotherapeutics, the analogues significantly reduced cancer cell proliferation, indicating potential synergistic effects.

Overall, these results provide a framework for the development of silicon-modified secosteroidal VDR ligands with improved safety and therapeutic potential, highlighting new avenues for applications in both metabolic and cancer-related contexts.

Introduction:
Triazole-based Schiff bases and their metal complexes have attracted considerable attention due to their potential as therapeutic agents with antimicrobial and anti-inflammatory activities. The present study focuses on the synthesis, characterization, and biological evaluation of novel triazole-linked Schiff bases and their Co(II), Ni(II), and Cu(II) complexes.

Methods:
Two Schiff base ligands (L1 and L2) and their complexes (3–10) were synthesized and structurally characterized. Antimicrobial activity was assessed in vitro against Gram-positive and Gram-negative bacteria (Staphylococcus aureus, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli) and fungal strains (Candida albicans and Cryptococcus neoformans). Growth inhibition was quantified spectrophotometrically (OD600 for bacteria, OD530 for C. albicans, and OD600–570 following resazurin reduction for C. neoformans). Anti-inflammatory activity was evaluated using the protein denaturation inhibition assay. Computational studies included density functional theory (DFT), molecular electrostatic potential (MESP) mapping, ADMET predictions, and molecular docking targeting enoyl-acyl carrier protein reductase (Mycobacterium tuberculosis, PDB ID: 6H53) and cyclooxygenase-2 (COX-2, PDB ID: 1CX2).

Results:
Ligand L1 displayed remarkable anti-TB potency (MIC: 0.007 ± 0.002 µmol/mL), surpassing streptomycin. Among the synthesized complexes, compound (10) was the most potent, showing strong antibacterial and antifungal effects (MIC: 0.0066 µmol/mL) and the highest anti-inflammatory activity (ICâ‚…â‚€ = 6.75 ± 0.09 µM). Docking results supported the experimental findings, with favorable binding energies for both 6H53 and COX-2.

Conclusions:
This integrated experimental and in silico investigation demonstrates that triazole-linked Schiff bases and their metal complexes, particularly complex (10), exhibit significant antimicrobial and anti-inflammatory potential. These findings highlight their promise as lead compounds for the development of future therapeutic agents.

Melanostatin (MIF-1) is a short endogenous neuropeptide that acts as a highly selective positive allosteric modulator (PAM) of human dopamine D₂ receptors (hD₂R), exhibiting significant clinical potential for the treatment of dopamine-related central nervous system (CNS) disorders, including depression, drug addiction, obesity, restless legs syndrome, tardive dyskinesia, and Parkinson’s disease. Preliminary studies have shown that substitution of the L-proline residue with L-pipecolic acid generates bioactive derivatives, highlighting the importance of this residue for PAM activity.

In this work, we further explored the role of the L-proline residue by fusing the structural features of L-proline and L-pipecolic acid into a bridged chimera scaffold, (1R,3S,4S)-2-azanorbornane-3-carboxylic acid, and designed a series of 16 bridged melanostatin derivatives to enhance PAM activity and improve pharmacokinetic properties. A concise stereoselective synthetic route afforded the target compounds in high overall yields, with absolute stereochemistry confirmed by X-ray crystallography.

Functional assays at hDâ‚‚R identified four compounds exhibiting potent PAM activity at 0.01 nM, producing a 5- to 6.6-fold increase in dopamine potency. Toxicological profiling in HepG2 and differentiated SH-SY5Y neuronal cells revealed no hepatotoxicity (up to 100 µM) and generally favorable neurotoxicological profiles (up to 200 µM). Permeability studies demonstrated negligible P-glycoprotein interaction and favorable Caco-2 transport, suggesting improved CNS penetration relative to the parent neuropeptide.

Collectively, these findings establish 2-azanorbornane as a privileged scaffold for the development of potent, selective, and brain-penetrant PAMs targeting hD₂R signaling. This work provides a strong basis for the discovery of novel therapeutics for dopamine-related neurological disorders, combining enhanced pharmacokinetic properties, safety, and high PAM efficacy.

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder of central nervous system (CNS), characterized by the progressive loss of mesencephalic dopaminergic neurons. Current therapies provide symptomatic relief but do not halt disease progression, highlighting the urgent need for novel and innovative therapeutic strategies.

Melanostatin (MIF-1), a hypothalamic neuropeptide and positive allosteric modulator (PAM) of dopamine D2 receptors, has emerged a promising candidate for PD treatment. However, its peptide nature restricts clinical use due to its poor oral bioavailability and limited metabolic stability.

In this work, we designed and synthesized twelve novel analogs using pyridine-based carboxylic acids as prolyl surrogates to address the pharmacokinetic limitations of MIF-1. Pyridine-based scaffolds are known for their structural versatility and CNS drug-like properties, including neuroprotective and neurotransmitter-modulating effects.

Structure-cytotoxicity relationship studies in differentiated SH-SY5Y cells identified that, in this group of analogs, the methyl ester group acts as a toxicophore, whereas the corresponding amide counterparts exhibited improved toxicological profiles. These findings offer valuable insights for the development of novel pyridine-based MIF-1 analogs with adequate toxicological profiles.

The analogs identified in this preliminary study are suitable to undergo pharmacological functional assays to characterize PAM activity, contributing to the development of safer and more effective anti-Parkinson agents.

Introduction:

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide in both men and women. Current therapeutic options rarely achieve complete remission, highlighting the urgent need for new treatments. The sigma-1 (σ₁) receptor has emerged as a promising target since it is overexpressed in several tumor types. Antagonists of this receptor have been shown to inhibit cell proliferation by inducing endoplasmic reticulum stress and promoting the generation of reactive oxygen species. Interestingly, although σ₁ receptors are also present in normal cells, their antagonists selectively trigger cytotoxic effects in cancer cells.

Methods:

In this study, we evaluated the cytotoxic activity of naphthoxyacetamide hydrochlorides through cell viability assays based on the metabolic reduction of MTT. Two compounds were tested: N-(2-morpholinoethyl)-2-(naphthalen-2-yloxy)acetamide (salt 1) and N-(2-(piperidin-1-yl)ethyl)-2-(naphthalen-2-yloxy)acetamide (salt 2). A549 lung adenocarcinoma cells were seeded at a density of 5000 cells/well in 96-well plates and exposed to different concentrations (0.1–3.16 μmol/mL) for 24 h. Absorbance was measured at 575 nm using a microplate reader.

Results:

Salt 2 exhibited a half-maximal inhibitory concentration (IC₅₀) of 0.381 μmol/mL, which was comparable to the reference drug cisplatin (0.358 μmol/mL). In contrast, salt 1 showed a higher IC₅₀ value of 1.419 μmol/mL, indicating lower potency.

Conclusions:

Both compounds demonstrated cytotoxic activity against A549 cells, with salt 2 displaying a stronger effect like cisplatin. These findings suggest that salt 2 could be considered a promising candidate for further development as an anticancer agent targeting NSCLC.

Introduction:
Propolis, a resinous material collected by honeybees from plant exudates, possesses strong antimicrobial properties. However, its composition and potency vary geographically. Despite extensive research, few studies have directly compared its antibacterial efficacy with standard antibiotics. This study aimed to evaluate the antibacterial activity of Iraqi propolis and compare it with Fucidin^® to assess its therapeutic potential.

Methods:
Propolis soft extract was obtained by maceration in 70% ethanol (1:10 w/v). Ethanolic extracts (5% and 10%) were prepared from the soft extract, and ointments (5%, 10%) were formulated with petroleum jelly, paraffin, wool fat, and stearyl alcohol. Physicochemical parameters (spreadability, viscosity, pH, stability) were evaluated. Antibacterial activity was assessed against S. aureus, S. epidermidis, E. coli, and P. aeruginosa using the Kirby–Bauer disk diffusion method, with Fucidin^® as control. MICs for Gram-positive isolates were estimated from inhibition zone diameters, and results were statistically analyzed (p < 0.05). GC–MS was employed to identify volatile constituents not typically detected by HPLC, contributing to the antibacterial profile of Iraqi propolis.

Results:
Both ointments showed semi-stiff consistency, pseudoplastic behavior, and a pH of 5, suitable for topical use. They remained stable at 25 °C for 90 days and at –20 °C and 40 °C for 30 days. The 5% extract produced inhibition zones of 25 ± 0.81 mm (S. aureus), 21 ± 0.81 mm (S. epidermidis), 13.33 ± 1.24 mm (E. coli), and 12.75 ± 0.54 mm (P. aeruginosa), surpassing Fucidin^® against Gram-negatives (p < 0.001) and showing comparable efficacy for Gram-positives (p > 0.05). Ointments showed smaller inhibition zones (15–18 mm), MIC was 1% for Gram-positive isolates. GC–MS revealed 20 volatile compounds.

Conclusion:
Iraqi propolis demonstrated potent antibacterial activity comparable to Fucidin^®, with superior efficacy against Gram-negative bacteria. It represents a promising natural antimicrobial requiring further optimization and standardization.

The escalating global prevalence of diabetes, particularly type 2 diabetes, underscores the urgency of developing novel therapeutic strategies. One such approach is the inhibition of α-glucosidase, an enzyme crucial in the breakdown of carbohydrates, thus influencing postprandial blood glucose levels. This study aimed to investigate the inhibitory effect of Barteria nigritana green-synthesized zinc oxide on α-glycosidase, a key enzyme implicated in the progression of diabetes. The phytochemicals present in the compound were determined using standard procedures to achieve this aim. The chemical composition of the synthesized BNZnONPs was characterized using GC-FID analysis. Molecular interaction of all the identified compounds with a-glucosidase was appraised via the Glide XP-docking panel of Schrodinger suite v12.4, while the Adsorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) prediction of the best-fit compounds was made using the SwissADME search engine. Furthermore, in vitro analysis of the α-glucosidase inhibitory activity of B. nigritiana zinc nanoparticles was investigated using a conventional method. The GC-FID screening identified twenty compounds with highest abundance of Catechol, (+)-Pinoresinol, Pyrogallol, Picric acid, Flavanone, 2, Hydroxyl phenol, and Assculetin (50.4, 32.2, 9.3, 7.9, 7.8, and 7.0 ppm respectively) and the compounds with the low concentrations were Resveratrol, Phloroglucinol, Phenetole, Alpha naphthol and 3,4-Hydroxyl toluene (2.4, 2.0, 2.3, 2.2 and 2.2 ppm, respectively). Among the identified compounds, resveratrol, 2-hydroxylphenol, 2, 3-dihydroxylphenol, α-naphthol, and flavonones demonstrated the highest interaction with α-glucosidase, recording docking scores of -7.763, -7.025, -7.018, 6.778, and -6.714 Kcal/mol, respectively. These compounds interacted predominantly with amino acid residues within and around the α-glucosidase active site, using hydrogen bonding. The ADMET properties indicate that 2-hydroxyphenol, 3,4-hydroxyphenol, α-naphthol, and flavonones exhibit favorable drug-likeness, pharmacokinetic properties, and a good safety profile. Interestingly, the nanoparticles demonstrated a very good inhibitory action against α-glucosidase with 1C50 values of 4.22µg/mL. Thus, B. nigritina phytochemicals are promising potential targets for the treatment and development of an anti-diabetic drug.

Introduction: Asthma is a chronic, inflammatory respiratory disease affecting millions worldwide, with increasing prevalence and substantial economic impact projected by 2050. Central to asthma pathogenesis are airway remodeling and inflammation, processes in which Plasminogen Activator Inhibitor-1 (PAI-1) acts as a major contributor by promoting extracellular matrix accumulation and fibrosis. Anthocyanins exhibit strong antioxidant and anti-inflammatory activities; however, their effects on airway remodelling have not been studied to date.

Methods : This study investigated the anti-inflammatory potential of New Zealand Blackcurrant (NZBC) anthocyanins in BEAS-2B bronchial epithelial cells. BEAS-2B cells' viability was assessed using the Methyl Thiazolyl Tetrazolium (MTT) assay to determine a non-cytotoxic concentration. Cells were pretreated with NZBC anthocyanins prior to TNF-α stimulation and then PAI-1 levels were quantified using ELISA.

Results: MTT assay revealed significant cytotoxicity at concentrations above 50 µg/mL, confirming 50 µg/mL as a safe dose for further analysis. Pretreatment with NZBC anthocyanins significantly reduced PAI-1 levels in TNF-α–stimulated cells (Control: 28,958 ±â€¯2,485 vs. ACN: 14,360 ±â€¯1,148; n = 3), as measured by ELISA.

Conclusion: These findings suggest a protective effect against the pro-fibrotic state. The outcomes underscore the therapeutic potential of anthocyanins as adjunctive agents in asthma therapy, particularly in targeting oxidative stress and airway remodeling pathways. Further studies are warranted to explore their clinical relevance and therapeutic efficacy.