Introduction

Alzheimer's Disease (AD) is a neurodegenerative illness causing severe cognitive decline, personality changes, and psychological issues, with over 10 million new cases per year which are expected to double by 2036. The most widely prescribed drug to treat symptoms of AD is the cholinesterase inhibitor donepezil, first approved in the US in 1996. Donepezil's activity comes largely from its nitrogen-containing heterocyclic piperidine structure. The piperidine ring appears frequently in other compounds targeting AD and has prompted AD research into piperidine containing derivatives.

Method

In this work, computer-aided drug design (CADD) was used to virtually screen a library of 32 piperidine-containing molecules derived from a lead against co-crystallized human acetylcholinesterase (AChE) and human butyrylcholinesterase (BuChE). Based on docking scores and detailed 2D and 3D interactions with the target, the top eight derivatives were synthesized via N-alkylation reaction, and confirmed with 1H-NMR and EI-MS. Their action on AChE and BuChE was determined via enzyme inhibition assay using Ellman’s method.

Result

The IC50 values of four derivatives showed significant action against both enzymes (MA13 [AChE IC50=69.2 µM; BuChE IC50=19.5 µM], MA29 [21.4; 13.2 µM], MA31 [20.4; 18.5 µM], MA32 [29.6; 23.5 µM]), while 2 within this group showed particularly strong inhibitory action against BuChE when compared with donepezil (MA29, MA31).

Conclusion

Overall, these results reveal new scaffolds with promising anti-Alzheimer’s potential, including two candidates that show particularly strong activity against BuChE. Further development of these molecules may yield viable candidates for next-generation therapeutics, providing new opportunities to slow or lessen the progression of AD.

Introduction: The unfolded protein response (UPR), a critical pathway managing endoplasmic reticulum (ER) stress, could be hijacked by malignant cancer cells to promote survival, angiogenesis, and metastasis. Its central sensor, IRE1α, has emerged as a key regulator of cancer cell adaptation and therapeutic resistance. Prostate cancer, the most common malignancy in European men, remains a significant clinical challenge, particularly upon progression to therapy-refractory forms, highlighting the urgent need for novel therapeutic strategies. Pharmacological modulation of IRE1α signaling offers a promising avenue to disrupt cancer cell homeostasis and enhance treatment efficacy.

Methods: In this work, we designed and synthesized a novel series of twelve benzenesulfonamide derivatives (APS) featuring a polynitrogen scaffold, with the goal of targeting the UPR. The compounds’ cytotoxic potential was determined in the DU‑145 prostate cancer cells by XTT assay after 24 and 48 hours of exposure.

Results: The screening identified two lead compounds with distinct activity profiles. APS 600 was the most potent agent at 24 hours (IC₅₀ = 10.23 µM), while APS 597 demonstrated superior activity after 48 hours (IC₅₀ = 14.67 µM). A preliminary structure-activity relationship analysis suggests that the cytotoxic effect could be influenced by the substitution pattern of the 1,2,4-triazole moiety.

Conclusions: These findings designate APS 597 and APS 600 as valuable lead candidates warranting continued development. The study provides compelling support for mechanistic follow‑up to determine their mode of action within IRE1α‑regulated signaling pathways. Further refinement of this scaffold has the potential to generate highly selective ER stress modulators with improved therapeutic specificity and reduced off‑target toxicity.

Deep mycoses are a type of fungal infection considered a neglected tropical disease by the World Health Organization (WHO), affecting at least hundreds of thousands of people around the world. While there are treatments for fungal diseases, the rise of antifungal resistance urges the research of novel antifungal agents. This study aims to discover new molecules from natural products and repurpose clinically evaluated drugs that present potential antifungal activity against deep mycoses pathogens, through the construction and deployment of machine learning models based on multitarget quantitative structure-activity relationships (QSAR). Using experimental IC50 data from the ChEMBL database, 40 machine learning algorithms were tested, and the 5 best performing algorithms (Bagging, Gradient Boosting, LightGBM, Random Forest, XGBoost) were used to predict the antifungal activity of nearly 460,000 compounds from natural products as well as repurposing databases . This analysis resulted in the selection of 57 compounds considered active by consensus of the 5 models, including beta-lactams, griseofulvin derivatives and peptides, as well as standard antifungal drugs, such as amphotericin B and Nystatin, demonstrating the capability of the models to identify antifungal activity. Furthermore, the calculaton of SHAP values provided mechanistic insight, confirming that the models' predictions were driven by molecular substructures characteristic of established antifungal agents. This study highlights potential antifungal agent candidates, both novel and repurposed, warranting further in silico, in vitro, and in vivo studies.

Neutral endopeptidase (NEP or neprilysin) is a key enzyme associated with the metabolic inactivation of numerous bioactive natriuretic peptides (NP). Among these, bradykinin, endothelin, angiotensin II, amyloid β protein, substance P and glucagon-like peptide 1 (GLP-1) are the key NPs that affect the heart, kidney, and other organs. Among these, GLP-1, an essential simulator of insulin secretion, is frequently found to be impaired or downregulated in the case of diabetes, particularly type 2 diabetes. The level of GLP-1 is also diminished by another serine protease, Dipeptidyl peptidase-4 (DPP-4). Utilizing this concept of NEP and DPP-4 in orchestrating the degradation of the GLP-1 level and consequently affecting the type 2 diabetes outcome, we developed dual NEP/DPP-4 inhibitors that could offer an alternative regimen for treating type 2 diabetes.

In the present study, we have developed a machine learning (ML) based prediction model considering the pharmacophoric features of both NEP and DPP-4. The model was tested against an array of in-house developed and newly designed and synthesized NCEs as training sets with the reported inhibitors against the enzyme. The work was further validated and standardized with molecular docking and dynamics studies and corroborated with numerous biological studies. The cumulative analysis yielded 1a and 1f as the best lead molecules with potent dual inhibition of NEP and DPP-4 with anti-diabetic potential.

The ionic liquid methyl imidazolium ethyl amine (MIE-NH₂) and its derivatives display a new role of modification of glycoproteins and oligosaccharides through a reductive amination mechanism for synthesizing versatile pharmaceuticals. This work focuses on the green processing of synthesis of the small molecules-ionic liquid (O-GLc-SMol-ILs), to be good applicable materials with significant bioactive properties as potential drugs anticancer. The MIE-NH₂ ionic liquids derivatives as intermediates for derivatization reaction with oligosaccharides in aqueous solution, which the new provide of oligosaccharides-ionic liquid enhancing its identification. The characterization and identification of small molecules ionic liquids linked to oligo- saccharides by LCMS, GCMS, NMR, UV-vis spectrophotometer. Bio-assay in vitro is the major aim promoted of this research. The evaluation of biologically active products is a significant challenge of these achievements and investigation. Using chemometric-modelling DFT-calculation for enhancing the interaction and SAR results. Particularly, the modified products (O-GLc-SMol-ILs) a small molecules is synthesized as anticancer activity, protein kinase B selected as a good target for interaction. New binding to protein kinase B was investigated through molecular docking to dig out their probable anticancer activity. All the products found with an exhibited the highest binding and potential inhibiting. This work will extend to study the potential effectiveness of (O-GLc-SMol-ILs) with liver cancer involving specific HepG2 cell lines via antproliferative activity and autophagy candidate genes.

Chikungunya fever is an arboviral disease that manifests as an acute illness, whose symptoms include fever, rash, and severe, debilitating arthralgia. Despite its low mortality rate, the disease can present severe forms, especially in at-risk groups such as neonates, the elderly, and individuals with comorbidities. In the search for new drugs to treat the disease, our group has been exploring N-acylhydrazone as a privileged structure in medicinal chemistry. Quinolines and their chemical derivatives have been assayed against a diverse panel of viruses with promising results. In this project, we hybridised the N-acylhydrazone with the 7-Chloroquinoline ring to produce a series of 33 compounds, which were synthesised, purified and subjected to antiviral activity assays to determine their Half Maximal Effective Concentration (EC₅₀) against the virus and the Cytotoxic Concentrations 50% (CC₅₀) against the host cells (Dose-response curves with 10 dilution points). Three compound exhibited EC₅₀ values lower than 10 µM: GPQF-8Q33 (EC_50: 0.56 µM; SI: 77.7), GPQF-8Q28 (EC₅₀: 1.26 µM; SI: 79.4) and GPQF-8Q34 (EC₅₀: 9.08 µM; SI: 40). These compounds were in silico docked into the NsP2 protease, a potential target of the virus and exhibited a panel of interaction consistent with molecular recognition. Molecular dynamics simulation corroborates the stability of the complexes as well as indicates which interactions are mostly predominant in recognition binding. Synthesis was accomplished by simple coupling of aldehydes with quinoline-hydrazines, in mild conditions (EtOH/AcOH, 80ºC, 24h). Docking studies were performed after a cross-docking assay, using Autodock software and considering a GRID centred at Trp1084 and with dimensions of 54x54x54 points. Molecular dynamics simulation of 400 ns was performed at 300ºC, considering steps of 1 fs each. Chamm-gui web-based software and Gromacs were employed in these studies.

Alzheimer’s disease (AD) remains one of the most difficult neurological disorders to manage, largely because existing treatments provide only modest benefit and most drug candidates fail to cross the blood–brain barrier (BBB) in effective amounts. DDL-920, a small molecule with neuroprotective activity, has shown encouraging preclinical effects, including a 45% improvement in spatial memory and a 38% reduction in amyloid plaque burden in transgenic mouse models. However, its clinical application has been limited by very low aqueous solubility (<0.5 µg/mL), poor oral bioavailability (~12%), and minimal brain penetration (brain/plasma ratio <0.08). To overcome these challenges, aquasome-based nanocarriers were developed as delivery systems for DDL-920. The optimized formulation demonstrated favorable physicochemical characteristics, with a particle size of 152.3 ± 6.4 nm, zeta potential of –21.6 ± 2.3 mV, and an encapsulation efficiency of 82.4 ± 3.5%. In vitro release experiments confirmed a sustained drug profile, with 74% release at 48 h, along with a 12-fold improvement in solubility compared to the free drug. BBB transport studies in hCMEC/D3 cells indicated a 4.3-fold higher permeability for the aquasomes, and in vivo testing revealed greater brain accumulation (2.6 ± 0.4 µg/g vs. 0.5 ± 0.1 µg/g). Behavioral evaluations in AD mice further showed superior memory recovery, with 65% improvement versus 28% for the free drug. Overall, these findings support aquasome technology as a promising platform for enhancing the therapeutic potential of DDL-920 in Alzheimer’s disease.

Heterocyclic compounds containing the thiazolo[3,2-a]pyrimidine scaffold are of significant interest in medicinal chemistry due to their broad spectrum of biological activities. In recent years, this heterocyclic fragment has been shown to serve as a key structural unit for the development of new pharmacophores exhibiting antimicrobial, antibacterial, and anti-inflammatory properties. One effective strategy for modifying such molecules to improve their drug-like properties is the introduction of lipophilic fragments. The addition of a long-chain alkyl substituent, such as an n-dodecyl group, can significantly increase the compound's lipophilicity. This, in turn, facilitates better penetration through cellular membranes and enhances bioavailability, potentially amplifying the therapeutic effect.

Within the framework of this study, a four-step synthesis of novel O-dodecyloxybenzylidene derivatives of thiazolo[3,2-a]pyrimidine was designed and accomplished. The synthesis of the target compounds involved the following sequential stages:

1) Conducting a three-component Biginelli reaction to obtain the initial pyrimidinethione precursor.

2) Condensation of the resulting product with ethyl chloroacetate to form the thiazolo[3,2-a]pyrimidine core.

3) Knoevenagel condensation with para-hydroxybenzaldehyde, which introduced the benzylidene fragment and yielded the para-hydroxybenzylidene derivatives.

4) A key alkylation step via a Mitsunobu reaction with n-dodecyl alcohol, which allowed for the introduction of the lipophilic "tail" and afforded the target O-dodecyl derivatives.

The structure and high purity of all synthesized intermediate and final compounds were unambiguously confirmed by a comprehensive set of physicochemical analysis methods, including NMR spectroscopy (¹H and ¹³C), mass spectrometry, and IR spectroscopy.

The synthesized compounds were subjected to in vitro screening for antitumor activity against a panel of cancer cell lines, including M-HeLa, Hutu-80 and PC-3. It was demonstrated that the introduction of the n-dodecyl fragment indeed led to the emergence of biological activity. The obtained compounds exhibited moderate, yet statistically significant, cytotoxic activity against all tested cell lines.

Oncological diseases represent a major global health challenge and are the second leading cause of mortality. The discovery of novel chemotherapeutic agents with improved efficacy and safety profiles remains a critical objective in medicinal chemistry. In this pursuit, heterocyclic compounds serve as privileged structures in drug design. Isoxazole derivatives, in particular, are recognized as a prime scaffold due to their remarkable ability to interact with diverse biological targets, demonstrating a broad spectrum of pharmacological activities.

This work focuses on the design, synthesis, and biological evaluation of a new series of heterocyclic compounds incorporating the synthetically versatile pyrrolo[3,4-d]isoxazole framework. The synthesized novel derivatives were screened for their in vitro antiproliferative activity against three human cancer cell lines: cervical carcinoma (HeLa), erythroleukemia (K-562), and melanoma (Sk-mel-2). The results revealed that several adducts exhibited significant cytotoxic effects, with half-maximal inhibitory concentration (IC₅₀) values as potent as 15 μg/mL.

To gain insight into the potential mechanism of action, a confocal microscopy analysis was conducted. Treatment with the active compounds induced pronounced cytoskeletal alterations, specifically a diffuse redistribution of granular actin within the cytoplasm concomitant with the disappearance of structured actin filaments. A notable reduction in filopodia-like membrane protrusions was also observed. These findings collectively substantiate the promising antitumor potential of the synthesized pyrrolo[3,4-d]isoxazole derivatives, warranting further investigation into their therapeutic applications.

COVID-19 has caused over 7 million deaths worldwide. The virus binds to ACE2 receptors, and disease progression can trigger a cytokine storm, an intense inflammatory response linked to a higher mortality rate. Given the potential role of α7nAChR in modulating anti-inflammatory pathways, this study investigates its agonists and their interactions, integrating pharmacophore modeling for virtual screening of FDA-approved drugs. Initially, EVP-6124 was redocked into 7EKP to establish a docking protocol. Subsequently, the 7EKI model underwent a 100 ns MD simulation, followed by cluster analysis to identify the most representative conformation for docking EVP-6124. The best docking pose was then subjected to a 500 ns MD simulation until convergence. Pharmacophore models derived from representative conformations were validated using ROC curves, yielding scores above 0.8. These models guided the screening of FDA-approved compounds, with top candidates further evaluated via MD simulations. To do so, all results were docked using GOLD and evaluated with GoldScore, ChemScore, ChemPLP, and ASP scoring functions. For each function, 100 poses were generated and clustered within <2 Å. Representative clusters were rescored using GNINA, and the top-scoring pose was selected for MD simulation. While additional compounds remain under evaluation, this approach highlighted aclidinium as a potential ligand for α7nAChR, sustaining receptor interactions for up to 300 ns so far.