Search Results (259)

Poly(organo)phosphazenes (PPZs) are increasingly recognized as versatile biomaterials for drug delivery applications in nanomedicine. Their unique hybrid structure—featuring an inorganic backbone and highly tunable organic side chains—confers exceptional biocompatibility and adaptability. Through precise synthetic methodologies, PPZs can be engineered to exhibit a wide spectrum of functional properties, including the formation of multifunctional nanostructures tailored for specific therapeutic needs. These attributes enable PPZs to address several critical challenges associated with conventional drug delivery systems, such as poor pharmacokinetics and pharmacodynamics. By modulating solubility profiles, enhancing drug stability, enabling targeted delivery, and supporting controlled release, PPZs offer a robust platform for improving therapeutic efficacy and patient outcomes. This review explores the fundamental chemistry, biopharmaceutical characteristics, and biomedical applications of PPZs, particularly emphasizing their role in zero-dimensional nanotherapeutic systems, including various nanoparticle formulations. PPZ-based nanotherapeutics are further examined based on their drug-loading mechanisms, which include electrostatic complexation in polyelectrolytic systems, self-assembly in amphiphilic constructs, and covalent conjugation with active pharmaceutical agents. Together, these strategies underscore the potential of PPZs as a next-generation material for advanced drug delivery platforms. Full article

Efflux is one of the key mechanisms used by Gram-negative bacteria to reduce internal antibiotic concentrations. These active transport systems recognize and expel a wide range of toxic molecules, including antibiotics, thereby contributing to reduced antibiotic susceptibility and allowing the bacteria to acquire additional resistance mechanisms. To date, unlike other resistance mechanisms such as enzymatic modification or target mutations/masking, efflux is challenging to detect and counteract in clinical settings, and no standardized methods are currently available to diagnose or inhibit this mechanism effectively. This review first outlines the structural and functional features of major efflux pumps in Gram-negative bacteria and their role in antibiotic resistance. It then explores various strategies used to curb their activity, with a particular focus on efflux pump inhibitors under development, detailing their structural classes, modes of action, and pharmacological potential. We discuss the main obstacles to their development, including the structural complexity and substrate promiscuity of efflux mechanisms, the limitations of current screening methods, pharmacokinetic and tissue distribution issues, and the risk of off-target toxicity. Overcoming these multifactorial barriers is essential to the rational development of less efflux-prone antibiotics or of efflux pump inhibitors. Full article

Peroxisome proliferator-activated receptor alpha (PPARα) is a key regulator of lipid metabolism, making its agonists valuable therapeutic targets for various diseases, including chronic peripheral neuropathy. Existing PPARα agonists face limitations such as poor selectivity, sub-optimal bioavailability, and safety concerns. We previously demonstrated that A190, a novel, potent, and selective PPARα agonist, effectively alleviates chemotherapy-induced peripheral neuropathy and CFA-induced inflammatory pain as a non-opioid therapeutic agent. However, A190 alone has solubility and permeability issues that limits its oral delivery. To overcome this challenge, in this study, four new-generation ester prodrugs of A190; A190-PD-9 (methyl ester), A190-PD-14 (ethyl ester), A190-PD-154 (isopropyl ester), and A190-PD-60 (cyclic carbonate) were synthesized and evaluated for their enzymatic bioconversion and chemical stability. The lead candidate, A190-PD-60, was further formulated as a microemulsion (A190-PD-60-ME) and optimized via Box–Behnken design. A190-PD-60-ME featured nano-sized droplets (~120 nm), low polydispersity (PDI < 0.3), and high drug loading (>90%) with significant improvement in artificial membrane permeability. Crucially, pharmacokinetic evaluation in rats demonstrated that A190-PD-60-ME reached a 16.6-fold higher Cmax (439 ng/mL) and a 5.9-fold increase in relative oral bioavailability compared with an A190-PD-60 dispersion. These findings support the combined prodrug-microemulsion approach as a promising strategy to overcome oral bioavailability challenges and advance PPARα-targeted therapies. Full article

Background: During food processing and storage, traditional protein-based delivery systems encounter significant challenges in maintaining the structural and functional integrity of bioactive compounds, primarily due to their temporal instability. Methods: In this study, a nanocomposite hydrogel was prepared through the co-assembly of a self-assembling peptide, 9-Fluorenylmethoxycarbonyl-phenylalanine-arginine-glycine-aspartic acid-phenylalanine (Fmoc-FRGDF), and hyaluronic acid (HA). The stability of this hydrogel as a quercetin (Que) delivery carrier was systematically investigated. Furthermore, the impact of Que co-assembly on the microstructural evolution and physicochemical properties of the hydrogel was characterized. Concurrently, the encapsulation efficiency (EE%) and controlled release kinetics of Que were quantitatively evaluated. Results: The findings indicated that HA significantly reduced the storage modulus (G′) from 256.5 Pa for Fmoc-FRGDF to 21.1 Pa with the addition of 0.1 mg/mL HA. Despite this reduction, HA effectively slowed degradation rates; specifically, residue rates of 5.5% were observed for Fmoc-FRGDF alone compared to 14.1% with 0.5 mg/mL HA present. Notably, Que enhanced G′ within the ternary complex, increasing it from 256.5 Pa in Fmoc-FRGDF to an impressive 7527.0 Pa in the Que/HA/Fmoc-FRGDF hydrogel containing 0.1 mg/mL HA. The interactions among Que, HA, and Fmoc-FRGDF involved hydrogen bonding, electrostatic forces, and hydrophobic interactions; furthermore, the co-assembly process strengthened the β-sheet structure while significantly promoting supramolecular ordering. Interestingly, the release profile of Que adhered to the Korsmeyer–Peppas pharmacokinetic equations. Conclusions: Overall, this study examines the impact of polyphenol on the rheological properties, microstructural features, secondary structure conformation, and supramolecular ordering within peptide–polysaccharide–polyphenol ternary complexes, and the Fmoc-FRGDF/HA hydrogel system demonstrates a superior performance as a delivery vehicle for maintaining quercetin’s bioactivity, thereby establishing a multifunctional platform for bioactive agent encapsulation and controlled release. Full article

Epilepsy remains a major therapeutic challenge, with approximately one-third of patients experiencing drug-resistant epilepsy (DRE) despite the availability of multiple antiseizure medications (ASMs). This review aims to evaluate emerging ASMs—cenobamate, fenfluramine, ganaxolone, ezogabine (retigabine), and perampanel—with a focus on their mechanisms of action, pharmacological profiles, and potential role in precision medicine. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science to identify preclinical and clinical studies evaluating the pharmacodynamics, pharmacokinetics, efficacy, and safety of the selected ASMs. Relevant trials, reviews, and mechanistic studies were reviewed to synthesize the current understanding of their application in DRE and specific epilepsy syndromes. Each ASM demonstrated unique mechanisms targeting hyperexcitability, including the modulation of γ-aminobutyric acid receptor A (GABA-A) receptors, sodium and potassium channels, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptors), and serotonin systems. These mechanisms correspond with specific pathophysiological features in syndromes such as Dravet and Lennox–Gastaut. Evidence from clinical trials supports their use as adjunctive therapies with generally favorable tolerability, though adverse events and variable efficacy profiles were noted. The mechanistic diversity of these emerging ASMs supports their value in personalized epilepsy management, particularly in treatment-resistant cases. While the promise of precision medicine is evident, further studies are required to address challenges related to long-term safety, cost, and equitable access. Full article

SGLT2 inhibitors have become increasingly used due to their effectiveness in improving not only type 2 diabetes but also cardiovascular, renal and hepatic diseases, as well as the obesity found in metabolic syndrome. Starting from the structure of gliflozins, modifications of the carbohydrate part, aglycone, and also the glycosidic bond between them can determine variations in pharmacokinetic and pharmacodynamic properties. SGLT2 inhibitors, in addition to reducing blood glucose levels, improve alterations in lipid metabolism by diverting excessively accumulated lipids in tissues towards mobilization, lipolysis, β-oxidation, ketogenesis and the utilization of ketone bodies. This enhances anti-inflammatory properties by decreasing the levels of some proinflammatory mediators and by modulating some cell signaling pathways. Thus, in this review, the intimate mechanisms by which SGLT2 inhibitors achieve these therapeutic effects in the various conditions belonging to metabolic syndrome and beyond were described, along with the structure–effect relationship with some specific features of each gliflozin. Starting from these findings, further modeling of these molecules may lead to the creation of new therapeutic uses. Further research is needed to broaden the range of indications and also eliminate adverse effects, such as phenomena leading to lower limb amputations. Full article

In acute myeloid leukemia (AML) it is important to elucidate the biological events that lead from remission to relapse, which have a high probability of leading to an adverse disease outcome. The cancer stem cell marker aldehyde dehydrogenase 1 (ALDH1A1) is underexpressed in AML cells when compared to healthy cells, both at the RNA level and at the protein level, and at least in the former, both in the bone marrow and in peripheral blood. Nonetheless, ALDH1A1/ALDH1A2 activity increases in AML cells during disease relapse and is higher in adverse prognosis AML in comparison with favorable prognosis AML. Furthermore, especially in relapsed AML and in unfavorable AML, AML cells rich in ALDH1A1 can contain high levels of reactive oxygen species (ROS), in parallel with high ALDH1A1/2 activity. This metabolic feature is clearly incompatible with normal stem cells. The term “stem-like” therefore is useful to coin malignant cells with a variety of genetic makeups, metabolic programming and biomarkers that converge in the function of survival of clones sufficient to sustain, spread and re-establish neoplastic disease. Therefore, AML “stem-like” cells survive cancer treatment that eradicates other malignant cell clones. This fact differentiates AML “stem-like” cells from normal stem and progenitor cells that function in tissue regeneration as part of a distinct hierarchical order of cell phenotypes. The ODYSSEY clinical trial is a Phase I/II study designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ABD-3001, a novel therapeutic agent, in patients with AML who have relapsed or are refractory to standard treatments. In this context, ABD-3001 is used as an inhibitor of cytosolic ALDH1 enzymes, such as ALDH1A1 and ALDH1A2. Full article

Liposomes represent a cornerstone of modern drug delivery systems due to their unique structural and physicochemical characteristics. Extensive research has refined their formulation, stability, and targeting capabilities, leading to numerous clinical applications, particularly in oncology. A key clinical feature is their ability to accumulate in malignant tissues via the enhanced permeability and retention effect, offering improved pharmacokinetics and reduced systemic toxicity. Advances in liposomal engineering, including PEGylation and ligand-based targeting, have significantly enhanced pharmacokinetic profiles and tissue specificity, minimizing off-target toxicity. The modern approach to nanocarrier-based drugs offers multidirectional perspectives on targeted therapy. Liposomes can bypass drug resistance mechanisms and provide controlled or stimuli-responsive drug release. Current trends in liposome research focus on hybrid nanocarriers, personalized medicine applications, and combination therapies. Full article

Background: The benzamide MMV030666 from MMV’s Malaria Box Project, the starting point of herein presented study, was initially tested against various Plasmodium falciparum strains as well as Gram-positive and Gram-negative bacteria. It exhibits multi-stage antiplasmodial potencies and lacks resistance development. Methods: The favorable structural features from previous series were kept while the influence of the N-Boc-piperazinyl substituent per se, as well as its ring position and its replacement by various heteroaromatic rings, was evaluated. Thus, this paper describes the preparation of the MMV030666-derived 4′-(piperazin-1-yl)benzanilides for the first time, exhibiting broad-spectrum activity not only against plasmodia but also various bacterial strains. Results: A series of insightful structure–activity relationships were determined. Furthermore, pharmacokinetic and physicochemical parameters of the new compounds were determined experimentally or in silico. Drug-likeliness according to Lipinski’s rules was calculated as well. Conclusions: A diarylthioether derivative of the lead compound was promisingly active against P. falciparum and exhibited broad-spectrum antibacterial activity against Gram-positive as well as Gram-negative bacteria. It is considered for testing against multi-resistant bacterial strains and in vivo studies. Full article

The SARS-CoV-2 main protease (Mpro) is a validated therapeutic target for inhibiting viral replication. Few compounds have advanced clinically, underscoring the difficulty in optimizing both target affinity and drug-like properties. To address this challenge, we integrated machine learning (ML), molecular docking, and molecular dynamics (MD) simulations to investigate the balance between pharmacodynamic (PD) and pharmacokinetic (PK) properties in Mpro inhibitor design. We developed ML models to classify Mpro inhibitors based on experimental IC₅₀ data, combining molecular descriptors with structural insights from MD simulations. Our Support Vector Machine (SVM) model achieved strong performance (training accuracy = 0.84, ROC AUC = 0.91; test accuracy = 0.79, ROC AUC = 0.86), while our Logistic Regression model (training accuracy = 0.78, ROC AUC = 0.85; test accuracy = 0.76, ROC AUC = 0.83). Notably, PK descriptors often exhibited opposing trends to binding affinity: hydrophilic features enhanced binding affinity but compromised PK properties, whereas hydrogen bonding, hydrophobic, and π–π interactions in Mpro subsites S2 and S3/S4 are fundamental for binding affinity. Our findings highlight the need for a balanced approach in Mpro inhibitor design, strategically targeting these subsites may balance PD and PK properties. For the first time, we demonstrate antagonistic trends between pharmacokinetic (PK) and pharmacodynamic (PD) features through the integrated application of ML/MD. This study provides a computational framework for rational Mpro inhibitors, combining ML and MD to investigate the complex interplay between enzyme inhibition and drug likeness. These insights may guide the hit-to-lead optimization of the novel next-generation Mpro inhibitors of SARS-CoV-2 with preclinical and clinical potential. Full article

Cancer remains a major global public health concern, driving the need for innovative therapeutic agents with intensified efficacy and safety. Growth factor receptors (GFRs), often overexpressed in cancer cells and critical in regulating cell proliferation, survival, and tumor progression, represent key targets for cancer therapy. Halophytic plants like Salicornia spp. are known for their diverse bioactive compounds with notable pharmacological properties. This study comprehensively evaluated the anti-cancer potentials of phytochemicals derived from Salicornia herbacea and Salicornia brachiata using molecular docking and ADME-Tox (absorption, distribution, metabolism, excretion, and toxicity) profiling. A total of 37 bioactive compounds from Salicornia spp. were screened against HER1, HER2, and HER4 receptors. Among them, 3,5-di-O-caffeoylquinic acid, 3-O-caffeoylquinic acid, myricetin, quercetin, stigmasterol, kaempferol, isorhamnetin, rhamnetin, and hesperitin featured strong predicted binding affinities to the HER1, HER2, and HER4 growth factor receptors, comparable to those of standard anti-cancer drugs such as gefitinib and dovitinib. Further pharmacokinetic assessments, including bioavailability and toxicity analyses, identified compounds with favorable drug-likeness properties and minimal toxicity risks, except for myricetin and quercetin. These findings underscore the potential of Salicornia-derived phytochemicals as promising candidates for the development of safe, novel, and effective anti-cancer agents targeting GFRs, contributing to the advances in precision oncology, pending further validation through in vitro and/or in vivo experiments. Full article

L-3-[¹⁸F]-fluoro-α-methyl tyrosine ([¹⁸F]FAMT) is an amino acid positron emission tomography (PET) tracer with high specificity for malignant tumors through its selective transport via L-type amino acid transporter (LAT) 1. Although extensively studied for its diagnostic performance, a comprehensive review of its molecular and clinical characteristics remains lacking. A systematic literature review (1997–2025) was conducted using PubMed and Web of Science, with keywords including “L-3-[¹⁸F]-fluoro-α-methyl tyrosine”, “[¹⁸F]FAMT”, “amino acid PET”, and “tumor imaging”. The review covered aspects of synthesis, structural properties, pharmacokinetics, and clinical applications. Notably, while research on [¹⁸F]FAMT has declined significantly in recent years, [¹⁸F]FAMT PET demonstrates superior specificity to [¹⁸F]FDG PET in distinguishing malignancies from inflammatory lesions and offers distinct advantages in lung, esophageal, and oral cancers, though with slightly lower sensitivity. Its key features include tumor-specific uptake patterns, rapid blood clearance, and a significant correlation between its uptake levels and both LAT1 expression and tumor proliferation. In conclusion, [¹⁸F]FAMT is a promising PET tracer with notable advantages in tumor imaging, particularly due to its LAT1 selectivity and favorable pharmacokinetics. Despite challenges in production, these characteristics underscore its clinical value in cancers requiring precise imaging. Future research should focus on optimizing synthesis, expanding clinical validation, and exploring theranostic applications. Full article

Disulfiram (DSF), a well-known anti-alcoholism drug, exhibits potent anticancer activity via its metabolite, diethyldithiocarbamate (DDC), which forms a cytotoxic copper complex that selectively targets cancer stem cells. However, its clinical utility is limited by poor solubility and rapid plasma metabolism. This study explores saccharide-linked DDCs as novel prodrugs designed to enhance stability, solubility, and tumour-selective activation. These compounds feature thioglycosidic bonds that shield the DDC moiety from premature degradation while retaining its metal-chelating function to form the active copper(II)bis(N,N-diethyldithiocarbamate) (Cu(DDC)₂) complex. The synthesised derivatives were characterised and evaluated for serum stability and in vitro cytotoxicity across several cancer cell lines, including colorectal, breast, lung, and brain cancers. Copper-complexed saccharide-DDC prodrugs demonstrated remarkable cytotoxicity, with improved biostability and solubility profiles. These findings highlight the potential of saccharide-linked DDCs as stable, copper-activated prodrugs for cancer therapy. Further in vivo studies are warranted to validate their pharmacokinetics and clinical relevance. Full article

Antioxidants, such as stilbenes, anthocyanidins, coumarins, tannins and flavonoids, are often based on oxygen-containing redox systems and tend to feature several hydroxyl groups in their chemical structures. From a synthetic perspective, oxygen atoms are prone to bioisosteric replacement with sulfur and, notably, selenium. The main objective of this narrative literature review is to explore if and how bioisosteric substitution of oxygen with sulfur or selenium can enhance the biological activity of natural products. This replacement boosts the biological activity of the resulting molecules considerably as they now combine the redox and antioxidant properties of the original flavonoids and other natural products with the specific redox behavior of sulfur and selenium. Besides sequestering free radicals and peroxides, they may, for instance, also catalyze the removal of oxidative stressors, capture free metal ions and even provide scope for selenium supplementation. Since these molecules resemble their natural counterparts, they also exhibit considerable selectivity inside the body and a good pharmacokinetic profile. Still, the synthesis of such hybrid molecules integrating sulfur and selenium into flavonoids and other natural products is a challenge and requires innovative synthetic strategies and approaches. Full article

Background/Objectives: Glycogen synthase kinase-3 beta (GSK3β) is a key enzyme involved in neurodegenerative diseases such as Alzheimer’s and Parkinson’s, contributing to tau hyperphosphorylation, amyloid-beta (Aβ) aggregation, and neuronal dysfunction. Methods: This study applied a machine learning-driven virtual screening approach to identify potent natural inhibitors of GSK3β. A dataset of 3092 natural compounds was analyzed using Support Vector Machine (SVM), Random Forest (RF), and K-Nearest Neighbors (KNN), with feature selection focusing on key molecular descriptors, including lipophilicity (ALogP: −0.5 to 5.0), hydrogen bond acceptors (0–10), and McGowan volume (0.5–2.5). RF outperformed SVM and KNN, achieving the highest test accuracy (83.6%), specificity (87%), and lowest RMSE (0.3214). Results: Virtual screening using AutoDock Vina and molecular dynamics simulations (100 ns, GROMACS 2022) identified artemisinin as the top GSK3β inhibitor, with a binding affinity of −8.6 kcal/mol, interacting with key residues ASP200, CYS199, and LEU188. Dihydroartemisinin exhibited a binding affinity of −8.3 kcal/mol, reinforcing its neuroprotective potential. Pharmacokinetic predictions confirmed favorable drug-likeness (TPSA: 26.3–70.67 Ų) and non-toxicity. Conclusions: While these findings highlight artemisinin-based inhibitors as promising candidates, experimental validation and structural optimization are needed for clinical application. This study demonstrates the effectiveness of machine learning and computational screening in accelerating neurodegenerative drug discovery. Full article