Optimization of 2,3-dihydrophthalazine-1,4-dione PARP inhibitor scaffold for nanomolar potency and specificity towards human PARP10.

PARP10 is a potential drug target due to its overexpression in several cancer types and its roles in DNA repair mechanisms and tumorigenesis. In this study, we performed an optimization campaign on our earlier compounds based on a 2,3-dihydrophthalazine-1,4-dione scaffold which emerged with dual PARP10 and PARP15 inhibitory activity. The specific aim was to improve the potency and selectivity towards PARP10.

Fluoromethylcarnitine, a novel inhibitor of trimethylamine levels in trimethylaminuria and trimethylamine N-oxide related disorders.

Excessive production of trimethylamine (TMA) by the gut microbiota leads to increased concentrations of TMA or trimethylamine N-oxide (TMAO) in the bloodstream, which is associated with health risks. High levels of TMAO have been linked to cardiovascular disease, inflammation and other health problems. In addition, people affected by a genetic deficiency of the liver enzyme FMO3, which oxidises TMA to TMAO, suffer from trimethylaminuria (TMAU), a rare disorder caused by mutations in the Fmo3 gene, in which the body odour resembles that of rotting fish, leading to significant discomfort and social isolation.

Harnessing prebiotic formamide chemistry: a novel platform for antiviral exploration.

Viruses and host cells are intricately connected through a shared "chemical language" that may trace back to the prebiotic chemistry of early Earth. In this study, we present an innovative platform for antiviral exploration inspired by this primordial chemical framework. By "doping" the formamide-based prebiotic chemistry model with orotic acid derivatives, we generated complex, non-natural chemical mixtures capable of disrupting the replication of multiple viruses with minimal or no toxicity for eukaryotic cells.

Investigating the potential of the SI306 Src inhibitor and its liposomal formulation in the non-small cell lung cancer treatment.

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and a cause of cancer-related death, characterized by poor survival outcomes. Significant progress has been made in developing new targeted therapies, including the use of tyrosine kinase inhibitors, which have shown promise in improving patient prognosis. This study focuses on SI306, a small competitive inhibitor of the c-Src tyrosine kinase and a promising anticancer agent, along with its liposomal formulation (Lipo-SI306), in the treatment of NSCLC.

Evaluation of Antitumoral Activity in a 3D Cell Model of a Src Inhibitor Prodrug for Glioblastoma Treatment.

: Three-dimensional (3D) cell models may bridge the gap between two-dimensional (2D) cell cultures and animal models. Technical advances have led to the development of 3D-bioprinted cell models, characterized by greater reproducibility and the ability to mimic in vivo conditions. Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with poor clinical outcomes due to its heterogeneity, angiogenic activity, and invasiveness.

Discovery of reversible monoacylglycerol lipase (MAGL) inhibitors based on ortho-hydroxyanilide scaffold.

Monoacylglycerol lipase (MAGL) represents a key enzyme in the regulation of the endocannabinoid system and arachidonic acid signaling, emerging as a promising target for the treatment of inflammation, neurodegeneration, and cancer. Herein, we report the design, synthesis, and biological evaluation of a novel series of o-hydroxyanilide derivatives as reversible MAGL inhibitors. Starting from a known salicylketoxime scaffold, we introduced strategic modifications to reduce lipophilicity and enhance selectivity and potency.

Deciphering the landscape of allosteric glutaminase 1 inhibitors as anticancer agents.

Glutamine is the second most utilised energy source after glucose for cancer cells to support their proliferation and survival. Glutaminase 1 (GLS1) is the rate-limiting enzyme during the glutaminolysis pathway and thus represents a promising therapeutic target for the development of innovative antitumor agents. Two main classes of GLS1 inhibitors, based on their different binding mode, are reported: the substrate active site and the allosteric site inhibitors.

Insects as Source of Nutraceuticals with Antioxidant, Antihypertensive, and Antidiabetic Properties: Focus on the Species Approved in Europe up to 2024.

Insects represent a traditional food in different parts of the world, where eating insects is not only related to nutrition, but also results from a variety of sociocultural customs. Insects' nutritional profiles typically vary by species. Nevertheless, in terms of nutrition, edible insects can be a rich source of protein, dietary fiber, healthy fatty acids, and micronutrients, including minerals and vitamins.

Light-mediated activation/deactivation control and in vitro ADME-Tox profiling of a donepezil-like Dual AChE/MAO-B Inhibitor.

The possibility to control the effects of drugs in time and space represents an ideal condition for developing safer and more personalized therapies against different disorders. In this context, photopharmacology has paved the way for the use of light in the modulation of drugs activity. Our interest is directed to photo-switchable molecules, capable of interconverting between two different isoforms upon light irradiation.

Exploitation of the Nutraceutical Potential of the Infesting Seaweed as a Yellow Mealworms' Feed: Focus on Nutrients and Antioxidant Activity.

According to the Sustainable Blue Economy Communication, the Farm to Fork Strategy, and the European Green Deal, novel business models supporting the use of resources from oceans and seas are of primary importance. Interestingly, several infesting seaweeds are consumed as foods in Asia and are fundamental ingredients in several traditional dishes. Herein, according to the circular economy approach, we investigate the use of (CL) as a larvae feed in different percentages: 20%, 50%, and 100%, respectively.

Upcycling Milk Industry Byproducts into Larvae: Investigation on Fat, Protein, and Sugar Composition.

Edible insects represent a growing sector of the food industry and have a low carbon footprint. Noteworthy, insects can upcycle different leftovers and byproducts into high-quality nutrients. Herein, the larvae of the edible insect (TML) were fed using local milk industry byproducts.

Inhibition of Carbonic Anhydrases, Exploring Ciprofloxacin Functionalization Toward New Antibacterial Agents: An In-Depth Multidisciplinary Study.

Ciprofloxacin (CPX) is one of the most employed antibiotics in clinics to date. However, the rise of drug-resistant bacteria is dramatically impairing its efficacy, especially against life-threatening pathogens, such as . This Gram-negative bacterium is an opportunistic pathogen, often infecting immuno-compromised patients with severe or fatal outcomes.

Applying molecular hybridization to design a new class of pyrazolo[3,4-d]pyrimidines as Src inhibitors active in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of liver solid tumor and the second leading cause of cancer-related deaths worldwide. Although new treatment options have been recently approved, the development of tumor resistance and the poor prognosis for advanced HCC make the current standard of care unsatisfying. In this scenario, the non-receptor tyrosine kinase (TK) c-Src emerged as a promising target for developing new anti-HCC agents.

Exploiting the bile acid binding protein as transporter of a Cholic Acid/Mirin bioconjugate for potential applications in liver cancer therapy.

Bioconjugation is one of the most promising strategies to improve drug delivery, especially in cancer therapy. Biomolecules such as bile acids (BAs) have been intensively explored as carriers, due to their peculiar physicochemical properties and biocompatibility. BAs trafficking is regulated by intracellular lipid-binding proteins and their transport in the liver can be studied using chicken liver Bile Acid-Binding Proteins (cL-BABPs) as a reference model.

Novel multitarget directed ligands inspired by riluzole: A serendipitous synthesis of substituted benzo[b][1,4]thiazepines potentially useful as neuroprotective agents.

Riluzole, the first clinically approved treatment for amyotrophic lateral sclerosis (ALS), represents a successful example of a drug endowed with a multimodal mechanism of action. In recent years, different series of riluzole-based compounds have been reported, including several agents acting as Multi-Target-Directed Ligands (MTLDs) endowed with neuroprotective effects. Aiming at identical twin structures inspired by riluzole (2a-c), a synthetic procedure was planned, but the reactivity of the system took a different path, leading to the serendipitous isolation of benzo[b][1,4]thiazepines 3a-c and expanded intermediates N-cyano-benzo[b][1,4]thiazepines 4a-c, which were fully characterized.

Optimization of potent, broad-spectrum, and specific anti-influenza compounds targeting RNA polymerase PA-PB1 heterodimerization.

Influenza viruses (IV) are single-stranded RNA viruses with a negative-sense genome and have the potential to cause pandemics. While vaccines exist for influenza, their protection is only partial. Additionally, there is only a limited number of approved anti-IV drugs, which are associated to emergence of drug resistance.

Infesting Seaweeds as a Novel Functional Food: Analysis of Nutrients, Antioxidants and ACE Inhibitory Effects.

Globalization and climate change are both contributing to an increase in the number of potentially invasive algae in coastal areas. In terms of biodiversity and financial losses, the invasiveness of algae has become a significant issue in Orbetello Lagoon. Indeed, studies from the Tuscany Regional Agency for Environmental Protection show that the reduction in dissolved oxygen caused by algal diffusion is detrimental to fisheries and biodiversity.

Phytochemical Composition, Anti-Inflammatory Property, and Anti-Atopic Effect of Extract.

Utilizing plant-based resources, particularly their by-products, aligns with sustainability principles and circular bioeconomy, contributing to environmental preservation. The therapeutic potential of plant extracts is garnering increasing interest, and this study aimed to demonstrate promising outcomes from an extract obtained from an underutilized plant waste. , an invasive macroalga found in the Orbetello Lagoon, thrives in eutrophic conditions, forming persistent mats covering approximately 400 hectares since 2005.

Serendipitous Identification of Azine Anticancer Agents Using a Privileged Scaffold Morphing Strategy.

The use of privileged scaffolds as a starting point for the construction of libraries of bioactive compounds is a widely used strategy in drug discovery and development. Scaffold decoration, morphing and hopping are additional techniques that enable the modification of the chosen privileged framework and better explore the chemical space around it. In this study, two series of highly functionalized pyrimidine and pyridine derivatives were synthesized using a scaffold morphing approach consisting of triazine compounds obtained previously as antiviral agents.

An update on antibacterial AlkylGuanidino Ureas: Design of new derivatives, synergism with colistin and data analysis of the whole library.

Antimicrobial resistance (AMR) represents one of the most challenging global Public Health issues, with an alarmingly increasing rate of attributable mortality. This scenario highlights the urgent need for innovative medicinal strategies showing activity on resistant isolates (especially, carbapenem-resistant Gram-negative bacteria, methicillin-resistant S. aureus, and vancomycin-resistant enterococci) yielding new approaches for the treatment of bacterial infections.

A Drug Discovery Approach to a Reveal Novel Antioxidant Natural Source: The Case of Chestnut Burr Biomass.

Currently, many environmental and energy-related problems are threatening the future of our planet. In October 2022, the Worldmeter recorded the world population as 7.9 billion people, estimating that there will be an increase of 2 billion by 2057.

Identification of Novel Non-Nucleoside Inhibitors of Zika Virus NS5 Protein Targeting MTase Activity.

Zika virus (ZIKV) is a positive-sense single-stranded virus member of the family. Among other arboviruses, ZIKV can cause neurological disorders such as Guillain Barré syndrome, and it can have congenital neurological manifestations and affect fertility. ZIKV nonstructural protein 5 (NS5) is essential for viral replication and limiting host immune detection.

Early investigation of a novel SI306 theranostic prodrug for glioblastoma treatment.

Glioblastoma multiforme (GBM) is one of the most aggressive malignancies with a high recurrence rate and poor prognosis. Theranostic, combining therapeutic and diagnostic approaches, arises as a successful strategy to improve patient outcomes through personalized medicine. Src is a non-receptor tyrosine kinase (nRTK) whose involvement in GBM has been extensively demonstrated.

Sweet Cherry Extract as Permeation Enhancer of Tyrosine Kinase Inhibitors: A Promising Prospective for Future Oral Anticancer Therapies.

Although patients would rather oral therapies to injections, the gastrointestinal tract's low permeability makes this method limiting for most compounds, including anticancer drugs. Due to their low bioavailability, oral antitumor therapies suffer from significant variability in pharmacokinetics and efficacy. The improvement of their pharmacokinetic profiles can be achieved by a new approach: the use of natural extracts enriched with polyphenolic compounds that act as intestinal permeability enhancers.