Spirotetrahydroisoquinoline-Based Histone Deacetylase Inhibitors as New Antifibrotic Agents: Biological Evaluation in Human Fibroblasts from Bronchoalveolar Lavages of Idiopathic Pulmonary Fibrosis Patients.

Idiopathic pulmonary fibrosis (IPF) is a rare interstitial lung disease typified by a progressive fibrosing phenotype. IPF has been associated with aberrant HDAC activity, particularly HDAC6. Combining synthetic and modeling studies, a new family of spirotetrahydroisoquinoline-capped histone deacetylase inhibitors - was developed.

Synthesis and biological investigation of peptidomimetic SARS-CoV-2 main protease inhibitors bearing quinoline-based heterocycles at P.

In the last few years, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been the cause of a worldwide pandemic, highlighting the need for novel antiviral agents. The main protease (M) of SARS-CoV-2 was immediately identified as a crucial enzyme for viral replication and has been validated as a drug target. Here, we present the design and synthesis of peptidomimetic M covalent inhibitors characterized by quinoline-based P moieties.

Targeting N-Methyl-lysine Histone Demethylase KDM4 in Cancer: Natural Products Inhibitors as a Driving Force for Epigenetic Drug Discovery.

KDM4A-F enzymes are a subfamily of histone demethylases containing the Jumonji C domain (JmjC) using Fe(II) and 2-oxoglutarate for their catalytic function. Overexpression or deregulation of KDM4 enzymes is associated with various cancers, altering chromatin structure and causing transcriptional dysfunction. As KDM4 enzymes have been associated with malignancy, they may represent novel targets for developing innovative therapeutic tools to treat different solid and blood tumors.

Targeting Relevant HDACs to Support the Survival of Cone Photoreceptors in Inherited Retinal Diseases: Identification of a Potent Pharmacological Tool with In Vitro and In Vivo Efficacy.

Inherited retinal diseases, which include retinitis pigmentosa, are a family of genetic disorders characterized by gradual rod-cone degeneration and vision loss, without effective pharmacological treatments. Experimental approaches aim to delay disease progression, supporting cones' survival, crucial for human vision. Histone deacetylases (HDACs) mediate the activation of epigenetic and nonepigenetic pathways that modulate cone degeneration in RP mouse models.

Intestinal Fibrogenesis in Inflammatory Bowel Diseases: Exploring the Potential Role of Gut Microbiota Metabolites as Modulators.

Fibrosis, sustained by the transformation of intestinal epithelial cells into fibroblasts (epithelial-to-mesenchymal transition, EMT), has been extensively studied in recent decades, with the molecular basis well-documented in various diseases, including inflammatory bowel diseases (IBDs). However, the factors influencing these pathways remain unclear. In recent years, the role of the gut microbiota in health and disease has garnered significant attention.

Metalloenzyme Inhibitors against Zoonotic Infections: Focus on and .

The term "zoonosis" denotes diseases transmissible among vertebrate animals and humans. These diseases constitute a significant public health challenge, comprising 61% of human pathogens and causing an estimated 2.7 million deaths annually.

A novel potent class I HDAC inhibitor reverses the STAT4/p66Shc apoptotic defect in B cells from chronic lymphocytic leukemia patients.

Chronic Lymphocytic Leukemia (CLL) patients have a defective expression of the proapoptotic protein p66Shc and of its transcriptional factor STAT4, which evoke molecular abnormalities, impairing apoptosis and worsening disease prognosis and severity. p66Shc expression is epigenetically controlled and transcriptionally modulated by STAT4; epigenetic modifiers are deregulated in CLL cells and specific histone deacetylases (HDACs) like HDAC1, are overexpressed. Reactivation of STAT4/p66Shc expression may represent an attractive and challenging strategy to reverse CLL apoptosis defects.

Effects of structurally distinct human HDAC6 and HDAC6/HDAC8 inhibitors against S. mansoni larval and adult worm stages.

Schistosomiasis is a major neglected parasitic disease that affects more than 240 million people worldwide caused by Platyhelminthes of the genus Schistosoma. The treatment of schistosomiasis relies on the long-term application of a single safe drug, praziquantel (PZQ). Unfortunately, PZQ is very effective on adult parasites and poorly on larval stage and immature juvenile worms; this can partially explain the re-infection in endemic areas where patients are likely to host parasites at different developmental stages concurrently.

Traceability and authentication in agri-food production: A multivariate approach to the characterization ofthe Italian food excellence elephant garlic (Allium ampeloprasum L.), a vasoactive nutraceutical.

A research platform for food authentication was set up by combining stable isotope ratio analysis, metabolomics by gas and liquid mass-spectrometry and NMR investigations, chemometric analyses for food excellences. This multi-analytical approach was tested on samples of elephant garlic (Allium ampeloprasum L.), a species belonging to the same genus of common garlic (Allium ampeloprasum L.

PAMPs and DAMPs in Sepsis: A Review of Their Molecular Features and Potential Clinical Implications.

Sepsis is a serious organ dysfunction caused by a dysregulated immune host reaction to a pathogen. The innate immunity is programmed to react immediately to conserved molecules, released by the pathogens (PAMPs), and the host (DAMPs). We aimed to review the molecular mechanisms of the early phases of sepsis, focusing on PAMPs, DAMPs, and their related pathways, to identify potential biomarkers.

Development of Potent and Selective Monoacylglycerol Lipase Inhibitors. SARs, Structural Analysis, and Biological Characterization.

New potent, selective monoacylglycerol lipase (MAGL) inhibitors based on the azetidin-2-one scaffold ((±)--, (±)--, and (±)--) were developed as irreversible ligands, as demonstrated by enzymatic and crystallographic studies for (±)-, (±)-, and (±)-. X-ray analyses combined with extensive computational studies allowed us to clarify the binding mode of the compounds. was identified as selective for MAGL when compared with other serine hydrolases.

Synthetic derivatives of natural cinnamic acids as potential anti-colorectal cancer agents.

Cinnamic acid and its derivatives represent attractive building blocks for the development of pharmacological tools. A series of piperoniloyl and cinnamoyl-based amides (6-9 a-f) have been synthesized and assayed against a wide panel of colorectal cancer (CRC) cells, with the aim of finding promising anticancer agents. Among all twenty-four synthesized molecules, 7a, 7e-f, 9c, and 9f displayed the best antiproliferative activity.

Nutritionally enriched tomatoes (Solanum lycopersicum L.) grown with wood distillate: chemical and biological characterization for quality assessment.

Bio-based products are nowadays useful tools able to affect the productivity and quality of conventionally cultivated crops. Several bio-based products are currently on the market; one of the newest and most promising is the wood distillate (WD) derived from the pyrolysis process of waste biomass after timber. Its foliar application has been widely investigated and shown to promote the antioxidant profile of cultivated crops.

Development of Quinazolinone Derivatives as Modulators of Virulence Factors of Cystic Fibrosis Strains.

(PA), one of the ESKAPE pathogens, is an opportunistic Gram-negative bacterium responsible for nosocomial infections in humans but also for infections in patients affected by AIDS, cancer, or cystic fibrosis (CF). Treatment of PA infections in CF patients is a global healthcare problem due to the ability of PA to gain antibiotic tolerance through biofilm formation. Anti-virulence compounds represent a promising approach as adjuvant therapy, which could reduce or eliminate the pathogenicity of PA without impacting its growth.

Pioneering first-in-class FAAH-HDAC inhibitors as potential multitarget neuroprotective agents.

Aiming to simultaneously modulate the endocannabinoid system (ECS) functions and the epigenetic machinery, we selected the fatty acid amide hydrolase (FAAH) and histone deacetylase (HDAC) enzymes as desired targets to develop potential neuroprotective multitarget-directed ligands (MTDLs), expecting to achieve an additive or synergistic therapeutic effect in oxidative stress-related conditions. We herein report the design, synthesis, and biological evaluation of the first-in-class FAAH-HDAC multitarget inhibitors. A pharmacophore merging strategy was applied, yielding 1-phenylpyrrole-based compounds 4a-j.

Development of potent and selective FAAH inhibitors with improved drug-like properties as potential tools to treat neuroinflammatory conditions.

The neuroprotective performance against neuroinflammation of the endocannabinoid system (ECS) can be remarkably improved by indirect stimulation mediated by the pharmacological inhibition of the key ECS catabolic enzyme fatty acid amide hydrolase (FAAH). Based on our previous works and aiming to discover new selective FAAH inhibitors , we herein reported a new series of carbamate-based FAAH inhibitors (4a-t) which showed improved drug disposition properties compared to the previously reported analogues 2a-b. The introduction of ionizable functions allowed us to obtain new FAAH inhibitors of nanomolar potency characterized by good water solubility and chemical stability at physiological pH.

Synthesis of Unsymmetrical Squaramides as Allosteric GSK-3β Inhibitors Promoting β-Catenin-Mediated Transcription of TCF/LEF in Retinal Pigment Epithelial Cells.

The glycogen synthase kinase 3β (GSK-3β) is a ubiquitous enzyme that is a validated target for the development of potential therapeutics useful in several diseases including retinal degeneration. Aiming at developing an innovative class of allosteric inhibitors of GSK-3β potentially useful for retinal degeneration, we explored the class of squaramides. The developed compounds (6 a-l) were obtained through a nontoxic one-pot synthetic protocol, which employs low-cost goods and avoids any purification step.

The green chemistry of chalcones: Valuable sources of privileged core structures for drug discovery.

The sustainable use of resources is essential in all production areas, including pharmaceuticals. However, the aspect of sustainability needs to be taken into consideration not only in the production phase, but during the whole medicinal chemistry drug discovery trajectory. The continuous progress in the fields of green chemistry and the use of artificial intelligence are contributing to the speed and effectiveness of a more sustainable drug discovery pipeline.

In Vitro and In Silico Analyses of New Cinnamid and Rosmarinic Acid-Derived Compounds Biosynthesized in as Arginase Inhibitors.

Arginase is a metalloenzyme that plays a central role in infections. Previously, rosmarinic and caffeic acids were described as antileishmanial agents and as arginase inhibitors. Here, we describe the inhibition of arginase in by rosmarinic acid analogs () and new caffeic acid-derived amides ().

A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors.

Histone deacetylases (HDACs) are epigenetic enzymes which participate in transcriptional repression and chromatin condensation mechanisms by removing the acetyl moiety from acetylated ε-amino group of histone lysines and other non-histone proteins. In recent years, HDAC8, a class I HDAC, has emerged as a promising target for different disorders, including X-linked intellectual disability, fibrotic diseases, cancer, and various neuropathological conditions. Selective HDAC8 targeting is required to limit side effects deriving from the treatment with -HDAC inhibitors (HDACis); thus, many endeavours have focused on the development of selective HDAC8is.

The complexity of immunology: a rare adverse event following a Pfizer-BioNTech vaccine booster shot.

Objective: Several mRNA vaccines have been developed to tackle the global pandemic. Despite their remarkable clinical efficacy, they are not devoid of severe short- and long-term adverse events.

Case Presentation: In this paper, we describe a rare delayed adverse event (arterial and venous renal thrombosis with myocardial injury) in an otherwise healthy adult female, which occurred three months after she received a booster shot of Pfizer COVID-19 vaccine.

Crystal structures of Schistosoma mansoni histone deacetylase 8 reveal a novel binding site for allosteric inhibitors.

Parasitic diseases cause significant global morbidity and mortality particularly in the poorest regions of the world. Schistosomiasis, one of the most widespread neglected tropical diseases, affects more than 200 million people worldwide. Histone deacetylase (HDAC) inhibitors are prominent epigenetic drugs that are being investigated in the treatment of several diseases, including cancers and parasitic diseases.

Optimization of Potent and Specific Trypanothione Reductase Inhibitors: A Structure-Based Drug Discovery Approach.

spp. are responsible for up to 1 million new cases each year. The current therapeutic arsenal against is largely inadequate, and there is an urgent need for better drugs.