Tetrazole Is a Novel Zinc Binder Chemotype for Carbonic Anhydrase Inhibition.

The tetrazole group is here proposed as a zinc-binding warhead for the inhibition of the metalloenzyme carbonic anhydrases. A set of synthesized derivatives incorporating the tetrazole moiety were evaluated as inhibitors against a panel of human isoforms, exhibiting values spanning between the submicromolar and low-to-medium micromolar ranges (0.62-19.

Cybervictimization and Online Sexual Harassment: Prevalence, Association, and Predictors.

Background: The daily and massive use of the Internet and social media by adolescents has led to increased interest and attention to prevalence rates, risk factors, and potential consequences of different forms of online victimization. This study aims to examine the possible associations between cybervictimization and online sexual harassment among 697 Italian adolescents (M = 15.17; SD = 0.

Putting situational affordances in an intervention context: How the interaction between personality and intervention situations can help us explain differential intervention responses.

We propose a framework in which interventions are described as situations affording the expression of certain personality traits to provide a systematic understanding of differential intervention response by personality traits. The goal of the present paper is twofold: 1) elaborate on the proposed framework, and 2) provide an initial test of this framework. We empirically tested this framework using data from a Randomized Controlled Trial (N = 176) that examined a smartphone-based intervention aimed at increasing future-oriented thinking and behavior, and assessed HEXACO personality traits.

Exploring aliphatic sulfonamides as multiclass inhibitors of the carbonic anhydrases from the pathogen bacterium Vibrio cholerae.

This study investigates aliphatic sulfonamide derivatives as inhibitors of the α-, β-, and γ-class carbonic anhydrase (CA) isoforms from Vibrio cholerae (VchCAs). A series of 26 compounds bearing a triazole linker and urea- or ether-based tails were described and evaluated for their inhibitory action using a stopped-flow CO hydrase technique. These inhibitors demonstrated a preferential efficacy against VchCAβ.

Superacid-Synthesized Fluorinated Diamines Act as Selective hCA IV Inhibitors.

Carbonic anhydrase (CA) IV is a membrane-bound enzyme involved in important physio-pathological processes, such as excitation-contraction coupling in heart muscle, central nervous system (CNS) extracellular buffering, and mediation of inflammatory response after stroke. Known since the mid-1980s, this isoform is still largely unexplored when compared to other isoforms, mostly for the current lack of inhibitors targeting selectively this isoform. The discovery of selective CA IV inhibitors is thus largely awaited.

Benzoxaborinine, New Chemotype for Carbonic Anhydrase Inhibition: Synthesis, Crystallography, Studies, and Anti-Melanoma Cell Line Activity.

The benzoxaborinine scaffold, a homologue of benzoxaborole with an additional carbon atom in the boracycle, shows significant potential in developing new therapeutic agents. This study reports the synthesis, inhibition assays against four human carbonic anhydrase (hCA, EC 4.2.

Hydrogen Sulfide-Releasing Carbonic Anhydrase Inhibitors Effectively Suppress Cancer Cell Growth.

This study proposes a novel therapeutic strategy for cancer management by combining the antitumor effects of hydrogen sulfide (HS) and inhibition of carbonic anhydrases (CAs; EC 4.2.1.

Enhanced Recognition Memory through Dual Modulation of Brain Carbonic Anhydrases and Cholinesterases.

This study introduces a novel multitargeting strategy that combines carbonic anhydrase (CA) activators and cholinesterase (ChE) inhibitors to enhance cognitive functions. A series of tacrine-based derivatives with amine/amino acid moieties were synthesized and evaluated for their dual activity on brain CA isoforms and ChEs (AChE and BChE). Several derivatives, notably compounds , , , and , demonstrated potent CA activation, particularly of hCA II and VII, and strong ChE inhibition with subnanomolar to low nanomolar IC values.

Sulfonamide inhibitors of bacterial carbonic anhydrases.

The increasing prevalence of antibiotic-resistant bacteria necessitates the exploration of novel therapeutic targets. Bacterial carbonic anhydrases (CAs) have been known for decades, but only in the past ten years they have garnered significant interest as drug targets to develop antibiotics having a diverse mechanism of action compared to the clinically used drugs. Significant progress has been made in the field in the past three years, with the validation in vivo of CAs from Neisseria gonorrhoeae, and vancomycin-resistant enterococci as antibiotic targets.

Harnessing Nitric Oxide-Donating Benzofuroxans for Targeted Inhibition of Carbonic Anhydrase IX in Cancer.

We describe here the design and antitumor evaluation of benzofuroxan-based nitric oxide (NO)-donor hybrid derivatives targeting human carbonic anhydrases (hCAs) IX and XII. The most effective compounds, and , demonstrated potent dual action, exhibiting low nanomolar inhibition constants against hCA IX and significant NO release. Notably, compound showed significant antiproliferative effects against various cancer cell lines, particularly renal carcinoma A-498 cells.

Discovery of new sulfonamide-tethered 2-aryl-4-anilinoquinazolines as the first-in-class dual carbonic anhydrase and EGFR inhibitors.

In today's medical field, there is a growing trend of exploiting a single small molecule to target two different molecular targets concurrently. This approach is proving to be highly effective in fighting against cancer. The 4-anilinoquinazoline scaffold, known for its potential in cancer therapy and its effectiveness as a leading class of tyrosine kinase inhibitors, was employed to develop a novel series of anilinoquinazoline-sulfonamides (AQSs) (8a-d, 9a-f, and 10a-d) as dual inhibitors of the tumor-associated carbonic anhydrases (CA) IX/XII and EGFR.

Optimization of Ethoxzolamide Analogs with Improved Pharmacokinetic Properties for Efficacy against .

Drug-resistant gonorrhea is caused by the bacterial pathogen , for which there is no recommended oral treatment. We have demonstrated that the FDA-approved human carbonic anhydrase inhibitor ethoxzolamide potently inhibits ; however, is not effective at reducing bioburden in a mouse model. Thus, we sought to optimize the pharmacokinetic properties of the ethoxzolamide scaffold.

Dual Inhibitors of P-gp and Carbonic Anhydrase XII (hCA XII) against Tumor Multidrug Resistance with Piperazine Scaffold.

A new series of piperazine derivatives were synthesized and studied with the aim of obtaining dual inhibitors of P-glycoprotein (P-gp) and carbonic anhydrase XII (hCA XII) to synergistically overcome the P-gp-mediated multidrug resistance (MDR) in cancer cells expressing the two proteins, P-gp and hCA XII. Indeed, these hybrid compounds contain both P-gp and hCA XII binding groups on the two nitrogen atoms of the heterocyclic ring. All compounds showed good inhibitory activity on each protein (P-gp and hCA XII) studied individually, and many of them showed a synergistic effect in the resistant HT29/DOX and A549/DOX cell lines which overexpress both the target proteins.

Development of a multi-targeted chemotherapeutic approach based on G-quadruplex stabilisation and carbonic anhydrase inhibition.

A novel class of compounds designed to hit two anti-tumour targets, G-quadruplex structures and human carbonic anhydrases (hCAs) IX and XII is proposed. The induction/stabilisation of G-quadruplex structures by small molecules has emerged as an anticancer strategy, disrupting telomere maintenance and reducing oncogene expression. hCAs IX and XII are well-established anti-tumour targets, upregulated in many hypoxic tumours and contributing to metastasis.

Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) in cancer: a patent review.

Introduction: Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide (NAD) from nicotinamide. In addition to its role as essential redox cofactor, NAD also functions as a substrate for NAD-consuming enzymes, regulating multiple cellular processes such as DNA repair and gene expression, fundamental to sustain energetic needs for tumor growth. In this sense, NAMPT over-expression represents a common strategy that several tumor types adopt to sustain NAD production.

Benzothiadiazinone-1,1-Dioxide Carbonic Anhydrase Inhibitors Suppress the Growth of Drug-Resistant Strains.

2-Benzo[e][1,2,4]thiadiazin-3(4)-one 1,1-dioxide (BTD) based carbonic anhydrase (CA) inhibitors are here explored as new anti-mycobacterial agents. The chemical features of BTD derivatives meet the criteria for a potent inhibition of β-class CA isozymes. BTD derivatives show chemical features meeting the criteria for a potent inhibition of β-class CA isozymes.

Dual Inhibitors of Brain Carbonic Anhydrases and Monoamine Oxidase-B Efficiently Protect against Amyloid-β-Induced Neuronal Toxicity, Oxidative Stress, and Mitochondrial Dysfunction.

We report here the first dual inhibitors of brain carbonic anhydrases (CAs) and monoamine oxidase-B (MAO-B) for the management of Alzheimer's disease. Classical CA inhibitors (CAIs) such as methazolamide prevent amyloid-β-peptide (Aβ)-induced overproduction of reactive oxygen species (ROS) and mitochondrial dysfunction. MAO-B is also implicated in ROS production, cholinergic system disruption, and amyloid plaque formation.

Coumarins-lipophilic cations conjugates: Efficient mitocans targeting carbonic anhydrases.

Being aware of the need to develop more efficient therapies against cancer, herein we disclose an innovative approach for the design of selective antiproliferative agents. We have accomplished the conjugation of a coumarin fragment with lipophilic cations (triphenylphosphonium salts, guanidinium) for providing mitochondriotropic agents that simultaneously target also carbonic anhydrases IX and XII, involved in the development and progression of cancer. The new compounds prepared herein turned out to be strong inhibitors of carbonic anhydrases IX and XII of human origin (low-to-mid nM range), also endowed with high selectivity, exhibiting negligible activity towards cytosolic CA isoforms.

Leveraging SARS-CoV-2 Main Protease (M) for COVID-19 Mitigation with Selenium-Based Inhibitors.

The implementation of innovative approaches is crucial in an ongoing endeavor to mitigate the impact of COVID-19 pandemic. The present study examines the strategic application of the SARS-CoV-2 Main Protease (M) as a prospective instrument in the repertoire to combat the virus. The cloning, expression, and purification of M, which plays a critical role in the viral life cycle, through heterologous expression in in a completely soluble form produced an active enzyme.

Discovery of Novel Pyridazine-Tethered Sulfonamides as Carbonic Anhydrase II Inhibitors for the Management of Glaucoma.

As a progressive neuropathic condition, glaucoma can cause lifelong blindness if left untreated. Novel phenylpyridazine-tethered sulfonamides were designed as selective inhibitors for carbonic anhydrase (CA) isoform II to find effective therapeutic agents for glaucoma. Subsequently, the target inhibitors were synthesized and assessed for their inhibitory action against cytosolic CA I and II.

The Role of Environmental Sensitivity in the Relationship Between Childhood Maltreatment and Self-Conscious Emotions of Shame and Guilt: A Brief Report.

The association between childhood maltreatment and self-conscious emotions has been proven by the literature, but with limited attention to the specific moderating mechanisms involved. Highly sensitive individuals show emotional reactivity, ease of overstimulation, which make them more influenced by childhood maltreatment experiences. The study aims to test whether environmental sensitivity moderated the link between childhood maltreatment and self-conscious emotions of shame and guilt.