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.

Damsin and neoambrosin: Two sesquiterpene lactones with affinity and different activity for PPAR and TRPA1 receptors.

Ambrosia maritima L. (family Asteraceae) is an annual herb widely distributed throughout the Mediterranean region and Africa. The herb is employed in folk medicine for the treatment of many ailments.

Exploring the Polypharmacological Potential of PCI-27483: A Selective Inhibitor of Carbonic Anhydrases IX and XII.

PCI-27483, originally developed as a potent and selective inhibitor of the serine protease Factor VIIa (FVIIa) in complex with tissue factor (TF), has demonstrated significant promise in cancer therapy. In addition to its primary mechanism of action, the presence of a sulfonamide moiety in the PCI-27483 structure suggests further activities through the inhibition of carbonic anhydrases (CAs), particularly the tumor-associated human (h)CA isoforms hCA IX and XII. This study investigates the inhibitory activity of PCI-27483 against the complete panel of active hCAs, highlighting its polypharmacological potential in cancer treatment.

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.

Computational studies of tyrosinase inhibitors.

Computational studies have significantly advanced the understanding of tyrosinase (TYR) function, mechanism, and inhibition, accelerating the development of more effective and selective inhibitors. This chapter provides an overview of in silico studies on TYR inhibitors, emphasizing key inhibitory chemotypes and the main residues involved in ligand-target interactions. The chapter discusses tools applied in the context of TYR inhibitor development, e.

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.

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.

Probing benzenesulfonamide-thiazolidinone hybrids as multitarget directed ligands for efficient control of type 2 diabetes mellitus through targeting the enzymes: α-glucosidase and carbonic anhydrase II.

Diabetes mellitus is a chronic metabolic disorder characterized by improper expression/function of a number of key enzymes that can be regarded as targets for anti-diabetic drug design. Herein, we report the design, synthesis, and biological assessment of two series of thiazolidinone-based sulfonamides 4a-l and 5a-c as multitarget directed ligands (MTDLs) with potential anti-diabetic activity through targeting the enzymes: α-glucosidase and human carbonic anhydrase (hCA) II. The synthesized sulfonamides were evaluated for their inhibitory activity against α-glucosidase where most of the compounds showed good to potent activities.

Synthesis, carbonic anhydrase inhibition studies and modelling investigations of phthalimide-hydantoin hybrids.

A novel series of hydantoins incorporating phthalimides has been synthesised by condensation of activated phthalimides with 1-aminohydantoin and investigated for their inhibitory activity against a panel of human (h) carbonic anhydrase (CA, EC 4.2.1.

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.

Synthetic Approaches to Novel Human Carbonic Anhydrase Isoform Inhibitors Based on Pyrrol-2-one Moiety.

New dihydro-pyrrol-2-one compounds, featuring dual sulfonamide groups, were synthesized through a one-pot, three-component approach utilizing trifluoroacetic acid as a catalyst. Computational analysis using density functional theory (DFT) and condensed Fukui function explored the structure-reactivity relationship. Evaluation against human carbonic anhydrase isoforms (hCA I, II, IX, XII) revealed potent inhibition.

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.

Design and synthesis of sulfonamides incorporating a biotin moiety: Carbonic anhydrase inhibitory effects, antiproliferative activity and molecular modeling studies.

Sulfonamides constitute an important class of classical carbonic anhydrase (CA, EC 4.2.1.

Exploration of 3-aryl pyrazole-tethered sulfamoyl carboxamides as carbonic anhydrase inhibitors.

Herein, we report the design and synthesis of two series of pyrazole-tethered sulfamoyl phenyl acetamides and pyrazole-tethered sulfamoyl phenyl benzamides. The synthesized compounds were investigated for inhibiting two human carbonic anhydrases, human carbonic anhydrases (hCA) I and II, and those of the bacterial pathogen Mycobacterium tuberculosis, mtCA 1-3. The results indicate that, among the synthesized compounds, pyrazoles with 4-aminobenzene sulfonamide were more selective toward hCA I and II over mtCAs, and compounds with 3-aminobenzene sulfonamide were selective toward mtCA 1-3 over hCA I, II.

Inhibition Profiles of Some Novel Sulfonamide-Incorporated α-Aminophosphonates on Human Carbonic Anhydrases.

A series of hitherto unknown sulfonamide-incorporated α-aminophosphonate derivatives were synthesized through the one-pot, two-step FeCl-catalyzed coupling of 4-aminobenzenesulfonamide with the appropriate benzaldehydes and diethyl phosphite. The new sulfonamides inhibition studies were performed on four carbonic anhydrase isoforms, i.e.

Discovery of Novel Hydroxyimine-Tethered Benzenesulfonamides as Potential Human Carbonic Anhydrase IX/XII Inhibitors.

To discover novel carbonic anhydrase (CA, EC 4.2.1.

6-Substituted Triazolyl Benzoxaboroles as Selective Carbonic Anhydrase Inhibitors: Design, Synthesis, and X-ray Crystallography.

Benzoxaborole is currently a scaffold of great relevance in medicinal chemistry. In 2016, it was reported to be a new and valuable chemotype for designing carbonic anhydrase (CA) inhibitors. Herein, using an design, we report the synthesis and characterization of substituted 6-(1-1,2,3-triazol-1-yl)benzoxaboroles.

Pyrrolyl and Indolyl α-γ-Diketo Acid Derivatives Acting as Selective Inhibitors of Human Carbonic Anhydrases IX and XII.

Solid tumors are active tissues containing hypoxic regions and producing metabolic acids. By decreasing pH, cancer cells create a hostile environment for surrounding host cells and foster tumor growth and progression. By governing acid/base regulation, carbonic anhydrases (CAs) are involved in several physiological/pathological processes, including tumors.

Inhibition Studies on Human and Mycobacterial Carbonic Anhydrases with -((4-Sulfamoylphenyl)carbamothioyl) Amides.

A library of structurally diverse -((4-sulfamoylphenyl)carbamothioyl) amides was synthesized by selective acylation of easily accessible 4-thioureidobenzenesulfonamide with various aliphatic, benzylic, vinylic and aromatic acyl chlorides under mild conditions. Inhibition of three α-class cytosolic human (h) carbonic anhydrases (CAs) (EC 4.2.

Discovery of the first-in-class potent and isoform-selective human carbonic anhydrase III inhibitors.

Considering the unrecognised physio-pathological role of human carbonic anhydrase III (hCA III), a structure-based drug design was set up to identify the first-in-class potent and selective inhibitors of this neglected isoform. hCA III targeting was planned considering a unique feature of its active site among the other hCA isoforms, the Leu198/Phe198 substitution which interferes with the binding of aromatic/heterocyclic sulfonamides and other inhibitors. Thus, new aliphatic primary sulfonamides possessing long and flexible (CH)SONH moieties were designed to coordinate the zinc(II) ion, bypassing the bulky Phe198 residue.

Identification of new 4-(6-oxopyridazin-1-yl)benzenesulfonamides as multi-target anti-inflammatory agents targeting carbonic anhydrase, COX-2 and 5-LOX enzymes: synthesis, biological evaluations and modelling insights.

Multiple inhibitions of CA, COX-2 and 5-LOX enzymes has been recognised as a useful strategy for the development of anti-inflammatory drugs that can avoid the disadvantages of using NSAIDs alone. Here, we report new pyridazine-based sulphonamides ( and ) as potential multi-target anti-inflammatory candidates. First, the furanone heterocycle in the dual CA/COX-2 inhibitor Polmacoxib was replaced with the pyridazinone one.

Selenium-analogs based on natural sources as cancer-associated carbonic anhydrase isoforms IX and XII inhibitors.

In the relentless search for new cancer treatments, organoselenium compounds, and carbonic anhydrase (CA) inhibitors have emerged as promising drug candidates. CA isoforms IX and XII are overexpressed in many types of cancer, and their inhibition is associated with potent antitumor/antimetastatic effects. Selenium-containing compounds, particularly selenols, have been shown to inhibit tumour-associated CA isoforms in the nanomolar range since the properties of the selenium atom favour binding to the active site of the enzyme.