Novel -(3-(1-(4-sulfamoylphenyl)triazol-4-yl)phenyl)benzamide Derivatives as Potent Carbonic Anhydrase Inhibitors with Broad-Spectrum Anticancer Activity: Leveraging Tail and Dual-Tail Approaches.

Carbonic anhydrases (CAs) IX and XII are crucial for the survival and metastasis of solid tumors under hypoxic conditions. We designed compounds -, integrating triazole and benzenesulfonamide scaffolds known for inhibiting tumor-associated CAs IX/XII. Initial synthesis included compounds -, followed by diversification with small hydrophobic groups (-) and hydrophilic heterocyclic secondary amines (-).

Design, Synthesis, and In Vitro Evaluation of Aromatic Sulfonamides as Human Carbonic Anhydrase I, II, IX, and XII Inhibitors and Their Antioxidant Activity.

This study is focused on the design, synthesis, and evaluation of some sulfonamide derivatives for their inhibitory effects on human carbonic anhydrase (hCA) enzymes I, II, IX, and XII as well as for their antioxidant activity. The purity of the synthesized molecules was confirmed by the HPLC purity analysis and was found in the range of 93%-100%. The inhibition constant (K) against hCA I ranged from 0.

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.

Exploring the Inhibition of α-Carbonic Anhydrase by Sulfonamides: Insights into Potential Drug Targeting.

, the causative agent of toxoplasmosis, is a protozoan parasite capable of infecting a wide range of hosts, posing significant health risks, particularly to immunocompromised individuals and congenital transmission. Current therapeutic options primarily target the active tachyzoite stage but are limited by issues such as toxicity and incomplete efficacy. As a result, there is an urgent need for alternative therapies that can selectively target parasite-specific mechanisms critical for metabolic processes and host-parasite interactions.

Novel 3-Sulfonamide Dual-Tail Pyrrol-2-one Bridged Molecules as Potent Human Carbonic Anhydrase Isoform Inhibitors: Design, Synthesis, Molecular Modeling Investigation, and Anticancer Activity in MeWo, SK-BR-3, and MG-63 Cell Lines.

Novel 3-sulfonamide pyrrol-2-one derivatives containing two sulfonamide groups were synthesized via a one-pot, three-component method using trifluoroacetic acid as a catalyst. Structural confirmation was achieved using spectroscopic techniques. The compounds were tested against four selected human carbonic anhydrase isoforms (hCA I, hCA II, hCA IX, and hCA XII).

Unprecedented carbonic anhydrase inhibition mechanism: Targeting histidine 64 side chain through a halogen bond.

2,2'-Thio-bis(4,6-dichlorophenol), namely bithionol, is a small molecule endowed with a multifaceted bioactivity. Its peculiar polychlorinated phenolic structure makes it a suitable candidate to explore its potentialities in establishing interaction patterns with enzymes of MedChem interest, such as the human carbonic anhydrase (hCA) metalloenzymes. Herein, bithionol was tested on a panel of specific hCAs through the stopped-flow technique, showing a promising micromolar inhibitory activity for the hCA II isoform.

Depsides from Origanum dictamnus and Satureja pilosa as selective inhibitors of carbonic anhydrases: Isolation, structure elucidation, X-ray crystallography.

In this study, four depsides were isolated from Origanum dictamnus L. and Satureja pilosa Velen. medicinal plants and their structures were assessed by means of one-dimensional (1D)- and two-dimensional (2D)-nuclear magnetic resonance, high resolution mass spectrometry, and electronic circular dichroism analyses.

Multiple Binding Modes of Inhibitors to Human Carbonic Anhydrases: An Update on the Design of Isoform-Specific Modulators of Activity.

Human carbonic anhydrases (hCAs) are widespread zinc enzymes that catalyze the hydration of CO to bicarbonate and a proton. Currently, 15 isoforms have been identified, of which only 12 are catalytically active. Given their involvement in numerous physiological and pathological processes, hCAs are recognized therapeutic targets for the development of inhibitors with biomedical applications.

The Antiepileptic Drug Levetiracetam Inhibits Carbonic Anhydrase: and Studies on Catalytically Active Human Isoforms.

Several antiepileptic drugs (AEDs) have been found to inhibit human carbonic anhydrases (hCAs), paving the way for repurposing AEDs for the treatment of various diseases, including cancer. Here, the hCAs inhibitory effects of levetiracetam, a highly prescribed AED that does not bear a common zinc-binding group, were investigated and . Levetiracetam inhibited all tested hCAs, although with a specific profile compared to the reference acetazolamide, with remarkable efficacy against tumor-associated hCA IX and XII.

New 7-hydroxycoumarin acetamide derivatives as human carbonic anhydrase IX and XII inhibitors: Design, synthesis, biological evaluation and molecular docking studies.

Carbonic anhydrases (CAs) are crucial in regulating various physiological processes in the body. The overexpression of isoforms human carbonic anhydrases (hCA) IX and hCA XII is linked to tumour progression. The selective inhibition of CA IX and CA XII isoforms can result in the development of better cancer treatment strategies.

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.

Lactonase activity of α-carbonic anhydrases allows identification of novel inhibitors.

Lactones, a diverse and abundant class of molecules found in nature, exhibit a wide range of bioactivities, including anti-inflammatory, anticancer, and antibacterial effects. Among them, acyl homoserine lactones (AHSLs) play a crucial role in quorum sensing, influencing bacterial pathogenicity and biofilm formation in Gram-negative bacteria. Paraoxonases (PONs), calcium-containing enzymes known for their lactonase activity, have been shown to hydrolyze AHSLs and reduce the biofilm formation of several pathogenic bacteria.

Kinetic and structural studies of gamma-carbonic anhydrase from the oral pathogen Porphyromonas gingivalis.

Porphyromonas gingivalis, a key pathogen in periodontal, plays a critical role in systemic pathologiesdiseases by evading host defence mechanisms and invading periodontal tissues. Targeting its virulence mechanisms and overcoming drug resistance are essential steps toward effective therapeutic development. In this study, we focused on the Carbonic Anhydrase (CA, EC: 4.

Sulfonamide-Based Inhibition of the β-Carbonic Anhydrase from , a Multidrug-Resistant Bacterium.

is a Gram-negative opportunistic pathogen responsible for severe hospital-associated infections. Owing to its ability to develop resistance to a wide range of antibiotics, novel therapeutic strategies are urgently needed. One promising approach is to target bacterial carbonic anhydrases (CAs; EC 4.

New Structural Features of Isatin Dihydrothiazole Hybrids for Selective Carbonic Anhydrase Inhibitors.

Chemotherapeutic agents have remained the first-line treatment option for advanced-stage cancers when surgery or radiation therapy is not viable. Human carbonic anhydrase (hCA) isoforms IX and XII have been validated as anticancer targets. In particular, hCA IX is overexpressed in several solid tumor cells.

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.

4-(Pyrazolyl)benzenesulfonamide Ureas as Carbonic Anhydrases Inhibitors and Hypoxia-Mediated Chemo-Sensitizing Agents in Colorectal Cancer Cells.

Hypoxia in tumors contributes to chemotherapy resistance, worsened by acidosis driven by carbonic anhydrases (CA IX and XII). Targeting these enzymes can mitigate acidosis, thus enhancing tumor sensitivity to cytotoxic drugs. Herein, novel 4-(pyrazolyl)benzenesulfonamide ureas () were developed and evaluated for their inhibitory activity against CA IX and XII.

The carbonic anhydrase enzymes as new targets for the management of neglected tropical diseases.

Diseases caused by protozoan parasites represent a huge challenge to global health care, due to the lack of selective and efficient treatments for the management and spreading of such complex pathologies. The protozoans Trypanosoma cruzi (T. cruzi) and Leishmania spp.

Carbon Monoxide Release from Aryl-Propargyl Dicobalt(0)Hexacarbonyl Derivatives: A Computational and Experimental Study.

In the present study, we focus on dinuclear cobalt-based CO-RMs with the aim of elucidating their CO release mechanism, as well as to understand how structural changes targeted to modify the electronic properties of these compounds can modulate CO delivery. To this end, we specifically synthesized a set of phenyl-propargyl-based CO-RMs bearing -NO, -H, and -OCH as para-substituents (R) with varying mesomeric influence (M) and different heteroatoms (X = NH, O, or S) linking the propargyl tail and the aromatic ring. The effects of R and X in modulating CO release were assessed by using several experimental and computational techniques to obtain a coherent picture and to shed light on the stability and release properties of Co-based CO-RMs.

Synthesis of Chromene-linked Bis-indole Derivatives as Selective Tumor-associated Carbonic Anhydrase IX Inhibitors.

Background: Sulfonamide derivatives are well-reported hCA IX inhibitors; however, they inhibit all types of hCA without any selectivity, leading to severe adverse effects. Hence, developing a novel nonsulfonamide class of tumor-associated hCA IX inhibitors through non-classical inhibition may provide greater selectivity and better pharmacokinetics.

Objective: The objective of this study was to develop non-sulfonamide derivatives as potential human carbonic anhydrase (hCA) inhibitors and develop a new series of chromene-linked bis-indole derivatives.

Exploring the binding mode of phenyl and vinyl boronic acids to human carbonic anhydrases.

Boronic acids are an interesting but still poorly studied class of carbonic anhydrase inhibitors. Previous investigations proved that derivatives incorporating aromatic, arylalkyl, and arylalkenyl moieties are low micromolar to millimolar inhibitors for several α- and β-CAs involved in pathologic states. Here we report a high-resolution X-ray study on two classes of boronic acids (phenyl and vinyl) in complex with hCA II.

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.

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.