A comprehensive investigation of the anion inhibition profile of a ß-carbonic anhydrase from Acinetobacter baumannii for crafting innovative antimicrobial treatments.

This study refers to the intricate world of Acinetobacter baumannii, a resilient pathogenic bacterium notorious for its propensity at antibiotic resistance in nosocomial infections. Expanding upon previous findings that emphasised the bifunctional enzyme PaaY, revealing unexpected γ-carbonic anhydrase (CA) activity, our research focuses on a different class of CA identified within the A. baumannii genome, the ß-CA, designated as 𝛽-AbauCA (also indicated as CanB), which plays a crucial role in the resistance mechanism mediated by AmpC beta-lactamase. Here, we cloned, expressed, and purified the recombinant 𝛽-AbauCA, unveiling its distinctive kinetic properties and inhibition profile with inorganic anions (classical CA inhibitors). The exploration of 𝛽-AbauCA not only enhances our understanding of the CA repertoire of A. baumannii but also establishes a foundation for targeted therapeutic interventions against this resilient pathogen, promising advancements in combating its adaptability and antibiotic resistance.

Novel thiazolotriazole and triazolothiadiazine scaffolds as selective tumor associated carbonic anhydrase inhibitors endowed with cathepsin B inhibition.

The present research focused on the tail-approach synthesis of novel extended thiazolotriazoles (8a-8j) and triazolothiadiazines (11a-11j) including aminotriazole intermediate 10. After successful synthesis, all the compounds were evaluated for their inhibition potential against cytosolic isoforms of human carbonic anhydrase (hCA I, II), tumor-linked transmembrane isoforms (hCA IX, XII), and cathepsin B. As per the inhibition data, the newly synthesized compounds showed poor inhibition against hCA I. Many of the compounds showed effective inhibition toward hCA IX and/or XII in low nanomolar concentration. Despite the strong to moderate inhibition of hCA II by these compounds, more than half of them demonstrated better inhibition against hCA IX and/or XII, comparatively. Further, insights of CA inhibition data of these extended analogs and their comparison with earlier reported thiazolotriazole and triazolothiadiazine derivatives might help in the rational design of novel potent and selective hCA IX and XII inhibitors. The novel compounds were also found to possess anti-cathepsin B potential at a low concentration of 10-7 M. Broadly, compounds of series 11a-11j presented more effective inhibition against cathepsin B than their counterparts in series 8a-8j. Moreover, these in vitro results with respect to cathepsin B inhibition were also supported by the in silico insights obtained via molecular modeling studies.

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. In addition to its enzymatic role, NAMPT behaves as cytokine-like protein with pro-inflammatory function. Increasing evidence demonstrated that NAMPT inhibition represents a promising anti-cancer strategy to deplete NAD and impair cellular metabolism in cancer conditions. AREAS COVERED: By using Espacenet, we collected the patents which identified new molecules, compounds, formulations and methods able to inhibit NAMPT from 2007 to date. EXPERT OPINION: Most of the collected patents focused the attention on the ability of different compounds to inhibit the enzymatic activity of NAMPT, lacking other important aspects related to the extracellular role of NAMPT and the ability of alternative enzymes to counteract NAMPT-mediated NAD depletion. It is necessary to consider also these aspects to promote novel strategies and create novel inhibitors and molecules useful as anti-cancer compounds.

Management of Neisseria gonorrhoeae infection: from drug resistance to drug repurposing.

INTRODUCTION: Neisseria gonorrhoeae is a common sexually transmitted disease connected with extensive drug resistance to many antibiotics. Presently, only expanded spectrum cephalosporins (ceftriaxone and cefixime) and azithromycin remain useful for its management. AREAS COVERED: New chemotypes for the classical antibiotic drug target gyrase/topoisomerase IV afforded inhibitors with potent binding to these enzymes, with an inhibition mechanism distinct from that of fluoroquinolones, and thus less prone to mutations. The α-carbonic anhydrase from the genome of this bacterium (NgCAα) was also validated as an antibacterial target. EXPERT OPINION: By exploiting different subunits from the gyrase/topoisomerase IV as well as new chemotypes, two new antibiotics reached Phase II/III clinical trials, zoliflodacin and gepotidacin. They possess a novel inhibition mechanism, binding in distinct parts of the enzyme compared to the fluoroquinolones. Other chemotypes with inhibitory activity in these enzymes were also reported. NgCAα inhibitors belonging to a variety of classes were obtained, with several sulfonamides showing MIC values in the range of 0.25-4 µg/mL and significant activity in animal models of this infection. Acetazolamide and similar CA inhibitors might thus be repurposed as antiinfectives. The scientific/patent literature has been searched for on PubMed, ScienceDirect, Espacenet, and PatentGuru, from 2016 to 2024.

Benzenesulfonamides functionalized with triazolyl-linked pyrazoles possess dual cathepsin B and carbonic anhydrase inhibitory action.

The design and synthesis of a library of 21 novel benzenesulfonamide-bearing 3-functionalized pyrazole-linked 1,2,3-triazole derivatives as dual inhibitors of cathepsin B and carbonic anhydrase enzymes are reported. The target 1,2,3-triazole-linked pyrazolic esters (16) were synthesized by the condensation of 1,2,3-triazolic diketo esters with 4-hydrazinobenzenesulfonamide hydrochloride, and these were further converted into the corresponding carboxylic acid (17) and carboxamide (18) analogs. The synthesized compounds were assayed in vitro for their inhibition potential against human carbonic anhydrase (hCA) isoforms I, II, IX, and XII. They were found to be potent inhibitors at the low nanomolar level against the cancer-related hCA IX and XII and to be selective towards the cytosolic isoform hCA I. The physiologically important isoform hCA II was potently inhibited by all the newly synthesized compounds showing KI values ranging between 0.8 and 561.5 nM. The ester derivative 16c having 4-fluorophenyl (KI = 5.2 nM) was the most potent inhibitor of hCA IX, and carboxamide derivative 18b (KI = 2.2 nM) having 4-methyl substituted phenyl was the most potent inhibitor of hCA XII. The newly synthesized compounds exhibited potent cathepsin B inhibition at 10-7 M concentration. In general, the carboxamide derivatives (18) showed higher % inhibition as compared with the corresponding ester derivatives (16) and carboxylic acid derivatives (17) for cathepsin B. The interactions of the target compounds with the active sites of cathepsin B and CA were studied through molecular docking studies. Further, the in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) and drug-likeness properties of the target compounds were also studied.

Cloning, expression, and purification of an α-carbonic anhydrase from Toxoplasma gondii to unveil its kinetic parameters and anion inhibition profile.

Toxoplasmosis, induced by the intracellular parasite Toxoplasma gondii, holds considerable implications for global health. While treatment options primarily focusing on folate pathway enzymes have notable limitations, current research endeavours concentrate on pinpointing specific metabolic pathways vital for parasite survival. Carbonic anhydrases (CAs, EC 4.2.1.1) have emerged as potential drug targets due to their role in fundamental reactions critical for various protozoan metabolic processes. Within T. gondii, the Carbonic Anhydrase-Related Protein (TgCA_RP) plays a pivotal role in rhoptry biogenesis. Notably, α-CA (TcCA) from another protozoan, Trypanosoma cruzi, exhibited considerable susceptibility to classical CA inhibitors (CAIs) such as anions, sulphonamides, thiols, and hydroxamates. Here, the recombinant DNA technology was employed to synthesise and clone the identified gene in the T. gondii genome, which encodes an α-CA protein (Tg_CA), with the purpose of heterologously overexpressing its corresponding protein. Tg_CA kinetic constants were determined, and its inhibition patterns explored with inorganic metal-complexing compounds, which are relevant for rational compound design. The significance of this study lies in the potential development of innovative therapeutic strategies that disrupt the vital metabolic pathways crucial for T. gondii survival and virulence. This research may lead to the development of targeted treatments, offering new approaches to manage toxoplasmosis.

In-vitro and in-silico investigations of SLC-0111 hydrazinyl analogs as human carbonic anhydrase I, II, IX, and XII inhibitors.

Two novel series of hydrazinyl-based benzenesulfonamides 9a-j and 10a-j were designed and synthesized using SLC-0111 as the lead molecule. The newly synthesized compounds were evaluated for their inhibitory activity against four different human carbonic anhydrase (hCA) isoforms I, II, IX, and XII. Both the series reported here were practically inactive against the off-target isozyme hCA I. Notably, derivative 10a exhibited superior potency (Ki of 10.2 nM) than acetazolamide (AAZ) against the cytosolic isoform hCA II. The hCA IX and XII isoforms implicated in tumor progression were effectively inhibited with Kis in the low nanomolar range of 20.5-176.6 nM and 6.0-127.5 nM, respectively. Compound 9g emerged as the most potent and selective hCA IX and XII inhibitor with Ki of 20.5 nM and SI of 200.1, and Ki of 6.0 nM and SI of 683.7, respectively, over hCA I. Furthermore, six compounds (9a, 9h, 10a, 10g, 10i, and 10j) exhibited significant inhibition toward hCA IX (Kis = 27.0, 41.1, 27.4, 25.9, 40.7, and 30.8 nM) relative to AAZ and SLC-0111 (Kis = 25.0 and 45.0 nM, respectively). These findings underscore the potential of these derivatives as potent and selective inhibitors of hCA IX and XII over the off-target hCA I and II.

Development of Penicillin-Based Carbonic Anhydrase Inhibitors Targeting Multidrug-Resistant Neisseria gonorrhoeae.

The development of antibacterial drugs with new mechanisms of action is crucial in combating the rise of antibiotic-resistant infections. Bacterial carbonic anhydrases (CAs, EC 4.2.1.1) have been validated as promising antibacterial targets against pathogens such as Helicobacter pylori, Neisseria gonorrhoeae, and vancomycin-resistant enterococci. A multitarget strategy is proposed to design penicillin-based CA inhibitor hybrids for tackling resistance by targeting multiple bacterial pathways, thereby resensitizing drug-resistant strains to clinical antibiotics. The sulfonamide derivatives potently inhibited the CAs from N. gonorrhoeae and Escherichia coli with KI values in the range of 7.1-617.2 nM. Computational simulations with the main penicillin-binding protein (PBP) of N. gonorrhoeae indicated that these hybrid derivatives maintained the mechanism of action of the lead ß-lactams. A subset of derivatives showed potent PBP-related antigonococcal effects against multidrug-resistant N. gonorrhoeae strains, with several compounds significantly outperforming both the lead ß-lactam and CA inhibitor drugs (MIC values in the range 0.25 to 0.5 µg/mL).

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. Compounds 4d and 4e showed potent inhibitory activities (IC50 = 0.440 and 0.3456 µM), comparable with that of the positive control (acarbose; IC50 = 0.420 µM). All the synthesized derivatives were also tested for their inhibitory activities against hCA I, II, IX, and XII. They exhibited different levels of inhibition against these isoforms. Compound 4d outstood as the most potent one against hCA II with Ki equals to 7.0 nM, more potent than the reference standard (acetazolamide; Ki = 12.0 nM). In silico studies for the most active compounds within the active sites of α-glucosidase and hCA II revealed good binding modes that can explain their biological activities. MM-GBSA refinements and molecular dynamic simulations were performed on the top-ranking docking pose of the most potent compound 4d to confirm the formation of stable complex with both targets. Compound 4d was screened for its in vivo antihyperglycemic efficacy by using the oral glucose tolerance test. Compound 4d decreased blood glucose level to 217 mg/dl, better than the standard acarbose (234 mg/dl). Hence, this revealed its synergistic mode of action on post prandial hyperglycemia and hepatic gluconeogenesis. Thus, these benzenesulfonamide thiazolidinone hybrids could be considered as promising multi-target candidates for the treatment of type II diabetes mellitus.

Discovery and Mechanistic Studies of Dual-Target Hits for Carbonic Anhydrase IX and VEGFR-2 as Potential Agents for Solid Tumors: X-ray, In Vitro, In Vivo, and In Silico Investigations of Coumarin-Based Thiazoles.

A dual-targeting approach is predicted to yield better cancer therapy outcomes. Consequently, a series of coumarin-based thiazoles (5a-h, 6, and 7a-e) were designed and constructed as potential carbonic anhydrase (CA) and VEGFR-2 suppressors. The inhibitory actions of the target compounds were assessed against CA isoforms IX and VEGFR-2. The assay results showed that coumarin-based thiazoles 5a, 5d, and 5e can effectively inhibit both targets. 5a, 5d, and 5e cytotoxic effects were tested on pancreatic, breast, and prostate cancer cells (PANC1, MCF7, and PC3). Further mechanistic investigation disclosed the ability of 5e to interrupt the PANC1 cell progression in the S stage by triggering the apoptotic cascade, as seen by increased levels of caspases 3, 9, and BAX, alongside the Bcl-2 decline. Moreover, the in vivo efficacy of compound 5e as an antitumor agent was evaluated. Also, molecular docking and dynamics displayed distinctive interactions between 5e and CA IX and VEGFR-2 binding pockets.

Novel 1,2,4-triazoles as selective carbonic anhydrase inhibitors showing ancillary anticathepsin B activity.

Background: Exploration of the multi-target approach considering both human carbonic anhydrase (hCA) IX and XII and cathepsin B is a promising strategy to target cancer. Methodology & Results: 22 novel 1,2,4-triazole derivatives were synthesized and evaluated for their inhibition efficacy against hCA I, II, IX, XII isoforms and cathepsin B. The compounds demonstrated effective inhibition against hCA IX and/or XII isoforms with considerable selectivity over off-target hCA I/II. All compounds presented significant anticathepsin B activities at a low concentration of 10-7 M and in vitro results were also supported by the molecular modeling studies. Conclusion: Insights of present study can be utilized in the rational design of effective and selective hCA IX and XII inhibitors capable of inhibiting cathepsin B.

Dual Inhibitors of Brain Carbonic Anhydrases and Monoamine Oxidase-B Efficiently Protect against Amyloid-ß-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-ß-peptide (Aß)-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. In this work, we combined a reversible MAO-B inhibitor of the coumarin and chromone type with benzenesulfonamide fragments as highly effective CAIs. A hit-to-lead optimization led to a significant set of derivatives showing potent low nanomolar inhibition of the target brain CAs (KIs in the range of 0.1-90.0 nM) and MAO-B (IC50 in the range of 6.7-32.6 nM). Computational studies were conducted to elucidate the structure-activity relationship and predict ADMET properties. The most effective multitarget compounds totally prevented Aß-related toxicity, reverted ROS formation, and restored the mitochondrial functionality in an SH-SY5Y cell model surpassing the efficacy of single-target drugs.

Effective Anticancer Potential of a New Sulfonamide as a Carbonic Anhydrase IX Inhibitor Against Aggressive Tumors.

This study examines efficiency of a newly synthesized sulfonamide derivative 2-bromo-N-(4-sulfamoylphenyl)propanamide (MMH-1) on the inhibition of Carbonic Anhydrase IX (CA IX), which is overexpressed in many solid tumors including breast cancer. The inhibitory potential of MMH-1 compound against its four major isoforms, including cytosolic isoforms hCA I and II, as well as tumor-associated membrane-bound isoforms hCA IX and XII, was evaluated. To this context, the cytotoxic effect of MMH-1 on cancer and normal cells was tested and found to selectively affect MDA-MB-231 cells. MMH-1 reduced cell proliferation by holding cells in the G0/G1 phase (72 %) and slowed the cells' wound healing capacity. MMH-1 inhibited CA IX under both hypoxic and normoxic conditions and altered the morphology of triple negative breast cancer cells. In MDA-MB-231 cells, inhibition of CA IX was accompanied by a decrease in extracellular pH acidity (7.2), disruption of mitochondrial membrane integrity (80 %), an increase in reactive oxygen levels (25 %), and the triggering of apoptosis (40 %). In addition, the caspase cascade (CASP-3, -8, -9) was activated in MDA-MB-231 cells, triggering both the extrinsic and intrinsic apoptotic pathways. The expression of pro-apoptotic regulatory proteins (Bad, Bax, Bid, Bim, Cyt-c, Fas, FasL, TNF-a, TNF-R1, HTRA, SMAC, Casp-3, -8, P21, P27, and P53) was increased, while the expression of anti-apoptotic proteins, apoptosis inhibitor proteins (IAPs), and heat shock proteins (HSPs) (Bcl-2, Bcl-w, cIAP-2, HSP27, HSP60, HSP70, Survivin, Livin, and XIAP) was decreased. These results propose that the MMH-1 compound could triggers apoptosis in MDA-MB-231 cells via the pH/MMP/ROS pathway through the inhibition of CA IX. This compound is thought to have high potential and promising anticancer properties in the treatment of aggressive tumors.

Tailored Tetrasubstituted Imidazole Carrying the Benzenesulfonamide Fragments as Selective Human Carbonic Anhydrase IX/XII Inhibitors.

A new series of tetrasubstituted imidazole carrying sulfonamide as zinc-anchoring group has been designed. The structures of the synthesized derivatives 5 a-l have been confirmed by spectroscopic analysis. These compounds incorporate an ethylenic spacer between the benzenesulfonamide and the rest of the trisubstituted imidazole moiety and were tested as inhibitors of carbonic anhydrases and for in-vitro cytotoxicity. Most of them act as effective inhibitors of the tumor-linked CA isoforms IX and XII, in nanomolar range. Also, different compounds have shown selectivity in comparable with the standard acetazolamide. Our IBS 5 d, 5 g, and 5 l (with Ki: 10.1, 19.4, 19.8 nM against hCA IX and 47, 45, 20 nM against hCA IX) showed the best inhibitory profile. In-vitro screening of all derivatives against a full sixty-cell-lined from NCI at a single dose of 10 µM offered growth inhibition of up to 45 %. Compound 5 b has been identified with the most potent cytotoxic activity and broad spectrum. Docking studies have also been implemented and were also in accordance with the biological outcomes. Our SAR analysis has interestingly proposed efficient tumor-related hCAs IX/XII suppression.

Identification of thienopyrimidine derivatives tethered with sulfonamide and other moieties as carbonic anhydrase inhibitors: Design, synthesis and anti-proliferative activity.

Eighteen novel compounds harboring the privileged thienopyrimidine scaffold (5a-q, and 6a),were designed based on molecular hybridization strategy. These compounds were synthesized and tested for their inhibitory activity against four different carbonic anhydrase isoforms: CA I, II, IX, and XII. Microwave and conventional techniques were applied for their synthesis. Compounds 5b, 5g, 5l, and 5p showed the highest inhibition activity against the four CA isoforms. Compound 5p exhibited promising inhibitory activity against CA II, CA IX and CA XII with KI values of8.6, 13.8, and 19 nM, respectively, relative to AAZ, where KIs = 12, 25, and 5.7 nM, respectively. Also, compound 5 l showed significant activity against the tumor-associated isoform CA IX with KI = 16.1 nM. All the newly synthesized compounds were also screened for their anticancer activity against NCI 60 cancer cell lines at a 10 µM concentration. Compound 5n showed 80.38, 83.95, and 87.39 % growth inhibition against the leukemic cell lines CCRF-CEM, HL-60 (TB), and RPMI-8226, respectively. Also, 5 h showed 87.57 % growth inhibition against breast cancer cell line MDA-MB-468; and 66.58 and 60.95 % inhibitionagainst renal cancer cell lines UO-31, and ACHN, respectively. A molecular docking studywas carried out to predict binding modes of our synthesized compounds in the binding pockets of the four carbonic anhydrase isoforms, and results revealed that compounds 5b, 5g, 5l, and 5p succeeded in mimicking the binding mode of AAZ through metal coordination with Zn+2 ion and binding to the amino acids Thr199, His94, and His96 that are critical for activity.

1,2,3-Triazole-based esters and carboxylic acids as nonclassical carbonic anhydrase inhibitors capable of cathepsin B inhibition.

Herein, we report the design and synthesis of a library of 28 new 1,2,3-triazole derivatives bearing carboxylic acid and ester moieties as dual inhibitors of carbonic anhydrase (CA) and cathepsin B enzymes. The synthesised compounds were assayed in vitro for their inhibition potential against four human CA (hCA) isoforms, I, II, IX and XII. The carboxylic acid derivatives displayed low micromolar inhibition against hCA II, IX and XII in contrast to the ester derivatives. Most of the target compounds showed poor inhibition against the hCA I isoform. 4-Fluorophenyl appended carboxylic acid derivative 6c was found to be the most potent inhibitor of hCA IX and hCA XII with a KI value of 0.7 µM for both the isoforms. The newly synthesised compounds showed dual inhibition towards CA as well as cathepsin B. The ester derivatives exhibited higher % inhibition at 10-7 M concentration as compared with the corresponding carboxylic acid derivatives against cathepsin B. The results from in silico studies of the target compounds with the active site of cathepsin B were found in good correlation with the in vitro results. Moreover, two compounds, 5i and 6c, showed cytotoxic activity against A549 lung cancer cells, with IC50 values lower than 100 µM.

Boron-containing carbonic anhydrases inhibitors.

Over the last decades, the medicinal chemistry of boron-based compounds has been extensively explored, designing valuable small molecule drugs to tackle diseases and conditions, such as cancer, infections, inflammatory and neurological disorders. Notably, boron has proven to also be a valuable element for the development of inhibitors of the metalloenzymes carbonic anhydrases (CAs), a class of drug targets with significant potential in medicinal chemistry. Incorporating boron into carbonic anhydrase inhibitors (CAIs) can modulate the ligand ability to recognize the target and/or influence selectivity towards different CA isoforms, using the tail approach and boron-based tails. The electron-deficient nature of boron and its associated properties have also led to the discovery of novel zinc-binding CAIs, such as boronic acids and the benzoxaboroles, capable of inhibiting the CAs upon a Lewis acid-base mechanism of action. The present manuscript reviews the state-of-the-art of boron-based CAIs. As research in the applications of boron compounds in medicinal chemistry continues, it is anticipated that new boron-based CAIs will soon expand the current array of such compounds. However, further research is imperative to fully unlock the potential of boron-based CAIs and to advance them towards clinical applications.

Inhibition of pathogenic bacterial carbonic anhydrases by monothiocarbamates.

Carbonic anhydrases (CAs) from the pathogenic bacteria Nesseria gonorrhoeae and vancomycin-resistant enterococci (VRE) have recently been validated as antibacterial drug targets. Here we explored the inhibition of the α-CA from N. gonorrhoeae (α-NgCA), of α- and γ-class enzymes from Enterococcus faecium (α-EfCA and γ-EfCA) with a panel of aliphatic, heterocyclic and aryl-alkyl primary/secondary monothiocarbamates (MTCs). α-NgCA was inhibited in vitro with KIs ranging from 0.367 to 0.919 µM. The compounds inhibited the α-EfCA and γ-EfCA with KI ranges of 0.195-0.959 µM and of 0.149-1.90 µM, respectively. Some MTCs were also investigated for their inhibitory effects on the growth of clinically-relevant N. gonorrhoeae and VRE strains. No inhibitory effects on the growth of VRE were noted for all MTCs, whereas one compound (13) inhibited the growth N. gonorrhoeae strains at concentrations ranging from 16 to 64 µg/mL. This suggests that compound 13 may be a potential antibacterial agent against N. gonorrhoeae.

Keto-bridged dual triazole-linked benzenesulfonamides as potent carbonic anhydrase and cathepsin B inhibitors.

Background: Inhibition of human carbonic anhydrase (hCA) isoforms IX and XII with concurrent inhibition of cathepsin B is a promising approach for targeting cancers. Methods/results: 28 keto-bridged dual triazole-containing benzenesulfonamides were synthesized and tested, following the multitarget approach, for their efficacy as inhibitors of cathepsin B and hCA isoforms (I, II, IX, XII). The synthesized compounds showed excellent inhibition of CA isoforms (IX and XII) and cathepsin B. Compound 8i exhibited better and more selective inhibition of the cancer-associated isoform hCA IX as compared with acetazolamide (reference drug) and SLC-0111 (potent lead as carbonic anhydrase inhibitor). Molecular docking studies were also carried out. Conclusion: The present work gives important generalizations for the development of isoform-selective hCA inhibitors endowed with anti-cathepsin properties.

Potent and selective carbonic anhydrase inhibition activities of pyrazolones bearing benzenesulfonamides.

This research introduces a series of fourteen 4-aryl-hydrazonopyrazolone sulfonamide derivatives, denoted as 3(a-g) and 4(a-g), which encompass various aromatic substitutions. The aim was to assess the inhibitory potential of these compounds against four significant isoforms, including the cytosolic isoforms hCA I and II, as well as the tumor-associated membrane-bound isoforms hCA IX and XII. Most of the tested compounds exhibited substantial inhibition against the tumor-associated isoform hCA IX, with Ki values spanning from 1.1 to 158.2 nM. Notably, compounds 3e and 3g showed particularly strong inhibitory activity against the tumor-associated membrane-bound isoforms, hCA IX and XII, while maintaining a high selectivity ratio over cytosolic off-target isoforms hCA I and II. This selectivity is vital due to the potential of hCA IX and hCA XII as drug targets for hypoxic tumors. In an effort to create novel analogs that exhibit enhanced carbonic anhydrase inhibitory activity and specificity, we investigated the structure-activity relationships of these compounds and provided a concise interpretation of our findings. Consequently, these compounds merit consideration for subsequent medicinal and pharmacological research, holding potential for developing novel therapeutic agents targeting specific isoforms in hypoxic tumors.