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Benzothiazole (BTA) belongs to the heterocyclic class of bicyclic compounds. BTA derivatives possesses broad spectrum biological activities such as anticancer, antioxidant, anti-inflammatory, anti-tumour, antiviral, antibacterial, anti-proliferative, anti-diabetic, anti-convulsant, analgesic, anti-tubercular, antimalarial, anti-leishmanial, anti-histaminic and anti-fungal among others. The BTA scaffolds showed a crucial role in the inhibition of the metalloenzyme carbonic anhydrase (CA). In this review an extensive literature survey over the last decade discloses the role of BTA derivatives mainly as anticancer agents. Such compounds are effective against various types of cancer cell lines through a multitude of mechanisms, some of which are poorly studied or understood. The inhibition of tumour associated CAs by BTA derivatives is on the other hand better investigated and such compounds may serve as anticancer leads for the development of agents effective against hypoxic tumours.

The carbonic anhydrases (CAs, EC 4.2.1.1) catalyse a simple but physiologically crucial reversible reaction, the carbon dioxide hydration with the production of bicarbonate and protons. In the last years, and especially, to the rapid emergence of the bacterial antibiotic resistance that is occurring worldwide, the understanding of the function of bacterial CAs has increased significantly. Recently, a new CA-class (ι-CA) was discovered in the marine diatom T. pseudonana. It has been reported that bacterial genomes may contain genes with relevant homology to the diatom ι-class CA. Still, the catalytic activity of the enzyme encoded by the gene was not investigated. Thus, herein, for the first time, we cloned, expressed, and purified the recombinant bacterial ι-CA (acronym BteCAι) identified in the genome of Burkholderia territorii. The recombinant BteCAι resulted in a good catalyst for the hydration of CO 2 to bicarbonate and protons, with a k cat of 3.0 × 10 5  s −1 and k cat /K M of 3.9 × 10 7  M −1 s −1 , and is also sensitive to inhibition by the sulphonamide acetazolamide. Furthermore, with the aid of the protonography, it has been demonstrated that BteCAι can be present as a dimer. This result is corroborated by the construction of a molecular model of BteCAι, which showed that the enzyme is formed by two equivalent monomers having a structure similar to a butterfly.

Coumarins are known to act as prodrug inhibitors of mammalian α-carbonic anhydrases (CAs, EC 4.2.1.1) but they were not yet investigated for the inhibition of bacterial α-CAs. Here we demonstrate that such enzymes from the bacterial pathogens Neisseria gonorrhoeae (NgCAα) and Vibrio cholerae (VchCAα) are inhibited by a panel of simple coumarins incorporating hydroxyl, amino, ketone or carboxylic acid ester moieties in various positions of the ring system. The nature and the position of the substituents in the coumarin ring were the factors which strongly influenced inhibitory efficacy. NgCAα was inhibited with K I s in the range of 28.6-469.5 µM, whereas VchCAα with K I s in the range of 39.8-438.7 µM. The two human (h)CA isoforms included for comparison reason in the study, hCA I and II, were less prone to inhibition by these compounds, with K I s of 137-948.9 µM for hCA I and of 296.5-961.2 µM for hCA II, respectively. These findings are relevant for discovering coumarin bacterial CA inhibitors with selectivity for the bacterial over human isoform, with potential applications as novel antibacterial agents.

Bilirubin (BR) is the final product of haem catabolism. Disruptions along BR metabolic/transport pathways resulting from inherited disorders can increase plasma BR concentration (hyperbilirubinaemia). Unconjugated hyperbilirubinemia may induce BR accumulation in brain, potentially causing irreversible neurological damage, a condition known as BR encephalopathy or kernicterus, to which newborns are especially vulnerable. Numerous pharmaceutical strategies, mostly based on hemoperfusion, have been proposed over the last decades to identify new valid, low-risk alternatives for BR removal from plasma. On the other hand, accumulating evidence indicates that BR produces health benefits due to its potent antioxidant, anti-inflammatory and immunomodulatory action with a significant potential for the treatment of a multitude of diseases. The present manuscript reviews both such aspects of BR pharmacology, gathering literature data on applied pharmaceutical strategies adopted to: (i) reduce the plasma BR concentration for preventing neurotoxicity; (ii) produce a therapeutic effect based on BR efficacy in the treatment of many disorders.

Helicobacter pylori, a Gram-negative neutrophilic pathogen, is the cause of chronic gastritis, peptic ulcers, and gastric cancer in humans. Current therapeutic regimens suffer from an emerging bacterial resistance rate and poor patience compliance. To improve the discovery of compounds targeting bacterial alternative enzymes or essential pathways such as carbonic anhydrases (CAs), we assessed the anti-H. pylori activity of thymol and carvacrol in terms of CA inhibition, isoform selectivity, growth impairment, biofilm production, and release of associated outer membrane vesicles-eDNA. The microbiological results were correlated by the evaluation in vitro of H. pylori CA inhibition, in silico analysis of the structural requirements to display such isoform selectivity, and the assessment of their limited toxicity against three probiotic species with respect to amoxicillin. Carvacrol and thymol could thus be considered as new lead compounds as alternative H. pylori CA inhibitors or to be used in association with current drugs for the management of H. pylori infection and limiting the spread of antibiotic resistance.

Carbonic anhydrase IX/XII (CA IX/XII), are cell-surface enzymes typically expressed by cancer cells as a form of adaptation to hypoxia and acidosis. It has been widely reported that these proteins play pivotal roles in cancer progression fostering cell migration, aggressiveness and resistance to first line chemo- and radiotherapies. CA IX has emerged as a promising target in cancer therapy and several approaches and families of compounds were characterised in the attempt to find optimal targeting by inhibiting of the high catalytic activity of the enzyme. In the present work, different cell lines representing glioblastoma, bladder and pancreatic cancer have been exploited to compare the inhibitory and antiproliferative effect of primary sulphonamide acetazolamide (AAZ), the Phase Ib/II clinical grade sulphonamide SLC-0111, and a membrane-impermeant positively charged, pyridinium-derivative (C18). New hints regarding the possibility to exploit CA inhibitors in these cancer types are proposed.

Resistance to antibiotic treatment developed by bacteria in humans and animals occurs when the microorganisms resist treatment with clinically approved antibiotics. Actions must be implemented to stop the further development of antibiotic resistance and the subsequent emergence of superbugs. Medication repurposing/repositioning is one strategy that can help find new antibiotics, as it speeds up drug development phases. Among them, the Zn2+ ion binders, such as sulfonamides and their bioisosteres, are considered the most promising compounds to obtain novel antibacterials, thus avoiding antibiotic resistance. Sulfonamides and their bioisosteres have drug-like properties well-known for decades and are suitable lead compounds for developing new pharmacological agent families for inhibiting carbonic anhydrases (CAs). CAs are a superfamily of metalloenzymes catalyzing the reversible reaction of CO2 hydration to HCO3− and H+, being present in most bacteria in multiple genetic families (α-, β-, γ- and ι-classes). These enzymes, acting as CO2 transducers, are promising drug targets because their activity influences microbe proliferation, biosynthetic pathways, and pathogen persistence in the host. In their natural or slightly modified scaffolds, sulfonamides/sulfamates/sulamides inhibit CAs in vitro and in vivo, in mouse models infected with antibiotic-resistant strains, confirming thus their role in contrasting bacterial antibiotic resistance.

A series of new 3- and 7-substituted sulfocoumarins was obtained by several cyclization reactions and subsequent derivatization for screening as prodrug inhibitors of the human (h) cancer-associated carbonic anhydrases (CAs) IX and XII. All products were ineffective inhibitors against the off-target hCA I and II, whilst hCAs IX and XII were inhibited with inhibition constants (KIs) spanning from low nanomolar to the high micromolar range, according to the sulfocoumarin derivatization pattern. In particular, sulfocoumarin 15 turned out to be the most potent and selective inhibitor herein reported (hCA I and II: KI > 100 µM; hCA IX: KI = 22.9 nM; hCA XII: KI = 19.2 nM). Considering that hCA IX and XII validated anti-tumor targets, such prodrug, isoform-selective inhibitors as the sulfocoumarins reported here may be useful for identifying suitable drug candidates for clinical trials.

Neisseria gonorrhoeae is a high-priority pathogen of concern due to the growing prevalence of resistance development against approved antibiotics. Herein, we report the anti-gonococcal activity of ethoxzolamide, the FDA-approved human carbonic anhydrase inhibitor. Ethoxzolamide displayed an MIC 50, against a panel of N. gonorrhoeae isolates, of 0.125 µg/mL, 16-fold more potent than acetazolamide, although both molecules exhibited almost similar potency against the gonococcal carbonic anhydrase enzyme (NgCA) in vitro. Acetazolamide displayed an inhibition constant (K i ) versus NgCA of 74 nM, while Ethoxzolamide ' s K i was estimated to 94 nM. Therefore, the increased anti-gonococcal potency of ethoxzolamide was attributed to its increased permeability in N. gonorrhoeae as compared to that of acetazolamide. Both drugs demonstrated bacteriostatic activity against N. gonorrhoeae, exhibited post-antibiotic effects up to 10 hours, and resistance was not observed against both. Taken together, these results indicate that acetazolamide and ethoxzolamide warrant further investigation for translation into effective anti-N. gonorrhoeae agents.

In this work, different series of benzothiazole-based sulphonamides 8a-c, 10, 12, 16a-b and carboxylic acids 14a-c were developed as novel SLC-0111 analogues with the goal of generating potent carbonic anhydrase (CA) inhibitors. The adopted strategy involved replacing the 4-fluorophenyl tail in SLC-0111 with a benzothiazole motif that attached to the ureido linker to produce compounds 8c and its regioisomers 8a-b. In addition, the ureido spacer was elongated by methylene or ethylene groups to afford the counterparts 10 and 12. In turn, the primary sulfamoyl zinc binding group (ZBG) was either substituted or replaced by carboxylic acid functionality in order to provide the secondary sulphonamide-based SLC-0111 analogues 16a-b, and the carboxylic acid derivatives 14a-c, respectively. All compounds (8a-c, 10, 12, 14a-c and 16a-b) were tested for their ability to inhibit CA isoforms CA I, II, IX and XII. Additionally, the in vitro anticancer properties of the developed CAIs were evaluated.