Benzenesulfonamide derivatives as
            <i>Vibrio cholerae</i>
            carbonic anhydrases inhibitors: a computational-aided insight in the structural rigidity-activity relationships

Fantacuzzi, Marialuigia; D’Agostino, Ilaria; Carradori, Simone; Liguori, Francesco; Carta, Fabrizio; Agamennone, Mariangela; Angeli, Andrea; Sannio, Filomena; Docquier, Jean Denis; Capasso, Clemente; Supuran, Claudiu T.

doi:10.1080/14756366.2023.2201402

Cited by 15 publications

(4 citation statements)

References 70 publications

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“…Photoactivatable compounds (2a-f) were designed to display CA inhibition, synthesized for the treatment of microbial infections, and assayed against several isoforms of bacterial carbonic anhydrase, displaying good selectivity compared with that to off-target human CAs I and II. In particular, derivatives 2a, 2b, and 2f showed moderate to good antibacterial activity against Gram-positive bacteria such as E. faecalis, S. aureus, and S. epidermidis, as also recently demonstrated in Gram-negative bacteria by other chemical scaffolds [25,26]. When these compounds were irradiated with a 652 nm laser, except for compound 2e, at least 1 log of growth reduction was observed for S. epidermidis and, notably, 2 log of growth reduction with compound 2b.…”

Section: Discussionsupporting

confidence: 69%

Photoactivatable Heptamethine-Based Carbonic Anhydrase Inhibitors Leading to New Anti-Antibacterial Agents

Carradori

Angeli

Sfragano

et al. 2023

IJMS

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With the aim to propose innovative antimicrobial agents able to not only selectively inhibit bacterial carbonic anhydrases (CAs) but also to be photoactivated by specific wavelengths, new heptamethine-based compounds decorated with a sulfonamide moiety were synthesized by means of different spacers. The compounds displayed potent CA inhibition and a slight preference for bacterial isoforms. Furthermore, minimal inhibitory and bactericidal concentrations and the cytotoxicity of the compounds were assessed, thus highlighting a promising effect under irradiation against S. epidermidis. The hemolysis activity test showed that these derivatives were not cytotoxic to human red blood cells, further corroborating their favorable selectivity index. This approach led to the discovery of a valuable scaffold for further investigations.

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Section: Discussionsupporting

confidence: 69%

Photoactivatable Heptamethine-Based Carbonic Anhydrase Inhibitors Leading to New Anti-Antibacterial Agents

Carradori

Angeli

Sfragano

et al. 2023

IJMS

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“…CAs play crucial roles in bacterial metabolism and pH regulation 10–14 . Many bacterial CAs have been investigated over the last decade, and they have been validated as a bacterial target 11–14 , for several bacteria such as Neisseria gonorrhoeae 15 , vancomycin-resistant enterococci (VRE) 16 , Helicobacter pylori 17 and Vibrio cholerae 18 . Most such studies have been performed with sulphonamide CA inhibitors (CAIs), one of the most investigated class of inhibitors for these enzymes.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of pathogenic bacterial carbonic anhydrases by monothiocarbamates

Giovannuzzi,

Marapaka,

Abutaleb

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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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 K I s ranging from 0.367 to 0.919 µM. The compounds inhibited the α-EfCA and γ-EfCA with K I 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 .

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“…Currently 15 CAs have been discovered and described in humans and are involved in several physiological and biochemical processes, such as pH homeostasis, gluconeogenesis, liquid secretion, and tumorgenicity. The active site of human CAs (hCAs) contains zinc ions in a tetrahedral geometric shape, coordinated by three amino acid residues, H94, H96, and H119, in addition to a H 2 O molecule or OH – ion. − The hCA IX and hCA XII isoenzymes have been deeply studied due to their important role in cancer cell survival. − Although small metabolic changes are tolerated in cancer cells, strong pH control is necessary for their survival and proliferation . Hydrogen carbonate ions, which are important pH buffers, are imported by transporters such as Cl – /HCO 3 – anion exchanger and Na + /HCO 3 – co-transporter, consuming cytosolic protons to give a new molecule of CO 2 which leaves the cytoplasm to be hydrated by hCA IX and XII .…”

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confidence: 99%

Discovery of a New Class of 1-(4-Sulfamoylbenzoyl)piperidine-4-carboxamides as Human Carbonic Anhydrase Inhibitors

Moi,

Vittorio,

Angeli

et al. 2024

ACS Med. Chem. Lett.

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A series of 1-(4-sulfamoylbenzoyl)piperidine-4-carboxamides deriving from substituted piperazines/benzylamines was designed, synthesized, and tested on human carbonic anhydrase (hCA). The inhibitory activity of the new sulfonamides was analyzed using acetazolamide (AAZ) as a standard inhibitor against hCA I, II, IX, and XII. Several sulfonamides showed both inhibitory activity at low nanomolar concentrations and selectivity against the cytosolic hCA II isoform, and the same trend was observed on the tumor-associated hCA IX and XII. The benzenesulfonamido carboxamides 11 and 15 were the most potent of the piperazino- and benzylamino-based series, respectively. Docking and molecular dynamics studies related the high selectivity of compound 11 toward the tumor-associated hCA isoforms to its capability to participate in favorable interactions within hCA IX and hCA XII active sites, whereas no such interactions were detected within both hCA I and hCA II isoforms.

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Benzenesulfonamide derivatives as Vibrio cholerae carbonic anhydrases inhibitors: a computational-aided insight in the structural rigidity-activity relationships

Cited by 15 publications

References 70 publications

Photoactivatable Heptamethine-Based Carbonic Anhydrase Inhibitors Leading to New Anti-Antibacterial Agents

Photoactivatable Heptamethine-Based Carbonic Anhydrase Inhibitors Leading to New Anti-Antibacterial Agents

Inhibition of pathogenic bacterial carbonic anhydrases by monothiocarbamates

Discovery of a New Class of 1-(4-Sulfamoylbenzoyl)piperidine-4-carboxamides as Human Carbonic Anhydrase Inhibitors

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