Benzenesulfonamide derivatives as Vibrio cholerae carbonic anhydrases inhibitors : a computational-aided insight in the structural rigidity-activity relationships
Vibrio cholerae causes life-threatening infections in low-income countries due to the rise of antibacterial resistance. Innovative pharmacological targets have been investigated and carbonic anhydrases (CAs, EC: 4.2.1.1) encoded by V. cholerae (VchCAs) emerged as a valuable option. Recently, we developed a large library of para- and meta-benzenesulfonamides characterised by moieties with a different flexibility degree as CAs inhibitors. Stopped flow-based enzymatic assays showed strong inhibition of VchαCA for this library, while lower affinity was detected against the other isoforms. In particular, cyclic urea 9c emerged for a nanomolar inhibition of VchαCA (KI = 4.7 nM) and high selectivity with respect to human isoenzymes (SI≥ 90). Computational studies revealed the influence of moiety flexibility on inhibitory activity and isoform selectivity and allowed accurate SARs. However, although VchCAs are involved in the bacterium virulence and not in its survival, we evaluated the antibacterial activity of such compounds, resulting in no direct activity.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:38 |
|---|---|
| Enthalten in: |
Journal of enzyme inhibition and medicinal chemistry - 38(2023), 1 vom: 31. Dez., Seite 2201402 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Fantacuzzi, Marialuigia [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Carbonic Anhydrase Inhibitors |
|---|
| Anmerkungen: |
Date Completed 20.04.2023 Date Revised 13.12.2023 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.1080/14756366.2023.2201402 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM355773961 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM355773961 | ||
| 003 | DE-627 | ||
| 005 | 20231227131220.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1080/14756366.2023.2201402 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1225.xml |
| 035 | |a (DE-627)NLM355773961 | ||
| 035 | |a (NLM)37073528 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Fantacuzzi, Marialuigia |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Benzenesulfonamide derivatives as Vibrio cholerae carbonic anhydrases inhibitors |b a computational-aided insight in the structural rigidity-activity relationships |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 20.04.2023 | ||
| 500 | |a Date Revised 13.12.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Vibrio cholerae causes life-threatening infections in low-income countries due to the rise of antibacterial resistance. Innovative pharmacological targets have been investigated and carbonic anhydrases (CAs, EC: 4.2.1.1) encoded by V. cholerae (VchCAs) emerged as a valuable option. Recently, we developed a large library of para- and meta-benzenesulfonamides characterised by moieties with a different flexibility degree as CAs inhibitors. Stopped flow-based enzymatic assays showed strong inhibition of VchαCA for this library, while lower affinity was detected against the other isoforms. In particular, cyclic urea 9c emerged for a nanomolar inhibition of VchαCA (KI = 4.7 nM) and high selectivity with respect to human isoenzymes (SI≥ 90). Computational studies revealed the influence of moiety flexibility on inhibitory activity and isoform selectivity and allowed accurate SARs. However, although VchCAs are involved in the bacterium virulence and not in its survival, we evaluated the antibacterial activity of such compounds, resulting in no direct activity | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Carbonic anhydrase | |
| 650 | 4 | |a MD | |
| 650 | 4 | |a Vibrio cholerae | |
| 650 | 4 | |a docking | |
| 650 | 4 | |a homology modelling | |
| 650 | 4 | |a imidazolidinone | |
| 650 | 4 | |a isoform selectivity | |
| 650 | 4 | |a sulfonamides | |
| 650 | 7 | |a Carbonic Anhydrase Inhibitors |2 NLM | |
| 650 | 7 | |a Carbonic Anhydrases |2 NLM | |
| 650 | 7 | |a EC 4.2.1.1 |2 NLM | |
| 700 | 1 | |a D'Agostino, Ilaria |e verfasserin |4 aut | |
| 700 | 1 | |a Carradori, Simone |e verfasserin |4 aut | |
| 700 | 1 | |a Liguori, Francesco |e verfasserin |4 aut | |
| 700 | 1 | |a Carta, Fabrizio |e verfasserin |4 aut | |
| 700 | 1 | |a Agamennone, Mariangela |e verfasserin |4 aut | |
| 700 | 1 | |a Angeli, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Sannio, Filomena |e verfasserin |4 aut | |
| 700 | 1 | |a Docquier, Jean-Denis |e verfasserin |4 aut | |
| 700 | 1 | |a Capasso, Clemente |e verfasserin |4 aut | |
| 700 | 1 | |a Supuran, Claudiu T |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of enzyme inhibition and medicinal chemistry |d 2002 |g 38(2023), 1 vom: 31. Dez., Seite 2201402 |w (DE-627)NLM121560376 |x 1475-6374 |7 nnns |
| 773 | 1 | 8 | |g volume:38 |g year:2023 |g number:1 |g day:31 |g month:12 |g pages:2201402 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1080/14756366.2023.2201402 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 38 |j 2023 |e 1 |b 31 |c 12 |h 2201402 | ||