Abstract

Abstract

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.

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Title
Benzenesulfonamide derivatives as Vibrio cholerae carbonic anhydrases inhibitors: a computational-aided insight in the structural rigidity-activity relationships
Author
Fantacuzzi, Marialuigia 1 ; Ilaria D’Agostino 1 ; Carradori, Simone 1 ; Liguori, Francesco 1 ; Carta, Fabrizio 2 ; Agamennone, Mariangela 1 ; Angeli, Andrea 2 ; Sannio, Filomena 3 ; Jean-Denis Docquier 4 ; Capasso, Clemente 5 ; Supuran, Claudiu T 2 

1  Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara , Chieti , Italy 
2  Neurofarba Department, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence , Florence , Italy 
3  Department of Medical Biotechnologies, University of Siena , Siena , Italy 
4  Department of Medical Biotechnologies, University of Siena , Siena , Italy, InBioS, Centre for Protein Engineering, University of Liège , Liège , Belgium 
5  Department of Biology, Agriculture and Food Sciences, National Research Council (CNR), Institute of Biosciences and Bioresources , Naples , Italy 
Publication year
2023
Publication date
Dec 2023
Publisher
Taylor & Francis Ltd.
ISSN
14756366
e-ISSN
14756374
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1080/14756366.2023.2201402
ProQuest document ID
2917548683
Copyright
© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.. This work is licensed under the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.