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

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 (K_I = 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.

Graphical Abstract

Keywords:

• Carbonic anhydrase
• sulfonamides
• Vibrio cholerae
• imidazolidinone
• isoform selectivity
• homology modelling
• docking
• MD

Acknowledgements

This research was partially supported by the Italian Ministry for University and Research (MIUR) grant number FISR2019_04819 BacCAD to S.C., C.C., and C.T.S. This work (J.D.D.) was supported also in part by the Italian MUR (Ministero dell’Università e Ricerca) in the frame of the PNRR PE-13 (“Piano Nazionale di Ripresa e Resilienza, Partenariato Esteso 13, Malattie infettive emergenti”) INF-ACT project (One Health Basic and Translational Research Actions addressing Unmet Needs on Emerging Infectious Diseases). Thanks are due to Dr. Stefania Cresti (Department of Medical Biotechnologies, University of Siena & Azienda Ospedaliero- Universitaria Senese, Siena, Italy) and to Tiziana Di Maggio and Prof. Lucia Pallecchi (Department of Medical Biotechnologies, University of Siena, Italy) and Prof. Gian Maria Rossolini (Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Clinical Microbiology and Virology Unit, Careggi University Hospital, Florence, Italy) for providing the bacterial strains used in this work.

Authors contributions

The manuscript was written through the contributions of all authors. All authors approved the final version of the manuscript.

Disclosure statement

C.T. Supuran is Editor-in-Chief of the Journal of Enzyme Inhibition and Medicinal Chemistry. He was not involved in the assessment, peer review, or decision-making process of this paper. The authors have no relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Additional information

Funding

This work was supported by Ministero dell’Istruzione, dell’Università e della Ricerca [FISR2019_04819].