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.

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

Moi, Davide
Primo
;
Onnis, Valentina
Ultimo
2024-01-01

Abstract

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.
2024
Carbonic anhydrase; Enzyme inhibition; Carboxamides; Sulfonamides
File in questo prodotto:
File Dimensione Formato  
moi-et-al-2024-discovery-of-a-new-class-of-1-(4-sulfamoylbenzoyl)piperidine-4-carboxamides-as-human-carbonic-anhydrase.pdf

Solo gestori archivio

Descrizione: articolo principale
Tipologia: versione editoriale
Dimensione 9.66 MB
Formato Adobe PDF
9.66 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
ACS Chem Lett 2024_SI.pdf

accesso aperto

Descrizione: Supporting informations
Tipologia: altro documento allegato
Dimensione 2.28 MB
Formato Adobe PDF
2.28 MB Adobe PDF Visualizza/Apri
ACS Chem Lett 2024_open.pdf

embargo fino al 14/03/2025

Descrizione: articolo principale
Tipologia: versione post-print
Dimensione 1.21 MB
Formato Adobe PDF
1.21 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11584/394743
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 0
  • ???jsp.display-item.citation.isi??? 0
social impact