Sulfonamides incorporating piperazine bioisosteres as potent human carbonic anhydrase I, II, IV and IX inhibitors

Niccolò Chiaramonte; Silvia Bua; Andrea Angeli; Marta Ferraroni; Ilaria Picchioni; Gianluca Bartolucci; Laura Braconi; Silvia Dei; Elisabetta Teodori; Claudiu T Supuran; Maria Novella Romanelli

doi:10.1016/j.bioorg.2019.103130

Sulfonamides incorporating piperazine bioisosteres as potent human carbonic anhydrase I, II, IV and IX inhibitors

Bioorg Chem. 2019 Oct:91:103130. doi: 10.1016/j.bioorg.2019.103130. Epub 2019 Jul 20.

Affiliations

¹ University of Florence, Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.
² University of Florence, Department of Chemistry, via della Lastruccia, 50019 Sesto Fiorentino, Italy.
³ University of Florence, Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy. Electronic address: claudiu.supuran@unifi.it.
⁴ University of Florence, Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy. Electronic address: novella.romanelli@unifi.it.

PMID: 31374520
DOI: 10.1016/j.bioorg.2019.103130

Abstract

Starting from the molecular simplification of (R) 4-(3,4-dibenzylpiperazine-1-carbonyl)benzenesulfonamide 9a, a compound endowed with selectivity for human Carbonic Anhydrase (hCA) IV, a series of piperazines and 4-aminopiperidines carrying a 4-sulfamoylbenzamide moiety as Zn-binding group have been designed and tested on human isoforms hCA I, II, IV and IX, using a stopped flow CO₂ hydrase assay. The aim of the work was to derive structure-activity relationships useful for designing isoform selective compounds. These structural modifications changed the selectivity profile of the analogues from hCA IV to hCA I and II, and improved potency. Several of the new compounds showed subnanomolar activity on hCA II. X-ray crystallography of ligand-hCAII complexes was used to compare the binding modes of the new piperazines and the previously synthesized 2-benzyl-piperazine analogues, explaining the inhibition profiles.

Keywords: Carbonic anhydrase; Carbonic anhydrase inhibitors; Isoform selectivity; Piperazine bioisosteres; Piperazines; Sulfonamides.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / metabolism
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / chemistry
Carbonic Anhydrases / metabolism
Catalytic Domain
Crystallography, X-Ray
Humans
Isoenzymes / chemistry
Isoenzymes / metabolism
Molecular Structure
Piperazines / chemical synthesis
Piperazines / metabolism
Piperazines / pharmacology*
Protein Binding
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / metabolism
Sulfonamides / pharmacology*

Substances

Carbonic Anhydrase Inhibitors
Isoenzymes
Piperazines
Sulfonamides
Carbonic Anhydrases