2-Benzylpiperazine: A new scaffold for potent human carbonic anhydrase inhibitors. Synthesis, enzyme inhibition, enantioselectivity, computational and crystallographic studies and in vivo activity for a new class of intraocular pressure lowering agents

Niccolò Chiaramonte; Silvia Bua; Marta Ferraroni; Alessio Nocentini; Alessandro Bonardi; Gianluca Bartolucci; Mariaconcetta Durante; Laura Lucarini; Donata Chiapponi; Silvia Dei; Dina Manetti; Elisabetta Teodori; Paola Gratteri; Emanuela Masini; Claudiu T Supuran; Maria Novella Romanelli

doi:10.1016/j.ejmech.2018.04.002

2-Benzylpiperazine: A new scaffold for potent human carbonic anhydrase inhibitors. Synthesis, enzyme inhibition, enantioselectivity, computational and crystallographic studies and in vivo activity for a new class of intraocular pressure lowering agents

Eur J Med Chem. 2018 May 10:151:363-375. doi: 10.1016/j.ejmech.2018.04.002. Epub 2018 Apr 3.

Authors

Niccolò Chiaramonte¹, Silvia Bua¹, Marta Ferraroni², Alessio Nocentini³, Alessandro Bonardi³, Gianluca Bartolucci¹, Mariaconcetta Durante⁴, Laura Lucarini⁴, Donata Chiapponi², Silvia Dei¹, Dina Manetti¹, Elisabetta Teodori¹, Paola Gratteri³, Emanuela Masini⁴, Claudiu T Supuran⁵, Maria Novella Romanelli⁶

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; University of Florence, Department NEUROFARBA - Pharmaceutical and Nutraceutical section; Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Firenze, via Ugo Schiff 6, I-50019, Sesto Fiorentino, Firenze, Italy.
⁴ University of Florence, Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmacology and Toxicology, Viale Gaetano Pieraccini 6, 50100, Florence, Italy.
⁵ 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.
⁶ 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: 29635168
DOI: 10.1016/j.ejmech.2018.04.002

Abstract

Two series of 2-benzylpiperazines have been prepared and tested for the inhibition of physiologically relevant isoforms of human carbonic anhydrases (hCA, EC 4.2.1.1). The new compounds carry on one nitrogen atom of the piperazine ring a sulfamoylbenzamide group as zinc-binding moiety, and different alkyl/acyl/sulfonyl groups on the other nitrogen. Regio- and stero-isomers are described. The majority of these compounds showed Ki values in the low-medium nanomolar range against hCA I, II and IV, but not IX. In many instances interaction with the enzyme was enantioselective. The binding mode has been studied by means of X-ray crystallography and molecular modelling. Two compounds, evaluated in rabbit models of glaucoma, were able to significantly reduce intraocular pressure, making them interesting candidates for further studies.

Keywords: Carbonic anhydrase; Enantioselectivity; Enzyme inhibitors; Glaucoma; Piperazine.

MeSH terms

Animals
Carbonic Anhydrase I / antagonists & inhibitors
Carbonic Anhydrase I / chemistry
Carbonic Anhydrase I / metabolism
Carbonic Anhydrase II / antagonists & inhibitors
Carbonic Anhydrase II / chemistry
Carbonic Anhydrase II / metabolism
Carbonic Anhydrase IV / antagonists & inhibitors
Carbonic Anhydrase IV / chemistry
Carbonic Anhydrase IV / metabolism
Carbonic Anhydrase IX / antagonists & inhibitors
Carbonic Anhydrase IX / chemistry
Carbonic Anhydrase IX / metabolism
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry*
Carbonic Anhydrase Inhibitors / pharmacology
Carbonic Anhydrase Inhibitors / therapeutic use*
Carbonic Anhydrases / chemistry
Carbonic Anhydrases / metabolism
Crystallography, X-Ray
Glaucoma / drug therapy*
Glaucoma / metabolism
Glaucoma / physiopathology
Humans
Intraocular Pressure / drug effects*
Male
Molecular Docking Simulation
Piperazines / chemical synthesis
Piperazines / chemistry*
Piperazines / pharmacology
Piperazines / therapeutic use*
Rabbits
Stereoisomerism

Substances

Carbonic Anhydrase Inhibitors
Piperazines
1-benzylpiperazine
Carbonic Anhydrase I
Carbonic Anhydrase II
Carbonic Anhydrase IV
Carbonic Anhydrase IX
Carbonic Anhydrases