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J Med Chem. 2017 May 25;60(10):4316-4326. doi: 10.1021/acs.jmedchem.7b00264. Epub 2017 May 9.

Probing Molecular Interactions between Human Carbonic Anhydrases (hCAs) and a Novel Class of Benzenesulfonamides.

Author information

1
Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali (CHIBIOFARAM), Università degli Studi di Messina , Viale Annunziata, I-98168 Messina, Italy.
2
Istituto di Biostrutture e Bioimmagini- CNR , Via Mezzocannone 16, I-80134 Napoli, Italy.
3
Dipartimento NEUROFARBA, Università di Firenze , Via Ugo Schiff 6, I-50019 Sesto Fiorentino, Italy.
4
Centro Nazionale Per il Controllo e la Valutazione Dei Farmaci, Istituto Superiore di Sanità , V.le Regina Elena 299, I-00161 Roma, Italy.

Abstract

On the basis of X-ray crystallographic studies of the complex of hCA II with 4-(3,4-dihydro-1H-isoquinoline-2-carbonyl)benzenesulfonamide (3) (PDB code 4Z1J ), a novel series of 4-(1-aryl-3,4-dihydro-1H-isoquinolin-2-carbonyl)benzenesulfonamides (23-33) was designed. Specifically, our idea was to improve the selectivity toward druggable isoforms through the introduction of additional hydrophobic/hydrophilic functionalities. Among the synthesized and tested compounds, the (R,S)-4-(6,7-dihydroxy-1-phenyl-3,4-tetrahydroisoquinoline-1H-2-carbonyl)benzenesulfonamide (30) exhibited a remarkable inhibition for the brain-expressed hCA VII (Ki = 0.20 nM) and selectivity over wider distributed hCA I and hCA II isoforms. By enantioselective HPLC, we solved the racemic mixture and ascertained that the two enantiomers (30a and 30b) are equiactive inhibitors for hCA VII. Crystallographic and docking studies revealed the main interactions of these inhibitors into the carbonic anhydrase (CA) catalytic site, thus highlighting the relevant role of nonpolar contacts for this class of hCA inhibitors.

PMID:
28453941
DOI:
10.1021/acs.jmedchem.7b00264
[Indexed for MEDLINE]

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