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J Med Chem. 2015 Nov 12;58(21):8564-72. doi: 10.1021/acs.jmedchem.5b01144. Epub 2015 Nov 4.

Discovery of 1,1'-Biphenyl-4-sulfonamides as a New Class of Potent and Selective Carbonic Anhydrase XIV Inhibitors.

Author information

1
Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma , Piazzale Aldo Moro 5, I-00185 Roma, Italy.
2
Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università di Firenze , Via Ugo Schiff 6, I-50019 Sesto Fiorentino, Firenze, Italy.
3
Dipartimento di Farmacia, Università di Pisa , Via Bonanno Pisano 6, I-56126 Pisa, Italy.
4
Istituto di Biostrutture e Bioimmmagini, Consiglio Nazionale delle Ricerche , Via Mezzocannone 16, I-80134 Napoli, Italy.
5
School of Medicine, University of Tampere and Tampere University Hospital , 33014 Tampere, Finland.

Abstract

New 1,1'-biphenylsulfonamides were synthesized and evaluated as inhibitors of the ubiquitous human carbonic anhydrase isoforms I, II, IX, XII, and XIV using acetazolamide (AAZ) as reference compound. The sulfonamides 1-21 inhibited all the isoforms, with Ki values in the nanomolar range of concentration, and were superior to AAZ against all of them. X-ray crystallography and molecular modeling studies on the adducts that compound 20, the most potent hCA XIV inhibitor of the series (Ki = 0.26 nM), formed with the five hCAs, provided insight into the molecular determinants responsible for the high affinity of this molecule toward the target enzymes. The results pave the way to the development of 1.1'-biphenylsulfonamides as a new class of highy potent hCA XIV inhibitors.

PMID:
26497049
DOI:
10.1021/acs.jmedchem.5b01144
[Indexed for MEDLINE]

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