Discovery of New 1,1'-Biphenyl-4-sulfonamides as Selective Subnanomolar Human Carbonic Anhydrase II Inhibitors

Giuseppe La Regina; Michela Puxeddu; Marianna Nalli; Daniela Vullo; Paola Gratteri; Claudiu Trandafir Supuran; Alessio Nocentini; Romano Silvestri

doi:10.1021/acsmedchemlett.9b00437

Discovery of New 1,1'-Biphenyl-4-sulfonamides as Selective Subnanomolar Human Carbonic Anhydrase II Inhibitors

ACS Med Chem Lett. 2019 Nov 11;11(5):633-637. doi: 10.1021/acsmedchemlett.9b00437. eCollection 2020 May 14.

Authors

Giuseppe La Regina¹, Michela Puxeddu¹, Marianna Nalli¹, Daniela Vullo², Paola Gratteri³, Claudiu Trandafir Supuran², Alessio Nocentini^{2

3}, Romano Silvestri¹

Affiliations

¹ Laboratory affiliated to Istitut Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185 Rome, Italy.
² NEUROFARBA Department - Pharmaceutical and Nutraceutical Section, University of Firenze, Via Ugo Schiff 6, I-50019 Sesto Fiorentino, Firenze, Italy.
³ NEUROFARBA Department - Pharmaceutical and Nutraceutical Section; Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Firenze, Via Ugo Schiff 6, I-50019 Sesto Fiorentino, Firenze, Italy.

Abstract

We report here the synthesis and human carbonic anhydrases (CA, EC 4.2.1.1) inhibitory properties of a series of 4'-substituted 1,1'-biphenyl-4-sulfonamides incorporating a 2″- or 3″-amino- or carboxyphenyl unit. Most compounds showed significant variations in their inhibition profiles against CA II and IX when compared to previously reported analogs 12-18 bearing a 4″-amino or a 4″-carboxy group. In particular, compounds 1-11 showed considerable improvement of the CA II inhibitory efficacy with K _I values in the subnanomolar range (K _Is spanning between 0.57 and 31.0 nM), a drop of activity against CA IX (K _Is in the range 92.0 to 555.7 nM) and were as potent as 12-18 toward CA I (K _Is in the range 5.9-217.7 nM). Docking and molecular dynamics were used to gain insights on the inhibition profiles. The reported inhibition data show that 1-11 have potential as novel agents to treat ocular pathologies, such as glaucoma, because of the potent and selective targeting of CA II, which is the isoform most implicated in this disease.