Discovery of new 1,1'-biphenyl-4-sulfonamides as selective subnanomolar human carbonic anhydrase II inhibitors

[Image: see text] 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(I)s spanning between 0.57 and 31.0 nM), a drop of activity against CA IX (K(I)s in the range 92.0 to 555.7 nM) and were as potent as 12–18 toward CA I (K(I)s 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.