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Discovery of New 1,1′-Biphenyl-4-sulfonamides as Selective Subnanomolar Human Carbonic Anhydrase II Inhibitors
journal contribution
posted on 2019-11-12, 20:04 authored by Giuseppe La Regina, Michela Puxeddu, Marianna Nalli, Daniela Vullo, Paola Gratteri, Claudiu Trandafir Supuran, Alessio Nocentini, Romano SilvestriWe 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 KI values in the subnanomolar range (KIs spanning between 0.57 and 31.0 nM), a drop
of activity against CA IX (KIs in the
range 92.0 to 555.7 nM) and were as potent as 12–18 toward CA I (KIs 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.