Phenyl(thio)phosphon(amid)ate Benzenesulfonamides as Potent and Selective Inhibitors of Human Carbonic Anhydrases II and VII Counteract Allodynia in a Mouse Model of Oxaliplatin-Induced Neuropathy

Human carbonic anhydrase
(CA; EC 4.2.1.1) isoforms II and VII are implicated
in neuronal excitation, seizures, and neuropathic pain (NP). Their
selective inhibition over off-target CAs is expected to produce an
anti-NP action devoid of side effects due to promiscuous CA modulation.
Here, a drug design strategy based on the observation of (dis)­similarities
between the target CA active sites was planned with benzenesulfonamide
derivatives and, for the first time, a phosphorus-based linker. Potent
and selective CA II/VII inhibitors were identified among the synthesized
phenyl­(thio)­phosphon­(amid)­ates 3–22. X-ray crystallography depicted the binding mode of phosphonic acid 3 to both CAs II and VII. The most promising derivatives,
after evaluation of their stability in acidic media, were tested in
a mouse model of oxaliplatin-induced neuropathy. The most potent compound
racemic mixture was subjected to HPLC enantioseparation, and the identification
of the eutomer, the (S)-enantiomer, allowed to halve
the dose totally relieving allodynia in mice.