Targeting Human Carbonic Anhydrases with Novel Piperazine and Homopiperazine Benzenesulfonamides to Alleviate Paclitaxel-Induced Peripheral Neuropathy

In this study, we developed novel carbonic anhydrase
(CA) inhibitors
potentially useful in managing paclitaxel-induced peripheral neuropathy.
A total of 64 new compounds were synthesized and evaluated for in vitro inhibitory activity against hCAs showing interesting
inhibition activity against hCA II, hCA VA, and hCA VII, the main
isoforms implicated in this pathology. X-ray crystallographic analysis
of compounds 9a, 11a, 13a,
and 24a on hCA II revealed, for the first time, distinct
orientations of piperazine and homopiperazine rings within the active
site. In vivo testing of the most promising derivatives
(9a, 11a, 13a, and 20a) demonstrated significant pain relieving effects in a mouse model
of paclitaxel-induced peripheral neuropathy, with potent and sustained
activity lasting up to 90 min postadministration. Notably, compound 13a produced antihypersensitivity effects at a dose 33-fold
lower than reference drugs such as acetazolamide and gabapentin.