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.