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 <i>in vitro</i> 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 <b>9a</b>, <b>11a</b>, <b>13a</b>, and <b>24a</b> on hCA II revealed, for the first time, distinct orientations of piperazine and homopiperazine rings within the active site. <i>In vivo</i> testing of the most promising derivatives (<b>9a</b>, <b>11a</b>, <b>13a</b>, and <b>20a</b>) 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 <b>13a</b> produced antihypersensitivity effects at a dose 33-fold lower than reference drugs such as acetazolamide and gabapentin.