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Carbonic Anhydrases have been recently validated as novel therapeutic targets in neuropathic pain. In this study, we combine the anticonvulsant propriety of spyrohydantoin and the CA inhibitor moiety of benzenesulfonamide to synthesize a novel series of spyrohydantoin bearing sulfonamides with strong activity against hCA II and VII. These isoforms are present in the nervous system and largely expressed both at the central as well as at peripheral level and can be modulated for pain relief. The crystal structures of hCA II in complex with selected compounds 5a-c demonstrate the importance of the tail in the binding modes within the isoform. Finally, in vivo , in an animal model of oxaliplatin induced neuropathy, compounds with organoselenium tails (8b-c) showed potent neuropathic pain attenuating effects. Taken together, these data strongly suggest the translational utility of these inhibitors as novel pain relievers. Image 1 • Synthesis of novel spyrohidantoin bearing benzenesulfonamide is reported. • Correlation between CAs and neuropathic pain calls for the synthesis of new agents with neuropathic pain modulating effect. • In vitro studies reported potent inhibition activity against CA isoforms correlated to connected to chronic pain. • Determined X-ray structure of hCA II in complex with 3 compounds in order to obtain ligand−protein interactions. • In vivo studies showed good neuropathic pain modulating effects. [ABSTRACT FROM AUTHOR]