6OE1

Benzensulfonamides bearing spyrohydantoin moieties act as potent inhibitors of human carbonic anhydrases II and VII and show neuropathic pain attenuating effects

Summary for 6OE1

• Entry DOI: 10.2210/pdb6oe1/pdb
• Descriptor: Carbonic anhydrase 2, ZINC ION, GLYCEROL, ... (6 entities in total)
• Functional Keywords: carbonic anhydrase inhibitors, metalloenzymes, organoselenium, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 29923.05

Authors

Peat, T.S. (deposition date: 2019-03-27, release date: 2019-06-12, Last modification date: 2023-10-11)

Primary citation

Angeli, A.,Di Cesare Mannelli, L.,Ghelardini, C.,Peat, T.S.,Bartolucci, G.,Menicatti, M.,Carta, F.,Supuran, C.T.
Benzensulfonamides bearing spyrohydantoin moieties act as potent inhibitors of human carbonic anhydrases II and VII and show neuropathic pain attenuating effects.
Eur.J.Med.Chem., 177:188-197, 2019

PubMed Abstract: 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.

PubMed: 31136893
DOI: 10.1016/j.ejmech.2019.05.058

Experimental method

X-RAY DIFFRACTION (1.45 Å)