We report a series of compounds 1–17 derived from the antiepileptic drug Sulthiame (SLT) from which both the benzenesulfonamide and the sultam moiety were retained. All compounds were tested in vitro for their inhibition activity against the human (h) Carbonic Anhydrase (CA; EC 4.2.1.1) I, II, VII, IX and XII isoforms. Among the series, derivatives 1 and 11 showed great enhancement of both inhibition potency and selectivity towards the hCA VII isoform, when compared to the reference SLT drug. The binding mode of 11 within the hCA VII active site was deciphered by means of X-ray crystallography and revealed the sultam moiety being exposed to the rim of the active site. In vivo experiments on a model of neuropathic pain induced by oxaliplatin clearly showed 11 being an effective pain relieving agent and therefore worth of further exploitation towards the validation of the hCA VII as new target for the management of neuropathies.
Sultam based Carbonic Anhydrase VII inhibitors for the management of neuropathic pain / Akgul O.; Lucarini E.; Mannelli L.D.C.; Ghelardini C.; D'Ambrosio K.; Buonanno M.; Monti S.M.; De Simone G.; Angeli A.; Supuran C.T.; Carta F.. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - ELETTRONICO. - 227:(2022), pp. 0-0. [10.1016/j.ejmech.2021.113956]
Sultam based Carbonic Anhydrase VII inhibitors for the management of neuropathic pain
Lucarini E.;Ghelardini C.;Angeli A.;Supuran C. T.;Carta F.
2022
Abstract
We report a series of compounds 1–17 derived from the antiepileptic drug Sulthiame (SLT) from which both the benzenesulfonamide and the sultam moiety were retained. All compounds were tested in vitro for their inhibition activity against the human (h) Carbonic Anhydrase (CA; EC 4.2.1.1) I, II, VII, IX and XII isoforms. Among the series, derivatives 1 and 11 showed great enhancement of both inhibition potency and selectivity towards the hCA VII isoform, when compared to the reference SLT drug. The binding mode of 11 within the hCA VII active site was deciphered by means of X-ray crystallography and revealed the sultam moiety being exposed to the rim of the active site. In vivo experiments on a model of neuropathic pain induced by oxaliplatin clearly showed 11 being an effective pain relieving agent and therefore worth of further exploitation towards the validation of the hCA VII as new target for the management of neuropathies.
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