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. 2022 Dec;37(1):1568-1576.
doi: 10.1080/14756366.2022.2080816.

4-(3-Alkyl/benzyl-guanidino)benzenesulfonamides as selective carbonic anhydrase VII inhibitors

Morteza Abdoli  1 , Simone Giovannuzzi  2 , Claudiu T Supuran  2 , Raivis Žalubovskis  1   3
Affiliations

4-(3-Alkyl/benzyl-guanidino)benzenesulfonamides as selective carbonic anhydrase VII inhibitors

Morteza Abdoli et al. J Enzyme Inhib Med Chem. 2022 Dec.

Abstract

The treatment of chronic neuropathic pain remains one of the most challenging of all neurological diseases and very much an art. There exists no consensus for the optimal management of this condition at the moment. Gaining inspiration from recent studies which pointed out the involvement of brain-associated carbonic anhydrase (CA, EC 4.2.1.1) isoform VII in the pathology of various neurodegenerative diseases, which highlighted the relationship between selective inhibition of this isozyme and relieve of neuropathic pain, herein we report the synthesis and CA VII inhibitory activity of novel 4-(3-alkyl/benzyl-guanidino)benzenesulfonamides. Ten benzyl-substituted and five alkyl-substituted 4-guanidinobenzenesulfonamide derivatives were obtained, some of which (7c, 7h, 7m and 7o) exhibited satisfactory selectivity towards CA VII over CA I and II, with KI-s in the subnanomolar range and good selectivity indexes for inhibiting the target versus the off-target isoforms.

Keywords: Neurological diseases; carbonic anhydrase isozyme VII; guanidine-benzenesulfonamides; neuropathic pain; sulfonamides.

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Conflict of interest statement

No potential conflict of interest was reported by all author(s) except CTS. CT Supuran is Editor-in-Chief of the Journal of Enzyme Inhibition and Medicinal Chemistry. He was not involved in the assessment, peer review, or decision-making process of this paper. The authors have no relevant affiliations of financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Figures

Figure 1.
Figure 1.
Selected examples of the guanidine-containing sulfonamide CAIs.
Figure 2.
Figure 2.
General structure of 4-(3-alkyl/benzyl-guanidino)benzenesulfonamides discussed in the paper.
Scheme 1.
Scheme 1.
Reagents and conditions: (i) KSCN, aq. 3.5 M HCl, reflux, 3 h, 31%; (ii) MeI, DMF, 40 °C, 2.5 h, 70%; (iii) HNR1R2 (8 equiv.), DMSO, 130 °C, 2–6 h.
See this image and copyright information in PMC

References

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