N-aryl-N’-ureido-O-sulfamates: Potent and selective inhibitors of the human Carbonic Anhydrase VII isoform with neuropathic pain relieving properties

• Published in: Bioorganic chemistry Vol. 89; p. 103033
• Main Authors: Bozdag, Murat, Poli, Giulio, Angeli, Andrea, Lucarini, Elena, Tuccinardi, Tiziano, Di Cesare Mannelli, Lorenzo, Selleri, Silvia, Ghelardini, Carla, Winum, Jean-Yves, Carta, Fabrizio, Supuran, Claudiu T.
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.08.2019; Elsevier
• Subjects: Biochemistry & Molecular Biology; Carbonic Anhydrase; Carbonic Anhydrase Inhibitors; Chemical Sciences; Chemistry; Chemistry, Organic; Life Sciences & Biomedicine; N-aryl-N’-ureido-O-sulfamates; Neuropathic pain; Physical Sciences; Science & Technology; N-aryl-N’-ureido-O-sulfamates; Carbonic Anhydrase; Carbonic Anhydrase Inhibitors; Neuropathic pain; SYSTEM; DESIGN; MECHANISM; COUMARINS; DISCOVERY; IX; N-aryl-N '-ureido-O-sulfamates; AFFINITY; GROWTH; SHOW
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.103033

[Display omitted] •An efficient synthesis of N-aryl-N’-ureido-O-sulfamates (AUSs) is reported.•AUS are a new class of CAIs with low nanomolar potencies against the human CA VII.•Modeling deciphered the features behind the selective inhibitory profile of AUS.•A selection of AUS showed promising neuropathic pain modulating effects on animals. Herein we report for the first time an efficient synthetic procedure for the preparation of N-aryl-N’-ureido-O-sulfamates (AUSs) as a new class of Carbonic Anhydrase Inhibitors (CAIs). The compounds were tested for the inhibition of several human (h) Carbonic Anhydrase (CA; EC 4.2.1.1) isoforms. Interesting inhibition activity and high selectivity against CA VII and XII versus CA I and II, with KIs in the low nanomolar range, were observed. Molecular modeling studies allowed us to decipher the structural features underpinning the selective inhibitory profile of AUSs towards isoforms CAs VII and XII. A selection of sulfamates showed promising neuropathic pain modulating effects in an in vivo animal model of oxaliplatin induced pain.