Sulfonamide/sulfamate switch with a series of piperazinylureido derivatives: Synthesis, kinetic and in silico evaluation as carbonic anhydrase isoforms I, II, IV, and IX inhibitors

  • Eur J Med Chem. 2020 Jan 15;186:111896. doi: 10.1016/j.ejmech.2019.111896.
Alessio Nocentini  1 ,  Davide Moi  2 ,  Alessandro Deplano  3 ,  Sameh M Osman  4 ,  Zeid A AlOthman  4 ,  Gianfranco Balboni  2 ,  Claudiu T Supuran  1 ,  Valentina Onnis  5
Affiliations
  • 1. Department NEUROFARBA - Pharmaceutical and Nutraceutical Section, University of Firenze, Via Ugo Schiff 6, I-50019, Sesto Fiorentino, Firenze, Italy.
  • 2. Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, Via Ospedale 72, I-09124, Cagliari, Italy.
  • 3. Pharmacelera, Placa Pau Vila, 1, Sector 1, Edificio Palau de Mar, Barcelona, 08039, Spain.
  • 4. Chemistry Department, College of Science, King Saud University, P. O. Box 2455, Riyadh, 11451, Saudi Arabia.
  • 5. Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, Via Ospedale 72, I-09124, Cagliari, Italy. Electronic address: [email protected].
PMID: 31784185 DOI: 10.1016/j.ejmech.2019.111896
Abstract

We report here a thorough structure-activity relationship (SAR) with piperazinylureido sulfamates as inhibitors of human (h) Carbonic Anhydrase (CA, EC 4.2.1.1). A SAR investigation over the structure of reported anti-cancer zinc-binder CAIs such as SLC-0111 and S4 was carried out by including the urea outer nitrogen atom into a substituted piperazine ring reducing the linker flexibility. The derivatives were assessed for the inhibition of CA I, II and IV (off-target isoforms) and the tumor-associated CA IX (Anticancer drug target). CA I and IV were not effectively inhibited, whereas many low nanomolar inhibitors were evidenced against CA II (KIs in the range of 1.0-705.5 nM), and IX (KIs in the range of 0.91-155.9 nM). Interestingly, a subset of CA II/IX selective inhibitors was detected which might represent interesting lead for the development of new Anticancer strategies.

Keywords
Antitumor; Bioisoster; Inhibitor; Metalloenzyme; Selectivity.
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