Abstract
A large library of fibrate-based N-acylsulphonamides was designed, synthesised, and fully characterised in order to propose them as zinc binders for the inhibition of human carbonic anhydrase (hCA) enzymatic activity. Synthesised compounds were tested against four hCAs (I, II, IX, and XII) revealing a promising submicromolar inhibitory activity characterised by an isozyme selectivity pattern. Structural modifications explored within this scaffold are: presence of an aryl ring on the sulphonamide, p-substitution of this aryl ring, benzothiazole or benzophenone as core nuclei, and an n-propyl chain or a geminal dimethyl at Cα carbon. Biological results fitted well with molecular modelling analyses, revealing a putative direct interaction with the zinc ion in the active site of hCA I, II and IX. These findings supported the exploration of less investigated secondary sulphonamides as potential hCA inhibitors.
Highlights
Sulphonamides and their N-acyl derivatives represent common functional groups occurring in natural and synthetic drugs
N-substituted sulphonamides, among other secondary sulphonamides, have been identified as strong human carbonic anhydrases (CAs) I and II inhibitors, showing nanomolar inhibition constants18,19. They were characterised by an ionisable moiety as zinc binder directly interacting with the zinc ion in the active site, as demonstrated by X-ray crystallographic studies of human carbonic anhydrase II-inhibitor adducts20
In the attempt to identify novel CA inhibitors, in this work, we describe the screening of N-acylsulphonamide derivatives previously synthesised and identified as PPAR antagonists21,22
Summary
Sulphonamides and their N-acyl derivatives represent common functional groups occurring in natural and synthetic drugs. Secondary sulphonamides represent an important class of drugs targeting carbonic anhydrases (CAs)13–16 These metalloenzymes, catalysing the CO2 hydration reaction, are involved in several physiologic functions, depending on their distribution in different tissues. N-substituted sulphonamides, among other secondary sulphonamides, have been identified as strong human CA I and II inhibitors, showing nanomolar inhibition constants. N-substituted sulphonamides, among other secondary sulphonamides, have been identified as strong human CA I and II inhibitors, showing nanomolar inhibition constants18,19 They were characterised by an ionisable moiety as zinc binder directly interacting with the zinc ion in the active site, as demonstrated by X-ray crystallographic studies of human carbonic anhydrase (hCA) II-inhibitor adducts. In the attempt to identify novel CA inhibitors, in this work, we describe the screening of N-acylsulphonamide derivatives previously synthesised and identified as PPAR antagonists. Molecular modelling studies were carried out to explain the putative interactions between this library of heterocyclic compounds and the active sites of the four isozymes in order to rationalise future synthetic approaches within this
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Journal of Enzyme Inhibition and Medicinal Chemistry
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
