Synthesis, ADME/T, and Carbonic Anhydrase Binding of Hydroxycarboxamide Compounds ^†

Abstract

The interconversion of carbon dioxide and the bicarbonate ion is carried out by carbonic anhydrases (CA), which are ubiquitous metalloenzymes with Zn in their active site. Disorder of CA enzymes can cause several diseases such as glaucoma, epilepsy, obesity, and cancer. Many existing drugs have shown effective inhibition of CAs including Acetazolamide, Dorzolamide, Methazolamide, and Valdecoxib. In order to conceive new agents inhibiting CAs, two small molecules were synthesized and characterized by the usual spectroscopic methods. The prepared compounds were obtained by the condensation of dimedone and cyclohexanedione with CSI (chlorosulfonyl isocyanate) in the presence of methanol as a proton donor. The synthesized derivatives contain a primary amide group (CONH₂) bio-isostere of the sulfonamide group (SO₂NH₂) which is present in the quasi-totality of CAs inhibitors. The interactions between our new synthesized molecules and the active site of CAII were determined using docking simulation (PDB: 2AW1); the results showed great stability of these compounds inside the active site with the presence of metallic and hydrogen bonds similar to the ones present between CAII and the reference Valdecoxib. Pharmacokinetic properties and toxicity were predicted using in silico tool SwissADME and Molsoft.