Probing the ‘bipolar’ nature of the carbonic anhydrase active site: Aromatic sulfonamides containing 1,3-oxazol-5-yl moiety as picomolar inhibitors of cytosolic CA I and CA II isoforms

• Published in: European journal of medicinal chemistry Vol. 101; pp. 334 - 347
• Main Authors: Krasavin, Mikhail, Korsakov, Mikhail, Dorogov, Mikhail, Tuccinardi, Tiziano, Dedeoglu, Nurcan, Supuran, Claudiu T.
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 28.08.2015; Elsevier
• Subjects: 1,3-oxadiazol-5-yl aromatics; Anti-glaucoma drugs; Carbonic Anhydrase I - antagonists & inhibitors; Carbonic Anhydrase I - chemistry; Carbonic Anhydrase I - metabolism; Carbonic Anhydrase II - antagonists & inhibitors; Carbonic Anhydrase II - chemistry; Carbonic Anhydrase II - metabolism; Carbonic anhydrase inhibitors; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Catalytic Domain - drug effects; Chemistry, Medicinal; Chemoselective sulfochlorination; Dose-Response Relationship, Drug; Drug discovery; Humans; Isoenzymes - antagonists & inhibitors; Isoenzymes - chemistry; Isoenzymes - metabolism; Isoform selectivity; Life Sciences & Biomedicine; Molecular Structure; Oxazoles - chemistry; Oxazoles - pharmacology; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Isoform selectivity; Carbonic anhydrase inhibitors; 1,3-oxadiazol-5-yl aromatics; Chemoselective sulfochlorination; Drug discovery; Anti-glaucoma drugs; DIOXIDE HYDRATION ACTIVITY; DESIGN; DOMAIN; CRYSTAL-STRUCTURE; ACTIVATORS; RECEPTOR-BASED 3D-QSAR; POTENT; BENZENESULFONAMIDES; BINDING; DERIVATIVES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.06.022

A series of potent inhibitors of human carbonic anhydrase (CA) isoforms I and II has been prepared via a direct, chemoselective sulfochlorination of a range of 1,3-oxazolyl benzenes and thiophenes, followed by primary sulfonamide synthesis. The latter functionality is a known zinc-binding group (ZBG) responsible for anchoring the inhibitors to the CA's zinc metal ion. The compound's periphery as well as the overall scaffold geometry was designed to enable optimal interactions with the two distinct sides of the enzyme's active site, one of which is lined with hydrophobic residues and while the other is predominantly hydrophilic. As a result, several compounds inhibiting the therapeutically important cytosolic CA I and CA II in picomolar range have been identified. These compounds are one of the most potent CA inhibitors identified to-date. Not only the remarkable (>10 000-fold), cytosolic CA I and CA II selectivity vs. the membrane-bound CA IX and CA XII isoforms, but also the pronounced CA II/I selectivity observed in some cases, allow considering this series as a set of isoform-selective chemical biology tools and promising starting points for drug candidate development. [Display omitted] •Novel 1,3-oxazole solfonamides were designed to target carbonic anhydrases.•The chemistry allows varying the periphery groups in a wide range.•Polar and non-polar groups were used to probe the enzyme's bipolar active site.•Picomolar inhibitors of carbonic anhydrase II were identified.•High selectivity between CA I/II and vs. membrane CA IX/XII isoforms was observed.