Supplementary data for the article: Cvijetić, I. N.; Tanç, M.; Juranić, I. O.; Verbić, T. Ž.; Supuran, C. T.; Drakulić, B. J. 5-Aryl-1H-Pyrazole-3-Carboxylic Acids as Selective Inhibitors of Human Carbonic Anhydrases IX and XII. Bioorganic and Medicinal Chemistry 2015, 23 (15), 4649–4659. https://doi.org/10.1016/j.bmc.2015.05.052

Supplementary material for: [https://doi.org/10.1016/j.bmc.2015.05.052]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1742]Related to accepted version: [http://cherry.chem.bg.ac.rs/handle/123456789/3327

Supplementary data for the article: Cvijetić, I. N.; Tanç, M.; Juranić, I. O.; Verbić, T. Ž.; Supuran, C. T.; Drakulić, B. J. 5-Aryl-1H-Pyrazole-3-Carboxylic Acids as Selective Inhibitors of Human Carbonic Anhydrases IX and XII. Bioorganic and Medicinal Chemistry 2015, 23 (15), 4649–4659. https://doi.org/10.1016/j.bmc.2015.05.052

Supplementary material for: [https://doi.org/10.1016/j.bmc.2015.05.052]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1742]Related to accepted version: [http://cherry.chem.bg.ac.rs/handle/123456789/3327

Exploring carbonic anhydrase inhibition with multimeric coumarins displayed on a fullerene scaffold

This study reports the first synthesis of multimeric suicide inhibitors of carbonic anhydrases.</p

5-Aryl-1H-pyrazole-3-carboxylic acids as selective inhibitors of human carbonic anhydrases IX and XII

Inhibitory activity of a congeneric set of 23 phenyl-substituted 5-phenyl-pyrazole-3-carboxylic acids toward human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms I, II, IX and XII was evaluated by a stopped-flow CO2 hydrase assay. These compounds exerted a clear, selective inhibition of hCA IX and XII over hCAI and II, with Ki in two to one digit micromolar concentrations (4-50 mu M). Derivatives bearing bulkier substituents in para-position of the phenyl ring inhibited hCA XII at one-digit micromolar concentrations, while derivatives having alkyl substituents in both ortho-and meta-positions inhibited hCA IX with Kis ranging between 5 and 25 mu M. Results of docking experiments offered a rational explanation on the selectivity of these compounds toward CA IX and XII, as well as on the substitution patterns leading to best CA IX or CA XII inhibitors. By examining the active sites of these four isoforms with GRID generated molecular-interaction fields, striking differences between hCA XII and the other three isoforms were observed. The field of hydrophobic probe (DRY) appeared significantly different in CA XII active site, comparing to other three isoforms studied. To the best of our knowledge such an observation was not reported in literature so far. Considering the selectivity of these carboxylates towards membrane-associated over cytosolic CA isoforms, the title compounds could be useful for the development of isoform-specific non-sulfonamide CA inhibitors.Peer-reviewed manuscript: [http://cherry.chem.bg.ac.rs/handle/123456789/3327]Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3328

Human carbonic anhydrase inhibitory profile of mono- and bis-sulfonamides synthesized via a direct sulfochlorination of 3- and 4-(hetero)arylisoxazol-5-amine scaffolds

Three distinct series of isoxazole-based primary mono- and bis-sulfonamides have been synthesized via direct sulfochlorination, each of them delivering nanomolar inhibitors of human carbonic anhydrase. Certain pronounced SAR trends have been established and rationalized by in silico docking. These findings expand the structure-activity knowledge base for heterocycle-containing sulfonamide carbonic anhydrase inhibitors and further validate the power of direct electrophilic sulfochlorination as a means of introducing the pharmacophoric primary sulfonamide group into structurally diverse aromatic precursors

Isoform-selective inhibitory profile of 2-imidazoline-substituted benzene sulfonamides against a panel of human carbonic anhydrases

<p>A series of novel benzene sulfonamides (previously evaluated as selective cyclooxygenase-2 inhibitors) has been profiled against human carbonic anhydrases I, II, IV and VII in an attempt to observe the manifestation of the well established “tail” approach for designing potent, isoform-selective inhibitors of carbonic anhydrases (CAs, EC 4.2.1.1). The compounds displayed an excellent (pKi 7–8) inhibitory profile against CA II (a cytosolic anti-glaucoma and anti-edema biological target) and CA VII (also a cytosolic target believed to be involved in epilepsy and neuropathic pain) and a marked (1–2 orders of magnitude) selectivity against cytosolic isoform CA I and membrane-bound isoform CA IV. The separation of the CA II and CA IV (both of which are catalytically active isoforms, highly sensitive to sulfonamide-type inhibitors) is particularly remarkable and is adding significantly to the global body of data on the chemical biology of carbonic anhydrases.</p

Multimeric xanthates as carbonic anhydrase inhibitors

The field of multivalent inhibition of enzymes is growing exponentially from the first reported multivalent effect on a glycosidase enzyme. However, the investigations have generally remained restricted to carbohydrate-processing enzymes. Carbonic anhydrases are ubiquitous metallo-enzymes involved in many key biological processes, that catalyze the reversible hydration/dehydration of . This study reports the first synthesis of multimeric xanthates addressing the selectivity and potency of CA multivalent inhibition. Six multivalent compounds containing three, four, and six xanthate moieties were prepared and assayed against four relevant CA isoforms together with their monovalent analogues. Some of the multimers were stronger inhibitors than the monomeric species. For hCA I, the two best molecules 18 and 20 showed an improvement of the ligand affinity of 4.8 and 2.3 per xanthate units (valence-corrected values), respectively, which corresponds to a clear multivalent effect. Moreover, the biochemical assays demonstrated that the multimeric presentation of xanthates, also affected the selectivity of the relative inhibition among the four CAs assayed