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We report a series of novel metanilamide-based derivatives 3a – q bearing the 2-mercapto-4-oxo-4 H -quinazolin-3-yl moiety as tail. All compounds were synthesized by means of straightforward condensation procedures and were investigated in vitro for their inhibition potency against the human ( h ) carbonic anhydrase (CA; EC 4.2.1.1.1) isoforms I, II, IX and XII. Among all compounds tested the 6-iodo 3g and the 7-fluoro 3i derivatives were the most potent inhibitors against the tumor associated CA IX and XII isoform (K I s 1.5 and 2.7 nM respectively for the h CA IX and K I s 0.57 and 1.9 nM respectively for the h CA XII). The kinetic data reported here strongly support compounds of this type for their future development as radiotracers in tumor pathologies which are strictly dependent on the enzymatic activity of the h CA IX and XII isoforms. [ABSTRACT FROM AUTHOR]

Herein we report for the first time a series of 2-benzamido -N -(2-oxo-4-(methyl/trifluoromethyl)-2 H -chromen-7-yl) benzamide 3a – f and substituted quinazolin-4(3 H )-ones and 2 H -benzo[e][1,2,4]thiadiazin-3(4 H )-one 1,1-dioxides ( 5 , 6 , 8 and 10a – c ) as selective inhibitors of the tumor associated hCA IX and XII isoforms. Among the compounds reported the trifluoromethyl derivative 3d resulted the most potent against these CA isoforms with K I s of 10.9 and 6.7 nM. [ABSTRACT FROM AUTHOR]

Condensation of substituted anthranilic acids with 4-isothiocyanatoethyl-benzenesulfonamide led to series of heterocyclic benzenesulfonamides incorporating 2-mercapto-quinazolin-4-one tails. These sulfonamides were investigated as inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms hCA I and II (cytosolic isozymes), as well as hCA XII (a transmembrane, tumor-associated enzyme also involved in glaucoma-genesis). The new sulfonamides acted as medium potency inhibitors of hCA I ( K I s of 28.5–2954 nM), being highly effective as hCA II ( K I s in the range of 0.62–12.4 nM) and XII ( K I s of 0.54–7.11 nM) inhibitors. All substitution patterns present in these compounds (e.g., halogens, methyl and methoxy moieties, in positions 6, 7 and/or 8 of the 2-mercapto-quinazolin-4-one ring) led to highly effective hCA II/XII inhibitors. These compounds should thus be of interest as preclinical candidates in pathologies in which the activity of these enzymes should be inhibited, such as glaucoma (CA II and XII as targets) or some tumors in which the activity of isoforms CA II and XII is dysregulated. [ABSTRACT FROM AUTHOR]

Three series of sulfonamides incorporating long, bulky tails were obtained by applying synthetic strategies in which substituted anthranilic acids, quinazolines and aromatic sulfonamides have been used as starting materials. They incorporate long, bulky diamide-, 4-oxoquinazoline-3-yl- or quinazoline-4-yl moieties in their molecules, and were investigated for the inhibition of four physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic human (h) hCA I and II, as well as the transmembrane hCA IX and XII. Most of the new sulfonamides showed excellent inhibitory effects against the four isoforms, with K I s of 7.6–322 nM against hCA I, of 0.06–85.4 nM against hCA II; of 6.7–152 nM against hCA IX and of 0.49–237 nM against hCA XII; respectively. However no relevant isoform-selective behavior has been observed for any of them, although hCA II and XII, isoforms involved in glaucoma-genesis were the most inhibited ones. The structure–activity relationship for inhibiting the four CAs with these derivatives is discussed in detail. [ABSTRACT FROM AUTHOR]

Two new sulfonamides incorporating arylsulfonylureido moieties were complexed with gamma cyclodextrin (γ-CD), hydroxypropyl-gamma cyclodextrin (HPγ-CD), hydroxypropyl-beta cyclodextrin (HPβ-CD) and hydroxyethyl-beta cyclodextrin (HEβ-CD) in order to obtain drug formulations with effective topical intraocular pressure (IOP) lowering effects, in an animal model of glaucoma. The HPγ-CD was the best solubilizing agent for the two sulfonamides and its complexes were characterized in detail and administered to rabbits with eye hypertension of 45–50 mm Hg. The peak IOP lowering was observed after 1 h post-administration and was of 36–37 mm Hg. A low IOP pressure (of around—35 mm Hg) was then maintained for the next 24 h post-administration, which has not been observed before with any IOP lowering drug. [ABSTRACT FROM AUTHOR]

A new series of dithiocarbamates (DTCs) was prepared from primary/secondary amines incorporating amino/hydroxyl-alkyl, mono- and bicyclic aliphatic ring systems based on the quinuclidine, piperidine, hydroxy-/carboxy-/amino-substituted piperidine, morpholine and piperazine scaffolds, and carbon disulfide. The compounds were investigated for the inhibition of four mammalian α-carbonic anhydrases (CAs, EC 4.2.1.1) of pharmacologic relevance, that is, the human (h) hCA I, II, IX and XII, drug targets for antiglaucoma (hCA II and XII) or antitumor (hCA IX/XII) agents. The compounds were moderate or inefficient hCA I inhibitors (off-target isoform for both applications), efficiently inhibited hCA II, whereas some of them were low nanomolar/subnanomolar hCA IX/XII inhibitors. One DTC showed excellent intraocular pressure (IOP) lowering properties in an animal model of glaucoma, with a two times better efficiency compared to the clinically used sulfonamide dorzolamide. [ABSTRACT FROM AUTHOR]

Abstract: 5-(3-Tosylureido)pyridine-2-sulfonamide and 4-tosylureido-benzenesulfonamide (ts-SA) only differ by the substitution of a CH by a nitrogen atom, but they have very different inhibitory properties against the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). By means of X-ray crystallography on the human CA II adducts of the two compounds these differences have been rationalized. As all sulfonamides, the two compounds bind in deprotonated form to the Zn(II) ion from the enzyme active site and their organic scaffolds extend throughout the cavity, participating in many interactions with amino acid residues and water molecules. However the pyridine derivative undergoes a tilt of the heterocyclic ring compared to the benzene analog, which leads to a very different orientation of the two scaffolds when bound to the enzyme. This tilt also leads to a clash between a carbon atom from the pyridine ring of the first inhibitor and the OH moiety of Thr200, leading to less effective inhibitory properties of the pyridine versus the benzene sulfonamide derivative. Indeed, ts-SA is a promiscuous, low nanomolar inhibitor of 7 out of 10 human (h) CA isoforms, whereas the pyridine sulfonamide is a low nanomolar inhibitor only of the tumor-associated hCA IX and XII, being less effective against other 9 isoforms. Thus, a difference of one atom (N vs CH) in two isostructural sulfonamides leads to drastic differences of activity, phenomenon understood at the atomic level through the high resolution crystallographic structure and kinetic measurements reported in the paper. Combining the tail and the ring approaches in the same chemotype leads to isoform-selective, highly effective sulfonamide CA inhibitors. [Copyright &y& Elsevier]

Abstract: Protein arginin deaminase 4 (PAD4) is a calcium dependent enzyme which catalyses the conversion of peptidyl-arginine into peptidyl-citrulline and is implicated in several diseases such as rheumatoid arthritis (RA) and cancer. Herein we report the discovery of novel small-molecule, non peptidic PAD4 inhibitors incorporating primary/secondary guanidine moieties. [Copyright &y& Elsevier]

[Display omitted] We report for the first time a small series of compounds endowed in vitro with inhibitory properties for the human (h) expressed Carbonic Anhydrase (CAs, E.C. 4.2.1.1) enzymes of physiological interest (i.e. I, II, VA, IX and XII) and bearing the pyrazolo[1,5- a ]pyrimidine (PP) scaffold at the tail section. Among the series reported, 1a-3a , 7a , 8a , 1b and 2b resulted effective ligands and with good selectivities for the hCAs II, IX or XII. In consideration of the nearly matching K I values of 7a for both the hCA II and IX (i.e. 26.4 and 23.0 nM respectively) we explored its binding mode within the CA IX mimic isoform by means of X-ray crystal experiments on the corresponding adduct. [ABSTRACT FROM AUTHOR]

Carbonic anhydrase inhibitors (CAIs) of the sulfonamide, sulfamate and coumarin classes bearing the phenylureido tail found in the clinically used drug Sorafenib, a multikinase inhibitor actually used for the management of hepatocellular carcinomas, are reported. All compounds were assayed on human (h) CA isoforms I, II, VII and IX, involved in various pathologies. Among the sulfonamides, several compounds were selective for inhibiting hCA IX, with K I values in the low nanomolar ranges (i.e. 0.7–30.2 nM). We explored the binding modes of such compounds by means of X-ray crystallographic studies on isoform hCA I in adduct with one sulfonamide and a sulfamate inhibitor. Antiproliferative properties of some sulfamates on breast tumor cell lines were also investigated. Image 1 • CAIs by merging the multikinase inhibitor sorafenib with the benzene sulfonamide hCA IX inhibitor SLC-0111 are reported. • Sulfamates 23 and 24 decrease proliferation breast cancer cell lines at concentrations above 10 μM. • The binding modes of compounds 17 and 23 on the hCA I isoform by means of X-ray crystallographic studies are reported. [ABSTRACT FROM AUTHOR]

Abstract: A series of 7-substituted sulfocoumarins and 3,4-dihydrosulfocoumarins was obtained by cyclization of the methanesulfonate of 2,4-dihydroxy- or 2-hydroxy-4-methoxybenzaldehyde, followed by derivatization reactions. The new compounds incorporate a range of substituents in position 7 of the heterocyclic ring (hydroxyl, methoxy, carboxylic and alkylsulfonate ester). The compounds were tested for the inhibition of the zinc enzyme human (h) carbonic anhydrase (hCA, EC 4.2.1.1). Unlike the 6-substituted sulfocoumarins which were potent hCA IX and XII inhibitors and ineffective hCA I and II inhibitors, compounds from this series showed low nanomolar hCA II inhibitory properties, and inhibited the mitochondrial isoform hCA VA with K Is in the range of 91–9960nM, but were ineffective as hCA I, IX and XII inhibitors. The structure activity relationship for this class of inhibitors was rather clear, with the nature of the 7-substituent strongly influencing hCA VA inhibition, whereas the nature of these groups were less relevant for hCA II inhibition (all reported compounds were highly effective hCA II inhibitors, with K Is in the range of 1.5–8.4nM). Since both hCA II and hCA VA are important drug targets (hCA II for antiglaucoma agents; hCA VA for antiobesity drugs), these isoform-selective inhibitors reported here may be considered of interest for various biomedical applications. [Copyright &y& Elsevier]

A series of dithiocarbamates (DTCs) was investigated for the inhibition of the β-class carbonic anhydrase (CAs, EC 4.2.1.1) from the fungal parasite Malassezia globosa , MgCA, a validated anti-dandruff drug target. These DTCs incorporate various scaffold, among which those of N,N-dimethylaminoethylenediamine, the aminoalcohols with 3–5 carbon atoms in their molecule, 3-amino-quinuclidine, piperidine, morpholine and piperazine derivatives, as well as phenethylamine and its 4-sulfamoylated derivative. Several DTCs resulted more effective in inhibiting MgCA compared to the standard sulfonamide drug acetazolamide (K I of 74 μM), with K I s ranging between 383 and 6235 nM. A computational approach, involving a homology modeling of the enzyme and docking inhibitors within its active site, helped us rationalize the results. This study may contribute to better understand the inhibition profile of MgCA, and offer new ideas for the design of modulators of activity which belong to less investigated chemical classes, thus potentially useful to combat dandruff and other fungal infections. [ABSTRACT FROM AUTHOR]