Abstract
The inhibition of α-, β-, γ-, and δ-class carbonic anhydrases (CAs, EC 4.2.1.1) from bacteria (Vibrio cholerae and Porphyromonas gingivalis) and diatoms (Thalassiosira weissflogii) with a panel of N’-aryl-N-hydroxy-ureas is reported. The α-/β-CAs from V. cholerae (VchCAα and VchCAβ) were effectively inhibited by some of these derivatives, with KIs in the range of 97.5 nM – 7.26 µM and 52.5 nM – 1.81 µM, respectively, whereas the γ-class enzyme VchCAγ was less sensitive to inhibition (KIs of 4.75 – 8.87 µM). The β-CA from the pathogenic bacterium Porphyromonas gingivalis (PgiCAβ) was not inhibited by these compounds (KIs > 10 µM) whereas the corresponding γ-class enzyme (PgiCAγ) was effectively inhibited (KIs of 59.8 nM – 6.42 µM). The δ-CA from the diatom Thalassiosira weissflogii (TweCAδ) showed effective inhibition with these derivatives (KIs of 33.3 nM – 8.74 µM). As most of these N-hydroxyureas are also ineffective as inhibitors of the human (h) widespread isoforms hCA I and II (KIs > 10 µM), this class of derivatives may lead to the development of CA inhibitors selective for bacterial/diatom enzymes over their human counterparts and thus to anti-infectives or agents with environmental applications.
Highlights
N-Hydroxyurea has been reported1 by our group as a new chemotype belonging to the family of inhibitors of the metallo-enzyme carbonic anhydrase (CA, EC 4.2.1.1)2–6
N-hydroxyurea is a weak, micromolar inhibitor, it was observed to coordinate bidentately to the Zn(II) ion from the hCA II active site, both through its NH and OH groups of the CONHOH fragment of the molecule, which is rather unusual, as all the previously investigated inhibitors at that time were monodentate zinc ligands2. This discovery led to the detailed investigation of organic hydroxamates (RCONHOH) as CA inhibitors (CAIs), which are quite diverse from the main class, prototypical inhibitors of these enzymes, which are the sulfonamides and their isosteres, sulfamates, and sulfamides, all of them incorporating the SO2NH2 moiety as zinc-binding group (ZBG)2–7
The development of non-sulfonamide isoform- or class-selective CAIs is of great interest for targeting enzymes from parasitic bacteria, fungi, or protozoa, which in many cases contain non-a-CAs2–6
Summary
N-Hydroxyurea has been reported by our group as a new chemotype belonging to the family of inhibitors of the metallo-enzyme carbonic anhydrase (CA, EC 4.2.1.1). N-hydroxyurea is a weak, micromolar inhibitor, it was observed to coordinate bidentately to the Zn(II) ion from the hCA II active site, both through its NH and OH groups of the CONHOH fragment of the molecule (presumably deprotonated), which is rather unusual, as all the previously investigated inhibitors at that time were monodentate zinc ligands2 This discovery led to the detailed investigation of organic hydroxamates (RCONHOH) as CA inhibitors (CAIs), which are quite diverse from the main class, prototypical inhibitors of these enzymes, which are the sulfonamides and their isosteres, sulfamates, and sulfamides, all of them incorporating the SO2NH2 moiety as zinc-binding group (ZBG). In the search of isoform- or class-selective CAIs we investigated here a class of recently developed Nhydroxy-ureas, which incorporate a more elaborated organic scaffold attached to the second nitrogen atom (compared to the simple lead molecule, N-hydroxyurea) and which proved to be effective inhibitors of the tumor-associated isoforms hCA IX/XII14, without inhibiting considerably the off-target, house-keeping cytosolic isoforms hCA I and II, which are responsible for the many side effects seen with the sulfonamide type of CAIs2–6
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