Bacterial Carbonic Anhydrases as Drug Targets: Toward Novel Antibiotics?

Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes which catalyze the hydration of carbon dioxide to bicarbonate and protons. Many pathogenic bacteria encode such enzymes belonging to the α-, β-, and/or γ-CA families. In the last decade, the α-CAs from Neisseria spp. and Helicobacter pylori as well as the β-class enzymes from Escherichia coli, H. pylori, Mycobacterium tuberculosis, Brucella spp., Streptococcus pneumoniae, Salmonella enterica, and Haemophilus influenzae have been cloned and characterized in detail. For some of these enzymes the X-ray crystal structures were determined, and in vitro and in vivo inhibition studies with various classes of inhibitors, such as anions, sulfonamides and sulfamates reported. Although efficient inhibitors have been reported for many such enzymes, only for Neisseria spp., H. pylori, B. suis, and S. pneumoniae enzymes it has been possible to evidence inhibition of bacterial growth in vivo. Thus, bacterial CAs represent promising targets for obtaining antibacterials devoid of the resistance problems of the clinically used such agents but further studies are needed to validate these and other less investigated enzymes as novel drug targets

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Enzyme Inhibition and more--a tribute to John Smith.

When John Smith founded Journal of Enzyme Inhibition in 1985, there were only a few journals publishing interdisciplinary papers on medicinal/pharmaceutical chemistry. Since it focused on a niche a..

Metal Complexes of 1,3,4-Thiadiazole-2,5-Disulfonamide are Strong Dual Carbonic Anhydrase Inhibitors, although the Ligand Possesses very Weak such Properties

Coordination compounds of Co(II), Ni(II), Cu(II), Zn(II), and Cd(II) with 1,3,4-thiadiazole-2,5-disulfonamide as ligand were synthesized and characterized by IR and UV spectroscopy, conductimetry and thermogravimetry. The parent ligand is a very weak carbonic anhydrase (CA) inhibitor, although it constituted the lead for developing important classes of diuretics. The complex derivatives behave as much stronger CA inhibitors, with IC50 values around 10−8M against isozyme CA II, and 10−7 M against isozyme CAI

Special Issue: Sulfonamides

The sulfonamides and their structurally related derivatives, such as the sulfamates and sulfamides, possess the general formula A-SO2NHR, in which the functional group is either directly bound to an aromatic, heterocyclic, aliphatic, or sugar scaffold (of type A), or appended to such a scaffold via a heteroatom, most frequently oxygen or nitrogen (leading thus to sulfamates and sulfamides, respectively) [...

Complexes With Biologically Active Ligands. Part 1. Synthesis of Coordination Compounds of Diazoxide With Transition- and Main-Group Cations

Complexes of diazoxide (3-methyl-7-chloro-1,2,4-benzothiadiazine-1,1-dioxide) - an antihypertensive and hyperglycemic pharmacological agent - with a series of transition- and main-group di-, triand tetravalent metal ions were prepared and characterized by elemental analysis, spectroscopic, thermogravimetric, magnetic and conductimetric measurements. The complexes were tested as inhibitors of the enzyme carbonic anhydrase (CA), proving modest activity towards CA II and better inhibition of CA I

Complexes With Biologically Active Ligands. Part 2. Preparation of Copper(II) Complexes of Positively-Charged Derivatives of Aminoglutethimide

Cu(II) complexes of 1-[4-(3-ethyl-piperidine-2,6-dione)-3-yl]-phenyl-2,4,6-trisubstituted pyridinium perchlorates, containing alkyl, aryl and combinations of these two types of moieties in their molecule were synthesized and characterized by elemental analysis, spectroscopy, magnetic, thermogravimetric and conductimetric measurements. In these complexes, Cu(II) ions are in octahedral geometry with four water molecules occupying the equatorial coordination sites and the two organic ligands in deprotonated state the remaining axial ones. The donor atom of these ligands is constituted by the ionized nitrogen of the glutarimide moiety. The new derivatives possess weak inhibitory activity towards the zinc enzyme carbonic anhydrase

Thienothiopyransulfonamides as Complexing Agents for the Preparation of Dual Carbonic Anhydrase Inhibitors

Co(II); Zn(II) and Cu(II) complexes of two new sulfonamide carbonic anhydrase (CA) inhibitors, derivatives of thienothiopyran-2-sulfonamide, were prepared and characterized by analytic, spectroscopic, magnetic and conductimetric measurements. The new complexes are more potent CA inhibitors than the parent sulfonamides, with IC50 values around 0.1 nM, against isozyme CA II

Complexes With Biologically Active Ligands. Part 4. Coordination Compounds of Chlorothiazide With Transition Metal Ions Behave as Strong Carbonic Anhydrase Inhibitors

Complexes of the diuretic benzothiadiazine derivative chlorothiazide (6-chloro-7-sulfamoyl- 1,2,4-benzothiadiazine-1,1-dioxide) with V(IV); Fe(II); Co(II); Ni(II); Cu(II), Ag(I) and U(VI) were prepared and characterized by elemental analysis, spectroscopic, thermogravimetric, magnetic and conductimetric measurements. The complexes behave as effective inhibitors for two isozymes (I and II) of carbonic anhydrase (CA)