Sulfa drugs as inhibitors of carbonic anhydrase: new targets for the old drugs.

Sulfa drugs are well-known antibacterial agents containing N-substituted sulfonamide group on para position of aniline ring (NH2RSO2NHR'). In this study 2,4-dichloro-1,3,5-triazine derivatives of sulfa drugs, sulfamerazine (1b), sulfaquinoxaline (2b), sulfadiazine (3b), sulfadimidine (4b), and sulfachloropyrazine (5b) (1a-5a) were synthesized and characterized. Their carbonic anhydrase inhibition activity was evaluated against bovine cytosolic carbonic anhydrase isozyme II (bCA II). For the sake of comparison the CA inhibition activity of the parent sulfa drugs (1b-5b) was also evaluated. A significant increase in CA inhibition activity of sulfa drugs was observed upon substitution with 2,4-dichloro-1,3,5-triazine moiety. Molecular docking studies were carried out to highlight binding site interactions. ADME properties were calculated to evaluate drug likeness of the compounds.

Preparation and characterization of chitosan nanopores membranes for the transport of drugs.

In this paper, a novel chitosan nanopores membrane was developed by selective dissolution of its composition. Polyethylene glycol (PEG) as the porogen was selected to generate the nanopores structure of chitosan membrane. As the observation with scanning electron microscopy (SEM), we could find that the PEG content was greatly influenced on the structure of chitosan membrane. As the PEG content was larger than 50%, the chitosan nanopores membrane could successfully developed. Differential scanning calorimeter (DSC) measurement revealed that the PEG component could not be completely dissolved from the membrane and there was presence the possible interaction (hydrogen bond) between two components. Water adsorption test suggested that the obtained membranes have the great capacity of water adsorption ranging from 162.4 ± 22.5% to 321.5 ± 6.5%. In vitro degradation experiment showed that the obtained chitosan membranes have good biodegradability in the lysozyme solution. The permeability test was performed with two model drugs: vitamin B12 (non-ionic water-soluble drug) and sodium sulfamerazine (ionic water-soluble drug). And the results showed that these two drugs have significant differences in the permeability, indicating that chitosan nanopores membranes can potentially be used to the transport of drugs with controlled diffusion manner.

Antifungal activity of silver and zinc complexes of sulfadrug derivatives incorporating arylsulfonylureido moieties.

Two well known antimicrobial sulfonamides, sulfadiazine and sulfamerazine were reacted with arylsulfonyl isocyanates, affording several new arylsulfonylureido derivatives. These compounds were subsequently used as ligands (in the form of conjugate bases, as sulfonamide anions) for the preparation of metal complexes containing silver and zinc. The newly synthesized complexes, unlike the free ligands, proved to act as effective antifungal agents against several Aspergillus and Candida spp., some of them showing activities comparable to ketoconazole, with minimum inhibitory concentrations in the range of 1.5-5 microg/ml. The mechanism of antifungal action of these complexes seems to be different from that of the azole antifungals acting as lanosterol-14-alpha-demethylase inhibitors. Levels of sterols assayed in the fungi cultures treated with these new antifungals were equal in the absence or in the presence of the tested compounds. This is in strong contrast with similar experiments in which ketoconazole has been used as antifungal, when drastically reduced ergosterol amounts could be detected. Thus, it is probable that the inhibition of phosphomannose isomerase, a key enzyme in the biosynthesis of yeast cell walls, imparts antifungal activity to the new metal complexes reported here.

Pharmacokinetics, metabolism, and renal clearance of sulfadiazine, sulfamerazine, and sulfamethazine and of their N4-acetyl and hydroxy metabolites in calves and cows.

The effect of molecular structure on the drug disposition and protein binding in plasma and milk, the urinary recovery, and the renal clearance of sulfadiazine, sulfamerazine, and sulfamethazine and of their N4-acetyl and hydroxy derivatives were studied in calves and cows. Sulfadiazine was highly acetylated and was slightly hydroxylated. Sulfamerazine and sulfamethazine were hydroxylated predominantly at the methyl group of the pyrimidine side chain; hydroxylation of the pyrimidine ring itself was more extensive for sulfamethazine than for sulfamerazine. At dosages between 100 and 200 mg/kg of body weight, sulfamethazine had a capacity-limited elimination pattern, which was not observed for sulfadiazine or sulfamerazine. The concentrations of the parent sulfonamide and its metabolites in plasma and milk were parallel, the latter being lower. Metabolite concentrations in milk were at least 8 times lower than those of the parent drug. Metabolism speeds drug elimination, producing compounds with renal clearance values higher than those of the parent drug. The effect on the metabolism and renal clearance of methyl substitution in the pyrimidine side chain is discussed.

Isolation and identification of 4-hydroxysulfamerazine and preliminary studies on its pharmacokinetics in dogs.

For the following compounds: sulfamerazine, 4- hydroxysulfamerazine , N4- acetylsulfamerazine , N4-acetyl-4- hydroxysulfamerazine , the following data are reported: biosynthesis in the dog, isolation, identification by MS and NMR, TLC (Rf values) and HPLC (capacity factors and molar extinction), half-life of elimination, metabolism, renal excretion and protein binding in dog. Dogs are unable to acetylate sulfamerazine, but eliminate predominantly by hydroxylation of the N1-substituent. Administered N4- acetylsulfamerazine is predominantly eliminated by deacetylation to sulfamerazine which in turn is hydroxylated. The renal clearances of sulfamerazine and N4- acetylsulfamerazine in the dog are identical. The renal excretion of both compounds proceeds by the passive processes of glomerular filtration and tubular reabsorption. 4- Hydroxysulfamerazine and its glucuronide have a higher renal clearance than sulfamerazine.

Pharmacokinetics, acetylation-deacetylation, renal clearance, and protein binding of sulphamerazine, N4-acetylsulphamerazine, and N4-trideuteroacetylsulphamerazine in 'fast' and 'slow' acetylators.

Sulphamerazine shows a clear acetylator phenotype. The half-life of elimination of sulphamerazine is 12 h in 'fast' and 24 h in 'slow' acetylators. N4-Acetylsulphamerazine is eliminated biphasically, characterized by half-lives of 5 and 12 h in 'fast' and 5 and 24 h in 'slow' acetylators. Protein binding of sulphamerazine (86 per cent) and N4-acetylsulphamerazine (92 per cent) is independent of acetylator phenotype or the origin of the compound, whether it is present in the body as parent compound or metabolite. The renal clearance of sulphamerazine (20 ml min-1) and N4-acetylsulphamerazine (300-500) ml min-1) is independent of the acetylator type and the origin of the compound. The existence of an acetylation-deacetylation equilibrium in the metabolism of sulphamerazine has been demonstrated with the test drug N4-trideuteroacetylsulphamerazine, which inhibits the renal excretion and clearance of N4-acetylsulphamerazine.