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.

Liquid chromatography/electrospray ionization quadrupole time-of-flight mass spectrometry for the analysis of sulfaquinoxaline byproducts formed in water upon solar light irradiation.

RATIONALE: Sulfonamides such as sulfaquinoxaline (SQX) are among the most important antibiotic families due to their extensive use in veterinary medicine. The prediction of their fate under solar irradiation through the identification of the generated metabolites is required. However, unambiguous structural characterizations often remain a challenge particularly when several isomers could match with the same MS(2) data. METHODS: Liquid chromatography/electrospray ionization quadrupole time-of-flight mass spectrometry (LC/ESI-Q-TOFMS) in the positive ion mode, leading to the formation of the protonated forms of the studied compounds, [M + H(+)] ions, was employed. Collision-induced dissociation tandem mass spectrometry (CID-MS/MS) of the protonated molecules was carried out, and the effect of the collision energy as well as the elemental compositions of the product ions were used to propose chemical structures. Validation of the hypothesized structures was performed by the calculation of key fragmentation pathway energies using density functional theory (DFT) calculations (B3LYP/6-31 G (d,p)). RESULTS: The photoproducts were identified as 2-aminoquinoxaline, SQX isomers, 2-(N-parabenzoquinoneimine)quinoxaline and isomers resulting from SO(2) extrusion. The direct fragmentations of [SQX + H](+) and its protonated isomers mostly occurred through the loss of 2-aminoquinoxaline and/or the 4-sulfoaniline radical ion, while their rearrangements involved the migration of H and/or O atoms. For the desulfonated byproducts in their protonated forms, the main neutral losses were of the quinoxaline radical, aminoquinoxaline and NH(3). The fragmentation of the protonated 2-aminoquinoxaline mainly involved the elimination of NH(3) and HCN. CONCLUSIONS: LC/ESI-Q-TOFMS and DFT calculations have been shown to be useful and complementary methods for the identification of unknown isomeric compounds and the elucidation of fragmentation patterns, in the case of the sulfaquinoxaline veterinary antibiotic.

Tissue residues of some sulphonamides in normal and Eimeria stiedai infected rabbits.

Tissue residues of sulphadiazine (SDZ), sulphadimidine (SDD) and sulphquinoxaline (SQ) were studied in healthy and E. stiedai infected rabbits following oral administration of 0.5 g/l drinking water for 5 days. The solid-phase extraction and HPLC was used to determine the concentration of the three sulphonamides in a single tissue sample. SDZ was detected in the liver and kidney in concentrations below the tolerance levels at day 5 and no residues could be detected at day 7 after drug withdrawal. SDD and SQ were detected in all of the tested organs of healthy rabbits up to day 5, where the highest concentration was reported in the liver (0.08 +/- 0.02 and 0.09 +/- 0.02 g/g respectively). In infected rabbits, the three sulphonamides were detected up to day 7 in concentrations higher than the tolerance limits (> 0.1 g/g) in the liver and kidney and lower levels in other tissues. A withdrawal period of 4 days for SDZ and 5 days for SDD and SQ in healthy rabbits and 7 days for SDZ and 8 days for SDD and SQ in E. stiedai infected rabbits is suggested.

Decreasing profile of residual sulphaquinoxaline in eggs.

1. Sulphaquinoxaline (SQ) was added to the diet of laying hens at 200 mg/kg for 7 successive days. Contents (mg/kg) of SQ in albumen and egg yolk of eggs laid after drug withdrawal were determined by high pressure liquid chromatography (HPLC). The contents in the whole egg were calculated taking into consideration the respective weights of albumen and egg yolk. 2. A time-lag in the initiation of decrease of SQ from eggs after the withdrawal of dietary SQ was observed. 3. The decreasing pattern from whole egg could be well described by the following equation with a time-lag of 1.0 d, y = 2.07 e-0.5620(t-1.0), where y is the SQ content in whole egg, t is time (d) after the withdrawal of dietary SQ and a constant of 2.07 is the SQ content in whole egg laid at the withdrawal. 4. Biological half-life of SQ in the whole egg was estimated to be 1.23 d. 5. From the above equation, SQ residue of whole egg laid at 9th d after withdrawal will be below the detection limit of 0.01 mg/kg.

Liquid chromatographic analysis of sulfaquinoxaline and its application to pharmacokinetic studies in rabbits.

A specific, sensitive high-performance liquid chromatographic method is described for sulfaquinoxaline (I) and its major metabolite, the N4-acetyl metabolite (II), in biological fluids. Detection limits for I and II were 0.25 and 0.50 micrograms/mL in plasma and 0.10 and 0.20 micrograms/mL in urine, respectively. The pharmacokinetics of sulfaquinoxaline and its metabolite were studied in New Zealand White rabbits after individual doses of 50 mg/kg of sulfaquinoxaline and its metabolite were administered intravenously. Mean (+/- SD) plasma half-lives were 12.7 (8.0) h for sulfaquinoxaline and 15.4 (3.5) h for the metabolite. After administration of the N-acetyl metabolite sulfaquinoxaline appeared in the plasma and urine indicating that deacetylation had occurred. The repercussions of this observation are briefly discussed with respect to two rabbits in which plasma analyses and complete urine collections were made. As sulfaquinoxaline is administered prophylactically to rabbits by some breeders, it is recommended that investigators allow a washout period of about one week after receipt of the animals.