4-(2-Methyloxazol-4-yl)benzenesulfonamide was synthesized by the reaction of 4-(2-bromoacetyl)benzenesulfonamide with an excess of acetamide. The compound was evaluated as a potential inhibitor of human monoamine oxidase (MAO) A and B and was found to inhibit these enzymes with IC₅₀ values of 43.3 and 3.47 μM, respectively. The potential binding orientation and interactions of the inhibitor with MAO-B were examined by molecular docking, and it was found that the sulfonamide group binds and interacts with residues of the substrate cavity. 4-(2-Methyloxazol-4-yl)benzenesulfonamide showed no cytotoxic effect against human stromal bone cell line (HS-5) in the concentration range of 1–100 µmol. Thus, the new selective MAO-B inhibitor was identified, which may be used as the lead compound for the development of antiparkinsonian agents.

Introduction: 4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamide is a new selective type II carbonic anhydrase inhibitor with local action through instillation into the eyes. For a complete pharmacokinetic study of this drug, it is necessary to detect and synthesize its metabolites for their systemic exposure evaluation. Materials and Methods: The investigation was performed on 6 Wistar rats and 6 Soviet Chinchilla rabbits. The drug in the form of a 1% suspension was administered by intraperitoneal injection. Blood was sampled in a volume of 0.2 mL at the following time points: before administration and 1 h, 2 h, 4 h, 24 h after administration. Then 150 µL of each sample was centrifuged to produce plasma. Urine was simultaneously sampled in rats using metabolic cells: before administration and at intervals of 0-2 h, 2-4 h, 4-6 h, 6-24 h after administration of the drug. The identification of metabolites in these objects was performed using HPLC-MS/MS. Then the detected biotransformation products were synthesized. The structure of the obtained substances was confirmed by NMR spectroscopy and high-resolution mass spectrometry. At the final stage, animal biological fluids and model samples with the addition of the synthesized compounds were analyzed using HPLC-MS/MS to establish the structure of metabolites.Results and Discussion: N-hydroxy-4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamide, 4-(5-(hydroxymethyl)-1,3,4-oxadiazole-2-yl)-benzenesulfonamide and 4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonic acid were identified and synthesized. The complete coincidence of the structure of metabolites and the synthesized substances was established as a result of their comparison in retention time, the ratio of the areas of chromatographic peaks at the main MRM transitions, as well as mass spectra.Conclusion: N-hydroxy-4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamide and 4-(5-(hydroxymethyl)-1,3,4-oxadiazole-2-yl)-benzenesulfonamide are products of biotransformation of the studied drug. It was found that 4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonic acid is formed by decomposition of N-hydroxymetabolite in urine samples during the collection process.

By reaction between acetylbenzenesulfonamides with several substituted isatins, we have synthesized a series of 22 primary sulfonamides, 16 of which were tested for inhibition activity against MAO-A and MAO-B. At the same time, in order to diversify the resulting structures, we have carried out decarboxylation as well as further functionalization at the carboxylic acid. The results of the study show that methyl 6-chloro-2-(3-sulfamoylphenyl)quinoline-4-carboxylate selectively inhibited MAO-B with a value of IC₅₀ = 13.7 μM.

An improved synthesis of 3,5-disubstituted-1,2,4-oxadiazoles with a sulfonamide fragment is proposed. Our previously developed synthesis of the target 1,2,4-oxadiazoles, which involves reaction in the superbasic NaOH/DMSO medium, has a number of disadvantages. The improved synthesis involves the reaction of amidoximes with carboxylic acid esters in a t-BuON/DMAA medium. The reaction proceeds at room temperature for 8– 18 h. The advantages of the proposed method consist in the broader temperature range of the reaction (due to the change of solvent from DMSO to DMAA), as well as the absence of side hydrolysis processes, which is important for moisture sensitive substrates. The potential of the method was demonstrated by the synthesis of 9 novel 1,2,4-oxadiazole derivatives containing various substituents in the 3 position (R = 2-ClPh, 3-C₂H₅C(O)NH-Ph, i-Pr, Ph, thiophene, 4-Me-thiophene, 4-OMe-Ph, Py, 2-tolyl) and at the 5-position of the 1,2,4-oxadiazole ring (R = 4-SO₂NH₂-Ph, 2-OMe-4-SO₂NH₂-phenyl). The 3,5-disubstituted-1,2,4-oxadiazole derivatives synthesized in good yields (35–89%) are of interest for medicinal chemistry as potential drugs for the treatment of neurodegenerative diseases (such as Parkinson's syndrome and Alzheimer's disease) by inhibiting monoamine oxidase B. The synthesized compounds can be useful as antiglaucoma and anticancer agents, because they inhibit carbonic anhydrase I, II, IX, and XII isoforms. The structure and purity of the novel heterocyclic derivatives were confirmed by ¹H and ¹³C NMR spectroscopy and mass spectrometry. Biological ac testing of the synthesized compounds on cell and animal glaucoma models is planned.

We have recently reported that a series of 1,3,4-oxadiazol-2-ylbenzenesulfonamides acts as potent and specific monoamine oxidase B (MAO-B) inhibitors with some compounds possessing potencies in the nanomolar range. While sulfonamide compounds (e.g., zonisamide) have been reported to inhibit the MAO enzymes, nanomolar MAO inhibition potencies for this class are not frequently observed. The present study expanded on these findings by replacing the 1,3,4-oxazole moiety with a 1,3-thiazole heterocycle. A series of 23 primary sulfonamides were synthesized by reaction of an α-haloketone with a substituted carbothioamide. The results of the MAO inhibition studies showed that the 1,3-thiazolylbenzenesulfonamides were specific inhibitors of human MAO-B. The most potent MAO-B inhibitor exhibited an in vitro IC50 value of 0.103 µM (3j). The derivatives were, however, weaker inhibitors of human MAO-A with the most potent compound exhibiting an IC50 value of 11.9 µM (3a). Examination of the structure-activity relationships (SARs) showed that the most potent MAO-B inhibition was obtained with substitution of the sulfonamide on the meta position of the phenyl rather than the para position. This study concludes that 1,3-thiazolylbenzenesulfonamides represent a class of potent and specific MAO-B inhibitors, which may serve as leads for the development of new treatments for disease states such as Parkinson’s disease.

3-(3,4-Dichlorophenyl)-5-(1H-indol-5-yl)-1,2,4-oxadiazole was synthesized via the condensation of 3,4-dichlorobenzamidoxime and methyl 1H-indole-5-carboxylate using superbasic medium (NaOH/DMSO). The compound was tested as a potential inhibitor of human monoamine oxidase (MAO) A and B. It demonstrated notable inhibition with an IC50 value of 0.036 μM for MAO-B and isoform specificity. The product was characterized by 1H NMR, 13C NMR, and HRMS. In conclusion, the new active MAO-B inhibitor may serve as a candidate for the future discovery of therapeutic agents for neurodegenerative disorders such as Parkinson’s disease.