A series of 1,3,5-triazinyl aminobenzenesulfonamides substituted by aminoalcohol, aminostilbene, and aminochalcone structural motifs was synthesized as potential human carbonic anhydrase (hCA) inhibitors. The compounds were evaluated on their inhibition of tumor-associated hCA IX and hCA XII, hCA VII isoenzyme present in the brain, and physiologically important hCA I and hCA II. While the test compounds had only a negligible effect on physiologically important isoenzymes, many of the studied compounds significantly affected the hCA IX isoenzyme. Several compounds showed activity against hCA XII; (E)-4-{2-[(4-[(2,3-dihydroxypropyl)amino]-6-[(4-styrylphenyl)amino]-1,3,5-triazin-2-yl)amino]ethyl}benzenesulfonamide (31) and (E)-4-{2-[(4-[(4-hydroxyphenyl)amino]-6-[(4-styrylphenyl)amino]-1,3,5-triazin-2-yl)amino]ethyl}benzenesulfonamide (32) were the most effective inhibitors with KIs = 4.4 and 5.9 nM, respectively. In addition, the compounds were tested against vancomycin-resistant Enterococcus faecalis (VRE) isolates. (E)-4-[2-({4-[(4-cinnamoylphenyl)amino]-6-[(4-hydroxyphenyl)amino]-1,3,5-triazin-2-yl}amino)ethyl]benzenesulfonamide (21) (MIC = 26.33 μM) and derivative 32 (MIC range 13.80-55.20 μM) demonstrated the highest activity against all tested strains. The most active compounds were evaluated for their cytotoxicity against the Human Colorectal Tumor Cell Line (HCT116 p53 +/+). Only 4,4'-[(6-chloro-1,3,5-triazin-2,4-diyl)bis(iminomethylene)]dibenzenesulfonamide (7) and compound 32 demonstrated an IC50 of ca. 6.5 μM; otherwise, the other selected derivatives did not show toxicity at concentrations up to 50 μM. The molecular modeling and docking of active compounds into various hCA isoenzymes, including bacterial carbonic anhydrase, specifically α-CA present in VRE, was performed to try to outline a possible mechanism of selective anti-VRE activity.
- MeSH
- Anti-Bacterial Agents pharmacology MeSH
- Antineoplastic Agents pharmacology therapeutic use MeSH
- Vancomycin-Resistant Enterococci drug effects MeSH
- HCT116 Cells MeSH
- Carbonic Anhydrase Inhibitors pharmacology MeSH
- Carbonic Anhydrase I antagonists & inhibitors MeSH
- Carbonic Anhydrase II antagonists & inhibitors MeSH
- Carbonic Anhydrase IX antagonists & inhibitors MeSH
- Carbonic Anhydrases drug effects MeSH
- Humans MeSH
- Neoplasms drug therapy MeSH
- Molecular Dynamics Simulation MeSH
- Molecular Docking Simulation MeSH
- Sulfonamides pharmacology MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
There are numerous studies supporting the contribution of oxidative stress to the pathogenesis of epilepsy. Prolonged oxidative stress is associated with the overexpression of ATP-binding cassette transporters, which results in antiepileptic drugs resistance. During our studies, three 1,2,4-triazole-3-thione derivatives were evaluated for the antioxidant activity and anticonvulsant effect in the 6 Hz model of pharmacoresistant epilepsy. The investigated compounds exhibited 2-3 times more potent anticonvulsant activity than valproic acid in 6 Hz test in mice, which is well-established preclinical model of pharmacoresistant epilepsy. The antioxidant/ROS scavenging activity was confirmed in both single-electron transfer-based methods (DPPH and CUPRAC) and during flow cytometric analysis of total ROS activity in U-87 MG cells. Based on the enzymatic studies on human carbonic anhydrases (CAs), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), one can assume that the herein investigated drug candidates will not impair the cognitive processes mediated by CAs and will have minimal off-target cholinergic effects.
- MeSH
- Acetylcholinesterase metabolism MeSH
- Anticonvulsants chemical synthesis chemistry pharmacology MeSH
- Antioxidants chemical synthesis chemistry pharmacology MeSH
- Biphenyl Compounds antagonists & inhibitors MeSH
- Butyrylcholinesterase metabolism MeSH
- Cholinesterase Inhibitors chemical synthesis chemistry pharmacology MeSH
- Epilepsy drug therapy metabolism MeSH
- Carbonic Anhydrase Inhibitors chemical synthesis chemistry pharmacology MeSH
- Carbonic Anhydrases metabolism MeSH
- Humans MeSH
- Models, Molecular MeSH
- Molecular Structure MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Oxidative Stress drug effects MeSH
- Picrates antagonists & inhibitors MeSH
- Reactive Oxygen Species metabolism MeSH
- Triazoles chemical synthesis chemistry pharmacology MeSH
- Cell Survival drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
