Most cited article - PubMed ID 32077475
NERDD: a web portal providing access to in silico tools for drug discovery
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.
- Keywords
- benzenesulfonamide, carbonic anhydrase, chalcone, inhibition, stilbene, triazine, vancomycin-resistant enterococci,
- MeSH
- Anti-Bacterial Agents pharmacology 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
- Antineoplastic Agents pharmacology therapeutic use 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
- Names of Substances
- Anti-Bacterial Agents MeSH
- carbonic anhydrase XII MeSH Browser
- Carbonic Anhydrase Inhibitors MeSH
- Carbonic Anhydrase I MeSH
- Carbonic Anhydrase II MeSH
- Carbonic Anhydrase IX MeSH
- Carbonic Anhydrases MeSH
- Antineoplastic Agents MeSH
- Sulfonamides MeSH
To address the lack of high-resolution electron ionisation mass spectral libraries (HR-[EI+]-MS) for environmental chemicals, a retention-indexed HR-[EI+]-MS library has been constructed following analysis of authentic compounds via GC-Orbitrap MS. The library is freely provided alongside a compound database of predicted physicochemical properties. Currently, the library contains over 350 compounds from 56 compound classes and includes a range of legacy and emerging contaminants. The RECETOX Exposome HR-[EI+]-MS library expands the number of freely available resources for use in full-scan chemical exposure studies and is available at: https://doi.org/10.5281/zenodo.4471217.
