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.

• Klíčová slova
• benzenesulfonamide, carbonic anhydrase, chalcone, inhibition, stilbene, triazine, vancomycin-resistant enterococci,
• MeSH
• antibakteriální látky farmakologie   MeSH
• enterokoky rezistentní vůči vankomycinu účinky léků   MeSH
• HCT116 buňky MeSH
• inhibitory karboanhydras farmakologie   MeSH
• karboanhydrasa I antagonisté a inhibitory   MeSH
• karboanhydrasa II antagonisté a inhibitory   MeSH
• karboanhydrasa IX antagonisté a inhibitory   MeSH
• karboanhydrasy účinky léků   MeSH
• lidé MeSH
• nádory farmakoterapie   MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• sulfonamidy farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky MeSH
• carbonic anhydrase XII MeSH Prohlížeč
• inhibitory karboanhydras MeSH
• karboanhydrasa I MeSH
• karboanhydrasa II MeSH
• karboanhydrasa IX MeSH
• karboanhydrasy MeSH
• protinádorové látky MeSH
• sulfonamidy MeSH