A series of nineteen novel ring-substituted N-arylcinnamanilides was synthesized and characterized. All investigated compounds were tested against Staphylococcus aureus as the reference strain, two clinical isolates of methicillin-resistant S. aureus (MRSA), and Mycobacterium tuberculosis. (2E)-N-[3-Fluoro-4-(trifluoromethyl)phenyl]-3-phenylprop-2-enamide showed even better activity (minimum inhibitory concentration (MIC) 25.9 and 12.9 μM) against MRSA isolates than the commonly used ampicillin (MIC 45.8 μM). The screening of the cell viability was performed using THP1-BlueTM NF-κB cells and, except for (2E)-N-(4-bromo-3-chlorophenyl)-3-phenylprop-2-enamide (IC50 6.5 μM), none of the discussed compounds showed any significant cytotoxic effect up to 20 μM. Moreover, all compounds were tested for their anti-inflammatory potential; several compounds attenuated the lipopolysaccharide-induced NF-κB activation and were more potent than the parental cinnamic acid. The lipophilicity values were specified experimentally as well. In addition, in silico approximation of the lipophilicity values was performed employing a set of free/commercial clogP estimators, corrected afterwards by the corresponding pKa calculated at physiological pH and subsequently cross-compared with the experimental parameters. The similarity-driven property space evaluation of structural analogs was carried out using the principal component analysis, Tanimoto metrics, and Kohonen mapping.

• MeSH
• ampicilin farmakologie   MeSH
• analýza hlavních komponent MeSH
• antiflogistika farmakologie   MeSH
• cinnamáty chemická syntéza   MeSH
• inhibiční koncentrace 50 MeSH
• koncentrace vodíkových iontů MeSH
• lidé MeSH
• methicilin rezistentní Staphylococcus aureus účinky léků   MeSH
• mikrobiální testy citlivosti MeSH
• mikrovlny MeSH
• molekulární modely MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• NF-kappa B metabolismus   MeSH
• Staphylococcus aureus účinky léků   MeSH
• THP-1 buňky MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zánět MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The synthesis of inhibitors of SphK2 with novel structural scaffolds is reported. These compounds were designed from a molecular modeling study, in which the molecular interactions stabilizing the different complexes were taken into account. Particularly interesting is that 7-bromo-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1,4-epoxynaphtho[1,2-b]azepine, which is a selective inhibitor of SphK2, does not exert any cytotoxic effects and has a potent anti-inflammatory effect. It was found to inhibit mononuclear cell adhesion to the dysfunctional endothelium with minimal impact on neutrophil-endothelial cell interactions. The information obtained from our theoretical and experimental study can be useful in the search for inhibitors of SphK2 that play a prominent role in different diseases, especially in inflammatory and cardiovascular disorders.

• MeSH
• antiflogistika chemická syntéza   chemie   farmakologie   toxicita   MeSH
• azepiny chemická syntéza   chemie   farmakologie   MeSH
• buněčná adheze účinky léků   MeSH
• cévní endotel účinky léků   imunologie   MeSH
• endoteliální buňky pupečníkové žíly (lidské) MeSH
• epoxidové sloučeniny chemická syntéza   chemie   farmakologie   MeSH
• fosfotransferasy s alkoholovou skupinou jako akceptorem antagonisté a inhibitory   MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   toxicita   MeSH
• lidé MeSH
• neutrofily účinky léků   imunologie   MeSH
• racionální návrh léčiv MeSH
• simulace molekulového dockingu MeSH
• vazba proteinů MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH