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
In order to provide a more detailed view on the structure⁻antimycobacterial activity relationship (SAR) of phenylcarbamic acid derivatives containing two centers of protonation, 1-[2-[({[2-/3-(alkoxy)phenyl]amino}carbonyl)oxy]-3-(dipropylammonio)propyl]pyrrolidinium oxalates (1a⁻d)/dichlorides (1e⁻h) as well as 1-[2-[({[2-/3-(alkoxy)phenyl]amino}carbonyl)oxy]-3-(di-propylammonio)propyl]azepanium oxalates (1i⁻l)/dichlorides (1m⁻p; alkoxy = butoxy to heptyloxy) were physicochemically characterized by estimation of their surface tension (γ; Traube's stalagmometric method), electronic features (log ε; UV/Vis spectrophotometry) and lipophilic properties (log kw; isocratic RP-HPLC) as well. The experimental log kw dataset was studied together with computational logarithms of partition coefficients (log P) generated by various methods based mainly on atomic or combined atomic and fragmental principles. Similarities and differences between the experimental and in silico lipophilicity descriptors were analyzed by unscaled principal component analysis (PCA). The in vitro activity of compounds 1a⁻p was inspected against Mycobacterium tuberculosis CNCTC My 331/88 (identical with H37Rv and ATCC 2794, respectively), M.tuberculosis H37Ra ATCC 25177, M.kansasii CNCTC My 235/80 (identical with ATCC 12478), the M.kansasii 6509/96 clinical isolate, M.kansasii DSM 44162, M. avium CNCTC My 330/80 (identical with ATCC 25291), M.smegmatis ATCC 700084 and M. marinum CAMP 5644, respectively. In vitro susceptibility of the mycobacteria to reference drugs isoniazid, ethambutol, ofloxacin or ciprofloxacin was tested as well. A very unique aspect of the research was that many compounds from the set 1a⁻p were highly efficient almost against all tested mycobacteria. The most promising derivatives showed MIC values varied from 1.9 μM to 8 μM, which were lower compared to those of used standards, especially if concerning ability to fight M.tuberculosis H37Ra ATCC 25177, M.kansasii DSM 44162 or M. avium CNCTC My 330/80. Current in vitro biological assays and systematic SAR studies based on PCA approach as well as fitting procedures, which were supported by relevant statistical descriptors, proved that the compounds 1a⁻p represented a very promising molecular framework for development of 'non-traditional' but effective antimycobacterial agents.
- MeSH
- antituberkulotika chemická syntéza farmakologie MeSH
- azepiny chemická syntéza farmakologie MeSH
- ciprofloxacin chemie terapeutické užití MeSH
- ethambutol chemie terapeutické užití MeSH
- fenylkarbamáty chemická syntéza farmakologie MeSH
- isoniazid chemie terapeutické užití MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium avium účinky léků MeSH
- Mycobacterium kansasii účinky léků MeSH
- Mycobacterium smegmatis účinky léků MeSH
- Mycobacterium tuberculosis účinky léků MeSH
- Mycobacterium účinky léků MeSH
- ofloxacin chemie terapeutické užití MeSH
- oxaláty chemie farmakologie MeSH
- počítačová simulace MeSH
- pyrrolidiny chemická syntéza farmakologie MeSH
- racionální návrh léčiv MeSH
- rozpustnost MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
