Neurodegenerative diseases in which the decrease of the acetylcholine is observed are growing worldwide. In the present study, a series of new arylaminopropanone derivatives with N-phenylcarbamate moiety (1-16) were prepared as potential acetylcholinesterase and butyrylcholinesterase inhibitors. In vitro enzyme assays were performed; the results are expressed as a percentage of inhibition and the IC50 values. The inhibitory activities were compared with reference drugs galantamine and rivastigmine showing piperidine derivatives (1-3) as the most potent. A possible mechanism of action for these compounds was determined from a molecular modelling study by using combined techniques of docking, molecular dynamics simulations and quantum mechanics calculations.

• Klíčová slova
• N-phenylcarbamate, acetylcholinesterase, arylaminopropanone, butyrylcholinesterase, enzyme assays, molecular modelling,
• MeSH
• aktivace enzymů účinky léků   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární konformace MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• propanolaminy chemická syntéza   chemie   farmakologie   MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• vazba proteinů MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cholinesterasové inhibitory MeSH
• propanolaminy 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.

• Klíčová slova
• Mycobacterium spp., dibasic phenylcarbamates, electronic properties, lipophilicity, surface tension,
• 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
• Názvy látek
• antituberkulotika MeSH
• azepiny MeSH
• ciprofloxacin MeSH
• ethambutol MeSH
• fenylkarbamáty MeSH
• isoniazid MeSH
• ofloxacin MeSH
• oxaláty MeSH
• pyrrolidiny MeSH

The evaluation of the lipophilic characteristics of biologically active agents is indispensable for the rational design of ADMET-tailored structure⁻activity models. N-Alkoxy-3-hydroxynaphthalene-2-carboxanilides, N-alkoxy-1-hydroxynaphthalene-2-carboxanilides, and N-alkoxy-2-hydroxynaphthalene-1-carboxanilides were recently reported as a series of compounds with antimycobacterial, antibacterial, and herbicidal activity. As it was found that the lipophilicity of these biologically active agents determines their activity, the hydro-lipophilic properties of all three series were investigated in this study. All 57 anilides were analyzed using the reversed-phase high-performance liquid chromatography method for the measurement of lipophilicity. The procedure was performed under isocratic conditions with methanol as an organic modifier in the mobile phase using an end-capped non-polar C18 stationary reversed-phase column. In the present study, a range of software lipophilicity predictors for the estimation of clogP values of a set of N-alkoxyphenylhydroxynaphthalenecarboxamides was employed and subsequently cross-compared with experimental parameters. Thus, the empirical values of lipophilicity (logk) and the distributive parameters (π) were compared with the corresponding in silico characteristics that were calculated using alternative methods for deducing the lipophilic features. To scrutinize (dis)similarities between the derivatives, a PCA procedure was applied to visualize the major differences in the performance of molecules with respect to their lipophilic profile, molecular weight, and violations of Lipinski’s Rule of Five.

• Klíčová slova
• hydroxynaphthalenecarboxamides, lipophilicity determinations, structure-lipophilicity relationships,
• MeSH
• anilidy chemie   MeSH
• chromatografie s reverzní fází MeSH
• hydrofobní a hydrofilní interakce MeSH
• molekulární struktura MeSH
• naftaleny chemie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• anilidy MeSH
• naftaleny MeSH