Alzheimer disease (AD) is the most common cause of progressive dementia in the elderly population, with prevalence of 5% after 65 year of age and is increasing to about 30% in people over 85 year. AD is a neurodegenerative and incurable disease. Currently, three inhibitors of acetylcholinesterase (AChE), galantamine, donepezil and rivastigmine, and one inhibitor of N-methyl-d-aspartate (NMDA) receptor are available as drugs for amelioration of the disease. Demand to prepare drugs for the therapy providing at least relieve of symptoms remains. In this experiment, the ability of standards (donepezil, galantamine, huperzine A, tacrine and 7-methoxytacrine) and precursors used for synthesis of new AD drugs (l-tryptophan, pyridoxine B6, tryptamine, acridine, chinoline, isochinoline, indole, pyridine and piperidine) to inhibit AChE, BChE and BACE or to have the antioxidant properties were determined. The results were compared using statistical expression of the relationship between the performed tests. In this experiment, IC50 for every one method and every compound were found. Beside this, prediction of free energy in a link to ln(IC50) was assessed using in silico tests. This article focuses on possibility to find the most suitable chemical precursors to be used in the next development of drugs for AD
- MeSH
- akridiny farmakologie MeSH
- Alzheimerova nemoc * farmakoterapie MeSH
- antioxidancia farmakologie MeSH
- aspartátové endopeptidasy antagonisté a inhibitory MeSH
- chemie farmaceutická * metody statistika a číselné údaje MeSH
- chinoliny farmakologie MeSH
- cholinesterasové inhibitory farmakologie MeSH
- indoly farmakologie MeSH
- isochinoliny farmakologie MeSH
- neurodegenerativní nemoci farmakoterapie MeSH
- piperidiny farmakologie MeSH
- počítačová simulace MeSH
- pyridiny farmakologie MeSH
- pyridoxin farmakologie MeSH
- sekretasy antagonisté a inhibitory MeSH
- techniky in vitro statistika a číselné údaje MeSH
- tryptaminy farmakologie MeSH
- tryptofan farmakologie MeSH
- Publikační typ
- hodnotící studie MeSH
- práce podpořená grantem MeSH
The acid dissociation (ionization) constant pK(a) is one of the fundamental properties of organic molecules. We have evaluated different computational strategies and models to predict the pK(a) values of substituted phenols using partial atomic charges. Partial atomic charges for 124 phenol molecules were calculated using 83 approaches containing seven theory levels (MP2, HF, B3LYP, BLYP, BP86, AM1, and PM3), three basis sets (6-31G*, 6-311G, STO-3G), and five population analyses (MPA, NPA, Hirshfeld, MK, and Löwdin). The correlations between pK(a) and various atomic charge descriptors were examined, and the best descriptors were selected for preparing the quantitative structure-property relationship (QSPR) models. One QSPR model was created for each of the 83 approaches to charge calculation, and then the accuracy of all these models was analyzed and compared. The pK(a)s predicted by most of the models correlate strongly with experimental pK(a) values. For example, more than 25% of the models have correlation coefficients (R²) greater than 0.95 and root-mean-square errors smaller than 0.49. All seven examined theory levels are applicable for pK(a) prediction from charges. The best results were obtained for the MP2 and HF level of theory. The most suitable basis set was found to be 6-31G*. The 6-311G basis set provided slightly weaker correlations, and unexpectedly also, the STO-3G basis set is applicable for the QSPR modeling of pK(a). The Mulliken, natural, and Löwdin population analyses provide accurate models for all tested theory levels and basis sets. The results provided by the Hirshfeld population analysis were also acceptable, but the QSPR models based on MK charges show only weak correlations.
- MeSH
- chemické modely MeSH
- chemie farmaceutická metody statistika a číselné údaje MeSH
- fenoly analýza chemie MeSH
- kinetika MeSH
- kvantitativní vztahy mezi strukturou a aktivitou MeSH
- kvantová teorie MeSH
- léčivé přípravky analýza chemie MeSH
- molekulární konformace MeSH
- počítačová simulace MeSH
- statická elektřina MeSH
- statistické modely MeSH
- Publikační typ
- časopisecké články MeSH
Práce se věnuje syntéze a studiu některých fyzikálně-chemických vlastností skupiny látek, potenciálníchantagonistů beta-adrenergních receptorů. Látky jsou hydrochloridy derivátů aryloxyaminopropanolu,kde bázickou část tvoří difenylmethylpiperazin a modifikována je aromatická částalkylestery (methyl až butyl) kyseliny karbamové v polohách 2-, 3-, 4-. Zastoupení prvků bylopotvrzeno elementární analýzou. Látky byly charakterizovány teplotou tání IČ a UV spektry. Bylastanovena jejich rozpustnost a povrchová aktivita. Pomocí TLC byla sledována čistota připravenýchlátek.
The paper is devoted to the synthesis and study of some physico-chemical properties of a group ofsubstances – potential antagonists of beta-adrenergic receptors. The substances are derivatives ofaryloxyaminopropanol, where the basic part consists of diphenylmethylpiperazine and the aromaticpart is modified with alkyl esters (methyl to butyl) of carbamic acid in positions 2-, 3-, 4-. Therepresentation of the elements was confirmed by elemental analysis. The substances were characterizedby melting point, IR and UV spectra. Their solubility and surface acitivity were determined.The purity of prepared substances was examined by means of TLC.
- MeSH
- beta blokátory farmakologie chemie MeSH
- chemie farmaceutická metody statistika a číselné údaje MeSH
- chromatografie na tenké vrstvě metody MeSH
- finanční podpora výzkumu jako téma MeSH
- kardiovaskulární látky chemická syntéza chemie MeSH
- propanolaminy farmakologie chemická syntéza chemie MeSH
- Publikační typ
- srovnávací studie MeSH
- MeSH
- antagonisté kyseliny listové farmakokinetika krev MeSH
- biologické modely MeSH
- chemie farmaceutická metody statistika a číselné údaje MeSH
- finanční podpora výzkumu jako téma MeSH
- lidé MeSH
- lineární modely MeSH
- methotrexát analogy a deriváty aplikace a dávkování farmakokinetika MeSH
- psoriáza metabolismus MeSH
- software MeSH
- Check Tag
- lidé MeSH
