Synthesis and Determination of Physicochemical Properties of New 3-(4-Arylpiperazin-1-yl)-2-hydroxypropyl 4-Alkoxyethoxybenzoates

Nine new dihydrochloride salts of 3-(4-arylpiperazin-1-yl)-2-hydroxypropyl 4-alkoxyethoxybenzoates were designed and synthesized. The physicochemical properties such as lipophilicity index (log kw) and dissociation constant (pKa) were experimentally determined and compared to the software calculated data. The lipophilicity index was determined by means of reversed-phase high performance liquid chromatography (RP-HPLC). The pKa values were determined by means of capillary zone electrophoresis. The “drug-likeness” properties according to the Lipinski Rule of Five and prediction of possible blood–brain barrier penetration were computed and discussed

Synthesis, Analysis, Cholinesterase-Inhibiting Activity and Molecular Modelling Studies of 3-(Dialkylamino)-2-hydroxypropyl 4-[(Alkoxy-carbonyl)amino]benzoates and Their Quaternary Ammonium Salts

Tertiary amines 3-(dialkylamino)-2-hydroxypropyl 4-[(alkoxycarbonyl)amino]benzoates and their quaternary ammonium salts were synthesized. The final step of synthesis of quaternary ammonium salts was carried out by microwave-assisted synthesis. Software-calculated data provided the background needed to compare fifteen new resulting compounds by their physicochemical properties. The acid dissociation constant (pKa) and lipophilicity index (log P) of tertiary amines were determined; while quaternary ammonium salts were characterized by software-calculated lipophilicity index and surface tension. Biological evaluation aimed at testing acetylcholinesterase and butyrylcholinesterase-inhibiting activity of synthesized compounds. A possible mechanism of action of these compounds was determined by molecular modelling study using combined techniques of docking; molecular dynamics simulations and quantum mechanics calculations

SAR-mediated Similarity Assessment of the Property Profile for New, Silicon-Based AChE/BChE Inhibitors

A set of 25 novel, silicon-based carbamate derivatives as potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors was synthesized and characterized by their in vitro inhibition profiles and the selectivity indexes (SIs). The prepared compounds were also tested for their inhibition potential on photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. In fact, some of the newly prepared molecules revealed comparable or even better inhibitory activities compared to the marketed drugs (rivastigmine or galanthamine) and commercially applied pesticide Diuron®, respectively. Generally, most compounds exhibited better inhibition potency towards AChE; however, a wider activity span was observed for BChE. Notably, benzyl N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(2-hydroxyphenyl)carbamoyl]ethyl]-carbamate and benzyl N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(3-hydroxyphenyl) carbamoyl]ethyl]-carbamate were characterized by fairly high selective indexes. Specifically, the first compound was prescribed with the lowest IC50 value that corresponds quite well with galanthamine inhibition activity, while the inhibitory profiles of the second molecule and benzyl-N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(4-hydroxyphenyl)carbamoyl]ethyl]-carbamate are in line with rivastigmine activity. Moreover, a structure-activity relationship (SAR)-driven similarity evaluation of the physicochemical properties for the carbamates examined appeared to have foreseen the activity cliffs using a similarity-activity landscape index for BChE inhibitory response values. The ‘indirect’ ligand-based and ‘direct’ protein-mediated in silico approaches were applied to specify electronic/steric/lipophilic factors that are potentially valid for quantitative (Q)SAR modeling of the carbamate analogues. The stochastic model validation was used to generate an ‘average’ 3D-QSAR pharmacophore pattern. Finally, the target-oriented molecular docking was employed to (re)arrange the spatial distribution of the ligand property space for BChE and photosystemII (PSII).Soubor 25 nových karbamátových derivátů na bázi křemíku jako potenciálních inhibitorů acetyl- a butyrylcholinesterázy (AChE/BChE) byl syntetizován a charakterizován jejich inhibičními profily in vitro a indexem selektivity (SIs). Připravené sloučeniny byly také testovány na jejich inhibiční potenciál ve fotosyntetickém elektronovém transportu (PET) ve špenátových (Spinacia oleracea L.) chloroplastech. Ve skutečnosti některé nově připravené molekuly odhalily srovnatelné nebo dokonce lepší inhibiční aktivity ve srovnání s obchodovanými léčivy (rivastigmin nebo galanthamin) a komerčně aplikovaným pesticidem Diuron®. Obecně většina sloučenin vykazovala lepší inhibiční účinnost vůči AChE; bylo však pozorováno širší rozpětí aktivity u BChE. Zejména benzyl N-[(1S)-2-[(terc-butyldimethylsilyl) oxy]-1-[(2-hydroxyfenyl)karbamoyl]ethyl]-karbamát a benzyl N-[(1S)-2-[(terc-butyldimethylsilyl)oxy]-1-[(3-hydroxyfenyl)karbamoyl]ethyl]-karbamát byl charakterizován poměrně vysokými indexy selektivity. Konkrétně první sloučenina měla nejnižší hodnotou IC50, která docela dobře odpovídá inhibiční aktivitě galantaminu, zatímco inhibiční profily druhé molekuly a benzyl-N-[(1S)-2-[(terc-butyldimethylsilyl)oxy]-1-[(4-hydroxyfenyl)karbamoyl]ethyl]karbamátu jsou v souladu s rivastigminovou aktivitou. Navíc vyhodnocení podobnosti fyzikálně-chemických vlastností zkoumaných karbamátů na základě vztahu struktura-aktivita (SAR) předpovídalo jistou aktivitu pomocí indexu podobnost-aktivita pro hodnoty inhibiční odpovědi BChE. „Nepřímé“ ligandy a „přímé“ proteiny zprostředkované v silikonových přístupech byly použity ke stanovení elektronických/sterických/lipofilních faktorů, které jsou potenciálně platné pro kvantitativní (Q)SAR modelování karbamátových analogů. Validace stochastického modelu byla použita k vytvoření „průměrného“ 3D-QSAR farmakoforu. Nakonec bylo použito cílené molekulární dokování aby se změnila prostorová distribuce vlastností ligandu pro BChE a fotosystém II (PSII)