RESUMEN
Hybrid inhibitors of acetyl- and butyrylcholinesterase are compounds that combine structural motifs of two different classical inhibitors, leading to a dual binding ligand. A rapidly growing collection of those compounds involves a wide diversity of structural motifs, but the way of linking two active fragments and its impact on the affinity toward cholinesterases usually remains beyond the extent of investigation. We present hereby a detailed analysis of this aspect using melatonin-donepezil hybrids. A new series of compounds, in which two fragments are connected using a carbamate linker, exhibits excellent activity and selectivity toward butyrylcholinesterase.
Asunto(s)
Acetilcolinesterasa/metabolismo , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Donepezilo/farmacología , Melatonina/farmacología , Acetilcolinesterasa/sangre , Sitios de Unión/efectos de los fármacos , Butirilcolinesterasa/sangre , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Donepezilo/química , Relación Dosis-Respuesta a Droga , Eritrocitos/enzimología , Humanos , Melatonina/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Novel inhibitors of cholinesterases, especially butyrylcholinesterase (BuChE), were obtained by coupling melatonin-tacrine heterodimers via the carbamate bond. Compounds 14a-i possessed potent cholinesterase inhibitory activity (with IC50 values as low as 1.18 nM for acetylcholinesterase (AChE) and 0.24 nM for butyrylcholinesterase (BuChE)). These heterodimers exhibit selectivity toward BuChE, being from 4- to 256-fold more active toward BuChE than AChE, but still acting as better AChE inhibitors than tacrine 4.
Asunto(s)
Butirilcolinesterasa/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Melatonina/farmacología , Tacrina/farmacología , Tacrina/químicaRESUMEN
In the title mol-ecule, C(19)H(17)N(3)O(6), the indole ring system is essentially planar (r.m.s. deviation = 0.009â Å) and forms a dihedral angle of 31.96â (9)° with the nitro-substituted benzene ring. In the crystal, mol-ecules are linked by pairs of N-Hâ¯O hydrogen bonds, forming inversion dimers which are connected by further N-Hâ¯O hydrogen bonds into a two-dimensional network parallel to (102).
RESUMEN
Isoprenoids, as common constituents of all living cells, are exposed to oxidative agents--reactive oxygen species, for example, singlet oxygen or hydroxyl radicals. Despite this fact, products of oxidation of polyisoprenoids have never been characterized. In this study, chemical oxidation of isoprenoid alcohols (Prenol-2 and -10) was performed using singlet oxygen (generated in the presence of hydrogen peroxide/molybdate or upon photochemical reaction in the presence of porphyrin), oxygen (formed upon hydrogen peroxide dismutation) or hydroxyl radical (generated by the hydrogen peroxide/sonication, UV/titanium dioxide or UV/hydrogen peroxide) systems. The structure of the obtained products, hydroxy-, peroxy- and heterocyclic derivatives, was studied with the aid of mass spectrometry (MS) and nuclear magnetic resonance (NMR) methods. Furthermore, mass spectrometry with electrospray ionization appeared to be a useful analytical tool to detect the products of oxidation of isoprenoids (ESI-MS analysis), as well as to establish their structure on the basis of the fragmentation spectra of selected ions (ESI-MS/MS analysis). Taken together, susceptibility of polyisoprenoid alcohols to various oxidizing agents was shown for the first time.