Literature data and authors’ own results on the role of serine hydrolases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), as drug targets for treatment of neurodegenerative diseases ...and carboxylesterase (CaE) inhibitors as modulators of CaE-hydrolysis of ester-containing drugs are analyzed. Today, a promising approach is the development of cholinesterase inhibitors with additional neuroprotective and disease-modifying properties. The developed esterase profile approach, that is, comparative assessment of the inhibitory activity against AChE, BChE, and CaE, can be used to evaluate both the main potential pharmacological effect and possible side effects of a new compound. Analysis of the esterase profile, in combination with computer modeling and assessment of radical-scavenging ability of the synthesized compounds and their potential ability to block AChE-induced β-amyloid aggregation revealed highly active multifunctional compounds for the treatment of Alzheimer’s disease: selective inhibitors of BChE and inhibitors of both cholinesterases without potential side effects associated with CaE inhibition. A number of effective and selective inhibitors of CaE, free from cholinergic side effects, were also found for modulation of the rate of hydrolytic metabolism and for rational use of ester-containing drugs.
A series of new conjugates of tacrine with ethyl 2-aminomethylidene-3-oxobutanoate with a spacer length of 4, 6, and 8 methylene groups was synthesized. The synthesized conjugates were shown to be ...effective inhibitors of acetylcholinesterase (IC
50
up to 0.143 µmol L
−1
) and butyrylcholinesterase (IC
50
up to 0.024 µmol L
−1
), with the inhibitory activity increasing with the spacer elongation. The new conjugates, as their diethyl malonate analogs, demonstrated a potential ability to block the AChE-induced β-amyloid aggregation and inhibited the self-aggregation of β-amyloid (1–42) with maximum activity at the level of the standard compound myricetin for derivatives with the octamethylene spacer. For the lead compound, a conjugate of tacrine with ethyl 2-aminomethylidene-3-oxobutanoate with the (CH
2
)
8
spacer, the ability to bind the biometal ions Cu
II
, Fe
II
and Zn
II
was also demonstrated. The obtained characteristics indicated the synthesized conjugates as promising multitarget agents for the treatment of Alzheimer’s disease.
The condensation of tacrine aminopolymethylene derivatives with diethyl (ethoxymethylidene)malonate led to the new hybrid compounds—conjugates, which were the effective inhibitors of ...acetylcholinesterase (AChE) (IC
50
up to 0.538 μM) and butyrylcholinesterase (IC
50
up to 0.0314 μM). They can displace propidium iodide from peripherical anionic site of AChE at the level of the reference drug donepezil and demonstrate a weak antioxidant activity. Conjugates are of interest for further extended research as potential drugs for the Alzheimer’s disease treatment.
Ipidacrine conjugates were synthesized by alkylation of 4-hydroxycoumarin, dihydrofuro3,4-
c
pyridine, bipyridine, and azolo1,5-
a
pyrimidines with 2-chloro-
N
-(hexahydrocyclopenta
b
...quinolin-9-yl)acetamide. Their isomeric structure was determined by NMR spectroscopy. Heterocycles containing ambident N,O-nucleophilic centers underwent alkylation at the oxygen atom, while in the presence of alternative carboxy and hydroxy functions, the alkylation occurred with the formation of an ester derivative. The study of the esterase profile, inhibitory effect on β-amyloid self-aggregation, as well as antioxidant activity of the conjugates, showed that coumarin derivatives are promising for the development of butyrylcholinesterase inhibitors, whereas conjugates of azolo1,5-
a
-pyrimidines are promising in the search for β-amyloid self-aggregation inhibitors.
The azo-coupling reaction of aryldiazonium chlorides containing a sulfone fragment with ethyl (trifluoro)acetylacetates and acetylacetone led to 2-sulfonarylhydrazinylidene 1,3-dicarbonyl compounds. ...According to NMR spectroscopy, 2-sulfonarylhydrazinylidene 3-oxoesters exist in solutions as
Z
-isomers. Micromolar inhibitors of three serine esterases, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CES), were found among the synthesized trifluoromethyl-substituted 3-oxoesters. A nanomolar BChE inhibitor was identified among the trifluoromethyl-substituted 1,3-diketone derivatives exhibiting selectivity towards BChE in combination with radical-scavenging activity. 3-Oxoesters with moderate activity against pathogenic fungi of the
T. mentagrophytes
strain were revealed.
Digital phenotyping as a new method of screening for mental disorders Kasyanov, E. D.; Kovaleva, Ya. V.; Mazo, G. E.
Obozrenie psihiatrii i medicinskoj psihologii im. V.M. Behtereva/Obozrenie psihiatrii i medicinskoj psihologii imeni V.M. Behtereva,
12/2022, Letnik:
56, Številka:
4
Journal Article
Recenzirano
Odprti dostop
The introduction of information technologies is inextricably linked with improving the quality and accessibility of medical care, as well as reducing the cost of medical services. Digital ...phenotyping is one of the clinical tools in the field of information technology that allows you to evaluate a person’s phenotype using various personal information devices, such as a smartphone, tablet, smartwatch, various sensors and other computer tools. The advantage of digital phenotyping is the ability to receive information about the patient’s condition in real time, without inpatient and outpatient monitoring and even without the active participation of the patient himself. This fact significantly expands the possibilities of screening and diagnosis of mental disorders, and also helps to track the risks of relapses and take timely measures to prevent an exacerbation of the disease. Information technologies have great prospects for use for scientific purposes — they provide an opportunity to conduct research online that does not require visiting research centers, while at the same time reducing the time and costs of ongoing clinical trials. However, the use of digital phenotyping for scientific and clinical purposes has a number of limitations. For further improvement of digital phenotyping in order to screen psychopathology and subsequent assessment of the condition of patients, it is necessary to develop new psychometric tools used in electronic form and devoid of the shortcomings of questionnaires that are currently being used. This critical review provides data on the current opportunities and problems of digital phenotyping, as well as the prospects for its development.
1
H,
19
F,
31
P NMR, DSC, and XRD methods are used to study ionic mobility and structural transformations in the CsSbF
3
(H
2
PO
4
) compound (
I
). Radical changes in
1
H,
19
F,
31
P NMR spectra ...above 390 K are associated with a crystalline disordered phase which forms in
I
at 400–420 K. This phase demonstrates high ionic mobility and further transforms (above 425 K) into the amorphous (glassy) phase. We have determined the types of ionic mobility in this compound and in its amorphous product. According to the NMR data, the diffusion in the proton sublattice of the disordered and amorphous phases proceeds even at room temperature.
This review summarizes data about structural and functional organization of steroidogenic P450-dependent enzymatic systems. Problems of catalysis of steroid substrate transformation, special features ...of mitochondrial type P450scc topogenesis, and abilities of some microbial electron transport proteins to support P450 activity in vitro and in vivo are considered. Principal steps in the creation and catalytic properties of transgenic strains of Escherichia coli, Saccharomyces cerevisiae, and Yarrowia lipolytica expressing both mammalian steroidogenic P450s and the corresponding electron transport proteins are also described. Achievements and prospects of using such transgenic strains for biotechnological synthesis and pharmacological screening are considered.
Display omitted
•(C5H12NO2)SbF4·H2O (I) and (C3H8NO3)Sb2F7 (II) compounds have been studied by X-ray diffraction, DSC and NMR spectroscopy.•Structure of I consists of (C5H12NO2)+ cations, SbF4nn– ...complex anions and H2O molecules.•Types of ionic motions in compounds I and II have been identified in the range 150–350 K.•The diffusion of F– and H+ ions in II is observed above 270 and 210 K, respectively.•Ion mobility in the compound I is absent in the studied temperature range.
Fluoride complexes of antimony(III) with amino acids (DL–valine and DL–serine) of the compositions (C5H12NO2)SbF4·H2O (I) and (C3H8NO3)Sb2F7 (II) have been synthesized. The crystal structure of the (C5H12NO2)SbF4·H2O compound (monoclinic syngony, Z = 4, space group P21/c) has been determined for the first time. The structure of I is composed of cations of DL-valinium ((C5H12NO2)+), complex SbF4nn– anions having a polymeric chain structure, and crystallization water molecules. Thermal properties and ionic mobility in fluoroantimonates I and II were studied by the DSC and NMR (1H, 19F) methods. It has been established that irreversible endo-effects on DSC curves at 351 and 385 K for the compounds I and II, respectively, are related to formation of X-ray-amorphous phases. In the complex I, ionic mobilities in fluoride and proton sublattices with frequencies above 104 Hz are absent in the studied temperature range (150–420 K), whereas the ions diffusion is observed in both sublattices of II at 320 K. The mechanisms of emergence of ions diffusion in sublattices of the compound II were suggested.
Structural transitions, ion mobility, and conductivity in CsSbF3(H2PO4) (I) have been investigated by the methods of 1H, 19F, 31P NMR (including 1H, 19F, 31P MAS NMR), DSC, X-ray diffraction, and ...impedance spectroscopy. It was found that the fundamental changes in 1H, 19F, 31P NMR spectra (above 390K) were associated with the formation of a crystalline disorder phase I with high ionic mobility in the proton and fluoride sublattices, as a result of a phase transition in the 400–420K range. In the same temperature range, the transition of PO2(OH)2– anions from the "rigid lattice" to fast reorientations takes place. Above 430K, there occurs a transition from the crystalline disordered phase to the amorphous one. The types of ion mobility in CsSbF3(H2PO4) and its amorphous phase have been established and temperature ranges of their realization have been determined (150–450K). According to the NMR data, the diffusion in the proton sublattice of the disordered crystalline and amorphous phases is preserved even at room temperature. The ionic conductivity in CsSbF3(H2PO4) reaches the values of ~ 2.6 × 10–4 S/cm in the temperature range 410–425K and decreases down to ~ 2.0 × 10–5 S/cm upon transition to the amorphous phase (435–445K).
1H, 31P MAS NMR spectra of crystalline and amorphous phase of the CsSbF3(H2PO4) at 300K. Display omitted
•Studied the phase transitions, ion mobility and conductivity in CsSbF3(H2PO4).•Above 425K a transition is observed: the crystalline phase→amorphous phase.•The types of ion mobility in CsSbF3(H2PO4) and its amorphous phase have been established.•The main type of ion motion above 300K in disordered phase is a diffusion H.•The conductivity of the CsSbF3(H2PO4) more than 10–4S/cm in 410–425K region.
