Effective therapeutics for Alzheimer's disease (AD) are in great demand worldwide. In our previous work, we responded to this need by synthesizing novel drug candidates consisting of ...4-amino-2,3-polymethylenequinolines conjugated with butylated hydroxytoluene via fixed-length alkylimine or alkylamine linkers (spacers) and studying their bioactivities pertaining to AD treatment. Here, we report significant extensions of these studies, including the use of variable-length spacers and more detailed biological characterizations. Conjugates were potent inhibitors of acetylcholinesterase (AChE, the most active was
IC
15.1 ± 0.2 nM) and butyrylcholinesterase (BChE, the most active was
: IC
5.96 ± 0.58 nM), with weak inhibition of off-target carboxylesterase. Conjugates with alkylamine spacers were more effective cholinesterase inhibitors than alkylimine analogs. Optimal inhibition for AChE was exhibited by cyclohexaquinoline and for BChE by cycloheptaquinoline. Increasing spacer length elevated the potency against both cholinesterases. Structure-activity relationships agreed with docking results. Mixed-type reversible AChE inhibition, dual docking to catalytic and peripheral anionic sites, and propidium iodide displacement suggested the potential of hybrids to block AChE-induced
-amyloid (A
) aggregation. Hybrids also exhibited the inhibition of A
self-aggregation in the thioflavin test; those with a hexaquinoline ring and C8 spacer were the most active. Conjugates demonstrated high antioxidant activity in ABTS and FRAP assays as well as the inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Quantum-chemical calculations explained antioxidant results. Computed ADMET profiles indicated favorable blood-brain barrier permeability, suggesting the CNS activity potential. Thus, the conjugates could be considered promising multifunctional agents for the potential treatment of AD.
Display omitted
A series of 31 N,N-disubstituted 2-amino-5-halomethyl-2-thiazolines was designed, synthesized, and evaluated for inhibitory potential against acetylcholinesterase (AChE), ...butyrylcholinesterase (BChE) and carboxylesterase (CaE). The compounds did not inhibit AChE; the most active compounds inhibited BChE and CaE with IC50 values of 0.22–2.3μM. Pyridine-containing compounds were more selective toward BChE; compounds with the para-OMe substituent in one of the two dibenzyl fragments were more selective toward CaE. Iodinated derivatives were more effective BChE inhibitors than brominated ones, while there was no influence of halogen type on CaE inhibition. Inhibition kinetics for the 9 most active compounds indicated non-competitive inhibition of CaE and varied mechanisms (competitive, non-competitive, or mixed-type) for inhibition of BChE. Docking simulations predicted key binding interactions of compounds with BChE and CaE and revealed that the best docked positions in BChE were at the bottom of the gorge in close proximity to the catalytic residues in the active site. In contrast, the best binding positions for CaE were clustered rather far from the active site at the top of the gorge. Thus, the docking results provided insight into differences in kinetic mechanisms and inhibitor activities of the tested compounds. A cytotoxicity test using the MTT assay showed that within solubility limits (<30μM), none of the tested compounds significantly affected viability of human fetal mesenchymal stem cells. The results indicate that a new series of N,N-disubstituted 2-aminothiazolines could serve as BChE and CaE inhibitors for potential medicinal applications.
Potato virus Y (PVY) is one of the most common and harmful plant viruses. Translation of viral RNA starts with the interaction between the plant cap-binding translation initiation factors eIF4E and ...viral genome-linked protein (VPg) covalently attached to the viral RNA. Disruption of this interaction is one of the natural mechanisms of plant resistance to PVY. The multigene eIF4E family in the potato (
Solanum tuberosum
L.) genome contains genes for the translation initiation factors eIF4E1, eIF4E2, and eIF(iso)4E. However, which of these factors can be recruited by the PVY, as well as the mechanism of this interaction, remain obscure. Here, we showed that the most common VPg variant from the PVY strain NTN interacts with eIF4E1 and eIF4E2, but not with eIF(iso)4E. Based on the VPg, eIF4E1, and eIF4E2 models and data on the natural polymorphism of VPg amino acid sequence, we suggested that the key role in the recognition of potato cap-binding factors belongs to the R104 residue of VPg. To verify this hypothesis, we created VPg mutants with substitutions at position 104 and examined their ability to interact with potato eIF4E factors. The obtained data were used to build the theoretical model of the VPg-eIF4E2 complex that differs significantly from the earlier models of VPg complexes with eIF4E proteins, but is in a good agreement with the current biochemical data.
Display omitted
•New conjugates of tacrine with 1,2,4-thiadiazole derivatives were synthesized.•Extensive QM characterization revealed most stable forms of the conjugates.•Conjugates effectively ...inhibited cholinesterases with BChE selectivity.•Docking showed binding to both the CAS and PAS of AChE.•Spectrum of biological activity was dependent on the conjugate spacer.
We synthesized conjugates of tacrine with 1,2,4-thiadiazole derivatives linked by two different spacers, pentylaminopropene (compounds 4) and pentylaminopropane (compounds 5), as potential drugs for the treatment of Alzheimer’s disease (AD). The conjugates effectively inhibited cholinesterases with a predominant effect on butyrylcholinesterase (BChE). They were also effective at displacing propidium from the peripheral anionic site (PAS) of acetylcholinesterase (AChE), suggesting that they could block AChE-induced β-amyloid aggregation. In addition, the compounds exhibited high radical-scavenging capacity. Conjugates 5 had higher anti-BChE activity and greater anti-aggregant potential as well relatively lower potency against carboxylesterase than compounds 4. Quantum-mechanical (QM) characterization agreed with NMR data to identify the most stable forms of conjugates for docking studies, which showed that the compounds bind to both CAS and PAS of AChE consistent with mixed reversible inhibition. Conjugates 4 were more potent radical scavengers, in agreement with HOMO localization in the enamine-thiadiazole system. Computational studies showed that all of the conjugates were expected to have good intestinal absorption, whereas conjugates 4 and 5 were predicted to have medium and high blood-brain barrier permeability, respectively. All conjugates were predicted to have medium cardiac toxicity risks. Overall, the results indicated that the conjugates are promising candidates for further development and optimization as multifunctional therapeutic agents for the treatment of AD.
An expanded series of alkyl 2-arylhydrazinylidene-3-oxo-3-polyfluoroalkylpropionates (HOPs) 3 was obtained via Cu(OAc)2-catalyzed azo coupling. All were nanomolar inhibitors of carboxylesterase ...(CES), while moderate or weak inhibitors of acetylcholinesterase and butyrylcholinesterase. Steady-state kinetics studies showed that HOPs 3 are mixed type inhibitors of the three esterases. Molecular docking studies demonstrated that two functional groups in the structure of HOPs, trifluoromethyl ketone (TFK) and ester groups, bind to the CES active site suggesting subsequent reactions: formation of a tetrahedral adduct, and a slow hydrolysis reaction. The results of molecular modeling allowed us to explain some structure-activity relationships of CES inhibition by HOPs 3: their selectivity toward CES in comparison with cholinesterases and the high selectivity of pentafluoroethyl-substituted HOP 3p to hCES1 compared to hCES2. All compounds were predicted to have good intestinal absorption and blood-brain barrier permeability, low cardiac toxicity, good lipophilicity and aqueous solubility, and reasonable overall drug-likeness. HOPs with a TFK group and electron-donor substituents in the arylhydrazone moiety were potent antioxidants. All compounds possessed low cytotoxicity and low acute toxicity. Overall, a new promising type of bifunctional CES inhibitors has been found that are able to interact with the active site of the enzyme with the participation of two functional groups. The results indicate that HOPs have the potential to be good candidates as human CES inhibitors for biomedicinal applications.
Display omitted
•Alkyl 2-arylhydrazinylidene-3-oxo-3-polyfluoroalkylpropionates (HOPs) were made.•HOPs were nanomolar inhibitors of carboxylesterase (CES).•HOPs dock to the CES active site with trifluoromethyl (TFK) and ester groups.•Some HOPs were potent antioxidants.•HOPs had good predicted ADMET profiles, low cytotoxicity, and low acute toxicity.
Recently, aminohydroximate ligands have found wide applications in the fascinating class of polynuclear metallamacrocyclic compounds named 15-MC-5 metallacrowns. The enhanced interest in ...water-soluble aminohydroximate Ln(
iii
)-Cu(
ii
) complexes is largely due to their rich coordination chemistry, diverse properties and ease of synthesis. We examined glycinehydroxamic acid as a simple ligand for the preparation of the first water-soluble polynuclear metallamacrocyclic Sr(
ii
)-Cu(
ii
) compound. The complex Sr(H
2
O)
3
15-MC
CuGlyha
-5(Cl)
2
was synthesized and characterized structurally and spectroscopically. The single-crystal structure reveals the classic metallamacrocyclic 15-MC-5 configuration. The Sr(
ii
) ion is located at the center of the 15-MC
Cu(II)Glyha
-5 ring and coordinated by five oxygen atoms of the cycle in the equatorial plane and an additional three oxygen atoms of the water molecules at apical positions. Detailed DFT and QT AIM studies were carried out for the hydrated isoelectronic Sr15-MC
CuGlyha
-5
2+
and Y15-MC
CuGlyha
-5
3+
systems. The ionic contribution to the metal-ligand interactions appears to be higher for the Sr(
ii
) derivative despite the smaller charge separation. DFT calculations suggest a thermodynamically favorable substitution of the Sr(
ii
) central ion with Y(
iii
). Indeed, it was shown experimentally that the strontium ion can be easily replaced by yttrium. Preliminary cytotoxic studies revealed the low toxicity of the strontium complex and its yttrium analogue, so the water-soluble Sr(
ii
) and Y(
iii
) metallacrowns can be further investigated as possible platforms for the development of new
90
Sr and
90
Y radiotherapy drugs.
Experimental and theoretical studies of a new strontium metallacrown reveal the specific central ion influence on molecular and electronic structures of metallamacrocycles.
Single-crystalline diamond plates were implanted by He+ ions with a set of energies and fluences that ensure uniform radiation damage (RD) in a 670-nm-thick layer. Implantation is carried out at a ...wide range of fluences, which allows one to cover the range of RD levels from very low to complete graphitization of diamond. Using the measurement data on the bending of diamond plates and the surface swelling of the ion-implanted material, we calculate the mechanical stress and the density of diamond for various levels of RD. Diamonds with various levels of RD are investigated by the Raman scattering and optical transmission methods. We establish that, above the graphitization threshold, the diamond phase almost completely disappears as the RD level increases, while the fraction of sp
2 material sharply increases. Such a material is unexpectedly ductile. It cannot be restored to diamond even by annealing under a pressure corresponding to thermodynamic stability of diamond.
Autoimmune gastritis (AIG) is the autoimmune disease of the stomach characterized by the destruction of the oxyntic mucosa, which stops producing acid and becomes both functionally and ...morphologically atrophic. There is no specific treatment for AIG. Previously, we identified a new immunoregulatory factor (regulatory rheumatoid factor (regRF)), the stimulation production of which reduces certain experimental autoimmune diseases. Epitopes specific to the regulatory rheumatoid factor (regRF epitopes) can be obtained on IgG Fc fragments. In the rat AIG model, the therapeutic efficacy of IgG Fc fragments bearing regRF epitopes was tested. Treatment with IgG Fc fragments bearing regRF epitopes reduced T lymphocytic infiltration of oxyntic mucosa and prevented its damage in the AIG rat model, while in rats treated with placebo, T lymphocytic infiltration of the mucosa, loss of parietal cells, including severe were observed. Therefore, IgG Fc fragments bearing regRF epitopes are a potential therapeutic agent for treating autoimmune gastritis in its early stages.
PDF
