Derivatives of 9-phosphorylated acridine as butyrylcholinesterase inhibitors with antioxidant activity and the ability to inhibit ß-amyloid self-aggregation: potential therapeutic agents for Alzheimer's disease.

We investigated the inhibitory activities of novel 9-phosphoryl-9,10-dihydroacridines and 9-phosphorylacridines against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CES). We also studied the abilities of the new compounds to interfere with the self-aggregation of ß-amyloid (Aß42) in the thioflavin test as well as their antioxidant activities in the ABTS and FRAP assays. We used molecular docking, molecular dynamics simulations, and quantum-chemical calculations to explain experimental results. All new compounds weakly inhibited AChE and off-target CES. Dihydroacridines with aryl substituents in the phosphoryl moiety inhibited BChE; the most active were the dibenzyloxy derivative 1d and its diphenethyl bioisostere 1e (IC50 = 2.90 ± 0.23 µM and 3.22 ± 0.25 µM, respectively). Only one acridine, 2d, an analog of dihydroacridine, 1d, was an effective BChE inhibitor (IC50 = 6.90 ± 0.55 µM), consistent with docking results. Dihydroacridines inhibited Aß42 self-aggregation; 1d and 1e were the most active (58.9% ± 4.7% and 46.9% ± 4.2%, respectively). All dihydroacridines 1 demonstrated high ABTS•+-scavenging and iron-reducing activities comparable to Trolox, but acridines 2 were almost inactive. Observed features were well explained by quantum-chemical calculations. ADMET parameters calculated for all compounds predicted favorable intestinal absorption, good blood-brain barrier permeability, and low cardiac toxicity. Overall, the best results were obtained for two dihydroacridine derivatives 1d and 1e with dibenzyloxy and diphenethyl substituents in the phosphoryl moiety. These compounds displayed high inhibition of BChE activity and Aß42 self-aggregation, high antioxidant activity, and favorable predicted ADMET profiles. Therefore, we consider 1d and 1e as lead compounds for further in-depth studies as potential anti-AD preparations.

Oxidative C-H/C-H Coupling of Dipyrromethanes with Azines by TiO2-Based Photocatalytic System. Synthesis of New BODIPY Dyes and Their Photophysical and Electrochemical Properties.

Oxidative C-H/C-H coupling reactions of dipyrromethanes with azines in the presence of a heterophase oxidative photocatalytic system (O2/TiO2/visible light irradiation) were carried out. As a result of cyclization of obtained compounds with boron trifluoride etherate, new hetaryl-containing derivatives of 4,4-difluoro-4-boron-3a,4a-diaza-s-indacene were synthesized. For the obtained compounds, absorption and luminescence spectra, quantum yields of luminescence as well as cyclic volt-amperograms were measured.

Oxidative Aromatization of 4,7-Dihydro-6-nitroazolo[1,5-a]pyrimidines: Synthetic Possibilities and Limitations, Mechanism of Destruction, and the Theoretical and Experimental Substantiation.

The reaction tolerance of the multicomponent process between 3-aminoazoles, 1-morpholino-2-nitroalkenes, and aldehydes was studied. The main patterns of this reaction have been established. Conditions for the oxidation of 4,7-dihydro-6-nitroazolo[1,5-a]pyrimidines were selected. Previous claims that the 4,7-dihydro-6-nitroazolo[1,5-a]pyrimidines could not be aromatised have now been refuted. Compounds with an electron-donor substituent at position seven undergo decomposition during oxidation. The phenomenon was explained based on experimental data, electro-chemical experiment, and quantum-chemical calculation. The mechanism of oxidative degradation has been proposed.

9-Substituted acridine derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors possessing antioxidant activity for Alzheimer's disease treatment.

We investigated the inhibitory activity of 4 groups of novel acridine derivatives against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carboxylesterase (CaE) using the methods of enzyme kinetics and molecular docking. Antioxidant activity of the compounds was determined using the 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+) radical decolorization assay as their ability to scavenge free radicals. Analysis of the esterase profiles and antiradical activities of the acridine derivatives showed that 9-aryl(heteroaryl)-N-methyl-9,10-dihydroacridines have a high radical-scavenging activity but low potency as AChE and BChE inhibitors, whereas 9-aryl(heteroaryl)-N-methyl-acridinium tetrafluoroborates effectively inhibit cholinesterases but do not exhibit antiradical activity. In contrast, a group of derivatives of 9-heterocyclic amino-N-methyl-9,10-dihydroacridine has been found that combine effective inhibition of AChE and BChE with rather high radical-scavenging activity. The results of molecular docking well explain the observed features in the efficacy, selectivity, and mechanism of cholinesterase inhibition by the acridine derivatives. Thus, in a series of acridine derivatives we have found compounds possessing dual properties of effective and selective cholinesterase inhibition together with free radical scavenging, which makes promising the use of the acridine scaffold to create multifunctional drugs for the therapy of neurodegenerative diseases.