Derivatives of 9-phosphorylated acridine as butyrylcholinesterase inhibitors with antioxidant activity and the ability to inhibit β-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 β-amyloid (Aβ42) 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 Aβ42 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 Aβ42 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

Palladium(II)-catalyzed oxidative C-H/C-H coupling and eliminative S N H reactions in direct functionalization of imidazole oxides with indoles

Two novel synthetic approaches to realize the direct C(sp2)-H bond functionalization in cyclic nitrones are reported. Palladium(II)-catalyzed oxidative C-C coupling of 2,2-dialkyl-4-phenyl-2H-imidazole 1-oxides with indoles was shown to result in the formation of 5-indolyl-3-yl derivatives, while nucleophilic substitution of hydrogen (SNH) at C(5) of the same imidazole system was found to afford the corresponding deoxygenated compounds. © 2012 American Chemical Society

Advanced Application of Planar Chiral Heterocyclic Ferrocenes

This manuscript is reviewing the superior catalytic activity and selectivity of ferrocene ligands in a wide range of reactions: reduction of ketones, hydrogenation of olefins, hydroboration, cycloaddition, enantioselective synthesis of biaryls, Tsuji–Trost allylation. Moreover, the correlation between a ligand structure and its catalytic activity is discussed in this review

Indolylazine Derivative Induces Chaperone Expression in Aged Neural Cells and Prevents the Progression of Alzheimer’s Disease

The risk of progression of most sporadic neurodegenerative diseases, including Alzheimer’s disease, increases with age. Traditionally, this is associated with a decrease in the efficiency of cell protection systems, in particular, molecular chaperones. Thus, the development of small molecules able to induce the synthesis of chaperones is a promising therapeutic approach to prevent neural diseases associated with ageing. Here, we describe a new compound IA-50, belonging to the class of indolylazines and featured by a low size of topological polar surface area, the property related to substances with potentially high membrane-penetrating activity. We also estimated the absorption, distribution, metabolism and excretion characteristics of IA-50 and found the substance to fit the effective drug criteria. The new compound was found to induce the synthesis and accumulation of Hsp70 in normal and aged neurons and in the hippocampi of young and old mice. The transgenic model of Alzheimer’s disease, based on 5xFAD mice, confirmed that the injection of IA-50 prevented the formation of β-amyloid aggregates, loss of hippocampal neurons and the development of memory impairment. These data indicate that this novel substance may induce the expression of chaperones in neural cells and brain tissues, suggesting its possible application in the therapy of ageing-associated disorders

Palladium(II)-Catalyzed Oxidative C–H/C–H Coupling and Eliminative S_N^H Reactions in Direct Functionalization of Imidazole Oxides with Indoles

Two novel synthetic approaches to realize the direct C­(sp²)–H bond functionalization in cyclic nitrones are reported. Palladium­(II)-catalyzed oxidative C–C coupling of 2,2-dialkyl-4-phenyl-2<i>H</i>-imidazole 1-oxides with indoles was shown to result in the formation of 5-indolyl-3-yl derivatives, while nucleophilic substitution of hydrogen (S_N^H) at C(5) of the same imidazole system was found to afford the corresponding deoxygenated compounds

Palladium(II)-Catalyzed Oxidative C–H/C–H Coupling and Eliminative S_N^H Reactions in Direct Functionalization of Imidazole Oxides with Indoles

Two novel synthetic approaches to realize the direct C­(sp²)–H bond functionalization in cyclic nitrones are reported. Palladium­(II)-catalyzed oxidative C–C coupling of 2,2-dialkyl-4-phenyl-2<i>H</i>-imidazole 1-oxides with indoles was shown to result in the formation of 5-indolyl-3-yl derivatives, while nucleophilic substitution of hydrogen (S_N^H) at C(5) of the same imidazole system was found to afford the corresponding deoxygenated compounds

Two Approaches in the Synthesis of Planar Chiral Azinylferrocenes

Two synthetic routes to the chiral azinylferrocenes (CAFs) <b>5</b> and <b>15</b>, key intermediates for the synthesis of new enantiomerically enriched <i>P</i>,<i>N</i>-ligands, have been compared. The first approach is based on the palladium-catalyzed cross-coupling reaction of halogenated azines with organozinc derivatives of ferrocenes (the Negishi reaction). The second approach exploits a new synthetic methodology, which provides a shorter pathway, through the direct C–H functionalization of aromatics by the C–C coupling of halogen-free (hetero)­arenes with lithium ferrocenes bearing stereogenic C and S atoms. The palladium complexes of <i>P</i>,<i>N</i>-ligands have been used as catalysts for the Tsuji–Trost reaction, which proceeds with high enantioselectivity to give allylic substitution products in good yields

Two Approaches in the Synthesis of Planar Chiral Azinylferrocenes

Two synthetic routes to the chiral azinylferrocenes (CAFs) <b>5</b> and <b>15</b>, key intermediates for the synthesis of new enantiomerically enriched <i>P</i>,<i>N</i>-ligands, have been compared. The first approach is based on the palladium-catalyzed cross-coupling reaction of halogenated azines with organozinc derivatives of ferrocenes (the Negishi reaction). The second approach exploits a new synthetic methodology, which provides a shorter pathway, through the direct C–H functionalization of aromatics by the C–C coupling of halogen-free (hetero)­arenes with lithium ferrocenes bearing stereogenic C and S atoms. The palladium complexes of <i>P</i>,<i>N</i>-ligands have been used as catalysts for the Tsuji–Trost reaction, which proceeds with high enantioselectivity to give allylic substitution products in good yields

Combination of a Chaperone Synthesis Inducer and an Inhibitor of GAPDH Aggregation for Rehabilitation after Traumatic Brain Injury: A Pilot Study

The recovery period after traumatic brain injury (TBI) is often complicated by secondary damage that may last for days or even months after trauma. Two proteins, Hsp70 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), were recently described as modulating post-traumatic processes, and in this study, we test them as targets for combination therapy using an inhibitor of GAPDH aggregation (derivative of hydrocortisone RX624) and an inducer of Hsp70 synthesis (the pyrrolylazine derivative PQ-29). The protective effect of the combination on C6 rat glioblastoma cells treated with the cerebrospinal fluid of traumatized animals resulted in an increase in the cell index and in a reduced level of apoptosis. Using a rat weight drop model of TBI, we found that the combined use of both drugs prevented memory impairment and motor deficits, as well as a reduction of neurons and accumulation of GAPDH aggregates in brain tissue. In conclusion, we developed and tested a new approach to the treatment of TBI based on influencing distinct molecular mechanisms in brain cells