Electrochemical Aromatization of Dihydroazines: Effect of Chalco­genophosphoryl (CGP) Substituents on Anodic Oxidation of 9-CGP-9,10-dihydroacridine

Schepochkin, Alexander V.; Чупахин, О. Н.; Demina, Nadezhda S.; Averkov, Maxim; Shimanovskaya, Tatyana; Слепухин, П. А.; Volkov, Pavel А.; Telezhkin, Anton A.; Трофимов, Б. А.; Charushin, Valery N.

doi:10.1055/a-1521-3166

Cited by 4 publications

(8 citation statements)

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“…9-Phosphoryl-9,10-dihydroacridines 1a–f and 9-phosphorylacridines 2a–f were obtained according to Figure 1 as described in our recent publication ( Shchepochkin et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2023

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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.

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“…9-Phosphoryl-9,10-dihydroacridines 1a–f and 9-phosphorylacridines 2a–f were obtained according to Figure 1 as described in our recent publication ( Shchepochkin et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2023

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“…The cyclic voltammetry showed [77] differences in the behavior of dihydroacridines 62, 63. The phosphoryl derivatives 62b,c, 63a,b,d,e (X = O) gave an irreversible peak of two-electron oxidation, while in the case of compounds 62e,f,h containing sulfur and selenium (X = S, Se), the voltammogram had two one-electron oxidation peaks.…”

Section: S N H Phosphorylation Of Acridinesmentioning

confidence: 97%

“…The reaction was shown to be applicable to dialkyl and diaryl H-phosphonates (Scheme 53) [75,77]. Acridine dihydro intermediates were unable to be oxidized (aromatized) by electrondeficient acetylenes such as benzoylphenylacetylene.…”

Section: S N H Phosphorylation Of Acridinesmentioning

confidence: 99%

“…Indeed, in the case of dihydroacridines 62, 63, aromatization proceeded [77] with the saving of the phosphorus-containing substituents to afford the phosphorylated aromatic acridines 64b,c, 65a-d in high yields (81-89%) (Scheme 57). However, the decomposition of the starting dihydroacridines with phosphoryl sulfide and selenide substituents 62e,f,h with the cleavage of the C-P bond was observed (Scheme 57).…”

Section: S N H Phosphorylation Of Acridinesmentioning

confidence: 99%

“…The phosphoryl derivatives 62b,c, 63a,b,d,e (X = O) gave an irreversible peak of two-electron oxidation, while in the case of compounds 62e,f,h containing sulfur and selenium (X = S, Se), the voltammogram had two one-electron oxidation peaks. From the quantum chemical calculations of the HOMO followed that the growth of the HOMO population corresponded to a decrease in E peak values [77].…”

Section: S N H Phosphorylation Of Acridinesmentioning

confidence: 99%

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Electron-Deficient Acetylenes as Three-Modal Adjuvants in SNH Reaction of Pyridinoids with Phosphorus Nucleophiles

2021

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Publications covering a new easy metal-free functionalization of pyridinoids (pyridines, quinolines, isoquinolines, acridine) under the action of the system of electron-deficient acetylenes (acetylenecarboxylic acid esters, acylacetylenes)/P-nucleophiles (phosphine chalcogenides, H-phosphonates) are reviewed. Special attention is focused on a SNH reaction of the regioselective cross-coupling of pyridines with secondary phosphine chalcogenides triggered by acylacetylenes to give 4-chalcogenophosphorylpyridines. In these processes, acetylenes act as three-modal adjuvants (i) activating the pyridine ring towards P-nucleophiles, (ii) deprotonating the P-H bond and (iii) facilitating the nucleophilic addition of the P-centered anion to a heterocyclic moiety followed by the release of the selectively reduced acetylenes (E-alkenes).

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Nucleophilic substitution of hydrogen in pyridine and its derivatives by organophosphorus nucleophiles in the presence of electron-deficient acetylenes

Telezhkin,

Volkov,

Khrapova

2023

Žurnal organičeskoj himii

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The review considers publications on a new easy functionalization of pyridinoids (pyridines, quinolines, isoquinolines, acridine, phenanthridine) by the electron-deficient acetylene (esters of acetylenecarboxylic acids, acylacetylenes, cyanoacetylenes)/P-nucleophile (phosphine chalcogenides, H -phosphonates) system. Particular attention is paid to the SN H reaction of regioselective cross-coupling of pyridines with secondary phosphine chalcogenides, initiated by acylacetylenes and leading to the formation of 4-chalcogenophosphorylpyridines. In these processes, acetylenes act as trimodal adjuvants by (1) activating the pyridine ring towards P-nucleophiles, (2) deprotonating the P-H bond, and (3) facilitating the nucleophilic addition of the P-centered anion to the heterocyclic fragment, followed by the release of selectively reduced (to E -alkenes) acetylenes.

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Electrochemical Aromatization of Dihydroazines: Effect of Chalcogenophosphoryl (CGP) Substituents on Anodic Oxidation of 9-CGP-9,10-dihydroacridine

Cited by 4 publications

References 8 publications

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

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

Electron-Deficient Acetylenes as Three-Modal Adjuvants in SNH Reaction of Pyridinoids with Phosphorus Nucleophiles

Nucleophilic substitution of hydrogen in pyridine and its derivatives by organophosphorus nucleophiles in the presence of electron-deficient acetylenes

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Electrochemical Aromatization of Dihydroazines: Effect of Chalco­genophosphoryl (CGP) Substituents on Anodic Oxidation of 9-CGP-9,10-dihydroacridine

Cited by 4 publications

References 8 publications

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

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

Electron-Deficient Acetylenes as Three-Modal Adjuvants in SNH Reaction of Pyridinoids with Phosphorus Nucleophiles

Nucleophilic substitution of hydrogen in pyridine and its derivatives by organophosphorus nucleophiles in the presence of electron-deficient acetylenes

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Electrochemical Aromatization of Dihydroazines: Effect of Chalcogenophosphoryl (CGP) Substituents on Anodic Oxidation of 9-CGP-9,10-dihydroacridine