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

Galina F Makhaeva; Nadezhda V Kovaleva; Elena V Rudakova; Natalia P Boltneva; Sofya V Lushchekina; Tatiana Yu Astakhova; Elena N Timokhina; Olga G Serebryakova; Alexander V Shchepochkin; Maxim A Averkov; Irina A Utepova; Nadezhda S Demina; Eugene V Radchenko; Vladimir A Palyulin; Vladimir P Fisenko; Sergey O Bachurin; Oleg N Chupakhin; Valery N Charushin; Rudy J Richardson

doi:10.3389/fphar.2023.1219980

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

Front Pharmacol. 2023 Aug 9:14:1219980. doi: 10.3389/fphar.2023.1219980. eCollection 2023.

Authors

Galina F Makhaeva¹, Nadezhda V Kovaleva¹, Elena V Rudakova¹, Natalia P Boltneva¹, Sofya V Lushchekina^{1

2}, Tatiana Yu Astakhova², Elena N Timokhina², Olga G Serebryakova¹, Alexander V Shchepochkin^{3

4}, Maxim A Averkov^{3

4}, Irina A Utepova^{3

4}, Nadezhda S Demina³, Eugene V Radchenko^{1

5}, Vladimir A Palyulin^{1

5}, Vladimir P Fisenko⁶, Sergey O Bachurin¹, Oleg N Chupakhin^{3

4}, Valery N Charushin^{3

4}, Rudy J Richardson^{6

7

8

9}

Affiliations

¹ Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka, Russia.
² Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, Russia.
³ Institute of Organic Synthesis, Russian Academy of Sciences, Yekaterinburg, Russia.
⁴ Department of Organic and Biomolecular Chemistry, Ural Federal University, Yekaterinburg, Russia.
⁵ Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia.
⁶ Department of Pharmacology of the Institute of Biodesign and Complex System Modeling of Biomedical Science & Technology Park of Sechenov I.M., First Moscow State Medical University, Moscow, Russia.
⁷ Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI, United States.
⁸ Department of Neurology, University of Michigan, Ann Arbor, MI, United States.
⁹ Center of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, United States.

Abstract

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.

Keywords: 9-phosphoryl-9,10-dihydroacridines; 9-phosphorylacridines; Alzheimer’s disease; acetylcholinesterase; butyrylcholinesterase.

Copyright © 2023 Makhaeva, Kovaleva, Rudakova, Boltneva, Lushchekina, Astakhova, Timokhina, Serebryakova, Shchepochkin, Averkov, Utepova, Demina, Radchenko, Palyulin, Fisenko, Bachurin, Chupakhin, Charushin and Richardson.

Grants and funding

This research was partly supported by grant # 22-13-00298 of the Russian Science Foundation and IPAC RAS State Targets Project # FFSN-2021-0005; quantum-chemical calculations were supported the IBCP RAS State Targets Project # 122041400110-4. The synthesis of the compounds was financially supported by the Russian Foundation for Basic Research (research project # 19-29-08037). Support for RR’s contributions to the computer modeling components of the work was provided in part by a grant from the Alternatives Research and Development Foundation (ARDF) and an Mcubed grant from the University of Michigan.