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Sun T, Zhen T, Harakandi CH, Wang L, Guo H, Chen Y, Sun H. New insights into butyrylcholinesterase: Pharmaceutical applications, selective inhibitors and multitarget-directed ligands. Eur J Med Chem 2024; 275:116569. [PMID: 38852337 DOI: 10.1016/j.ejmech.2024.116569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 05/30/2024] [Accepted: 06/02/2024] [Indexed: 06/11/2024]
Abstract
Butyrylcholinesterase (BChE), also known as pseudocholinesterase and serum cholinesterase, is an isoenzyme of acetylcholinesterase (AChE). It mediates the degradation of acetylcholine, especially under pathological conditions. Proverbial pharmacological applications of BChE, its mutants and modulators consist of combating Alzheimer's disease (AD), influencing multiple sclerosis (MS), addressing cocaine addiction, detoxifying organophosphorus poisoning and reflecting the progression or prognosis of some diseases. Of interest, recent reports have shed light on the relationship between BChE and lipid metabolism. It has also been proved that BChE is going to increase abnormally as a compensator for AChE in the middle and late stages of AD, and BChE inhibitors can alleviate cognitive disorders and positively influence some pathological features in AD model animals, foreboding favorable prospects and potential applications. Herein, the selective BChE inhibitors and BChE-related multitarget-directed ligands published in the last three years were briefly summarized, along with the currently known pharmacological applications of BChE, aiming to grasp the latest research directions. Thereinto, some emerging strategies for designing BChE inhibitors are intriguing, and the modulators based on target combination of histone deacetylase and BChE against AD is unprecedented. Furthermore, the involvement of BChE in the hydrolysis of ghrelin, the inhibition of low-density lipoprotein (LDL) uptake, and the down-regulation of LDL receptor (LDLR) expression suggests its potential to influence lipid metabolism disorders. This compelling prospect likely stimulates further exploration in this promising research direction.
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Affiliation(s)
- Tianyu Sun
- School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China
| | - Tengfei Zhen
- School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China
| | | | - Lei Wang
- School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China
| | - Huanchao Guo
- School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China
| | - Yao Chen
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China.
| | - Haopeng Sun
- School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.
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Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer's Disease. Int J Mol Sci 2023; 24:ijms24032285. [PMID: 36768608 PMCID: PMC9916969 DOI: 10.3390/ijms24032285] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/09/2023] [Accepted: 01/18/2023] [Indexed: 01/26/2023] Open
Abstract
A series of previously synthesized conjugates of tacrine and salicylamide was extended by varying the structure of the salicylamide fragment and using salicylic aldehyde to synthesize salicylimine derivatives. The hybrids exhibited broad-spectrum biological activity. All new conjugates were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. The structure of the salicylamide moiety exerted little effect on anticholinesterase activity, but AChE inhibition increased with spacer elongation. The most active conjugates were salicylimine derivatives: IC50 values of the lead compound 10c were 0.0826 µM (AChE) and 0.0156 µM (BChE), with weak inhibition of the off-target carboxylesterase. The hybrids were mixed-type reversible inhibitors of both cholinesterases and displayed dual binding to the catalytic and peripheral anionic sites of AChE in molecular docking, which, along with experimental results on propidium iodide displacement, suggested their potential to block AChE-induced β-amyloid aggregation. All conjugates inhibited Aβ42 self-aggregation in the thioflavin test, and inhibition increased with spacer elongation. Salicylimine 10c and salicylamide 5c with (CH2)8 spacers were the lead compounds for inhibiting Aβ42 self-aggregation, which was corroborated by molecular docking to Aβ42. ABTS•+-scavenging activity was highest for salicylamides 5a-c, intermediate for salicylimines 10a-c, low for F-containing salicylamides 7, and non-existent for methoxybenzoylamides 6 and difluoromethoxybenzoylamides 8. In the FRAP antioxidant (AO) assay, the test compounds displayed little or no activity. Quantum chemical analysis and molecular dynamics (MD) simulations with QM/MM potentials explained the AO structure-activity relationships. All conjugates were effective chelators of Cu2+, Fe2+, and Zn2+, with molar compound/metal (Cu2+) ratios of 2:1 (5b) and ~1:1 (10b). Conjugates exerted comparable or lower cytotoxicity than tacrine on mouse hepatocytes and had favorable predicted intestinal absorption and blood-brain barrier permeability. The overall results indicate that the synthesized conjugates are promising new multifunctional agents for the potential treatment of AD.
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Islamov II, Yusupova AV, D'yakonov VA, Dzhemilev UM. Synthesis of new ionic liquids based on (5Z,9Z)-alkadienoic acids and choline. MENDELEEV COMMUNICATIONS 2023. [DOI: 10.1016/j.mencom.2023.01.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Grishin IY, Malyuga VV, Aksenov DА, Kirilov NK, Abakarov GM, Ovcharov SN, Sarapii AV, Aksenov NА, Aksenov AV. A sequence of acylamination and acylation reactions in polyphosphoric acid – a novel approach to the Friedländer synthesis of 2-arylquinolines. Chem Heterocycl Compd (N Y) 2022. [DOI: 10.1007/s10593-022-03090-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Grishchenko MV, Makhaeva GF, Burgart YV, Rudakova EV, Boltneva NP, Kovaleva NV, Serebryakova OG, Lushchekina SV, Astakhova TY, Zhilina EF, Shchegolkov EV, Richardson RJ, Saloutin VI. Conjugates of Tacrine with Salicylamide as Promising Multitarget Agents for Alzheimer's Disease. ChemMedChem 2022; 17:e202200080. [PMID: 35322571 PMCID: PMC9314152 DOI: 10.1002/cmdc.202200080] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/04/2022] [Indexed: 12/29/2022]
Abstract
New conjugates of tacrine and salicylamide with alkylene spacers were synthesized and evaluated as potential multifunctional agents for Alzheimer's disease (AD). The compounds exhibited high acetylcholinesterase (AChE, IC50 to 0.224 μM) and butyrylcholinesterase (BChE, IC50 to 0.0104 μM) inhibitory activities. They were also rather poor inhibitors of carboxylesterase, suggesting a low tendency to exert potential unwanted drug-drug interactions in clinical use. The conjugates were mixed-type reversible inhibitors of both cholinesterases and demonstrated dual binding to the catalytic and peripheral anionic sites of AChE in molecular docking that, along with experimental results on propidium iodide displacement, suggest their potential to block AChE-induced β-amyloid aggregation. The new conjugates exhibited high ABTS.+ -scavenging activity. N-(6-(1,2,3,4-Tetrahydroacridin-9-ylamino)hexyl)salicylamide is a lead compound that also demonstrates metal chelating ability toward Cu2+ , Fe2+ and Zn2+ . Thus, the new conjugates have displayed the potential to be multifunctional anti-AD agents for further development.
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Affiliation(s)
- Maria V Grishchenko
- Postovsky Institute of Organic Synthesis, Urals Branch of Russian Academy of Sciences, 620990, Ekaterinburg, Russia
| | - Galina F Makhaeva
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432, Chernogolovka, Russia
| | - Yanina V Burgart
- Postovsky Institute of Organic Synthesis, Urals Branch of Russian Academy of Sciences, 620990, Ekaterinburg, Russia
| | - Elena V Rudakova
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432, Chernogolovka, Russia
| | - Natalia P Boltneva
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432, Chernogolovka, Russia
| | - Nadezhda V Kovaleva
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432, Chernogolovka, Russia
| | - Olga G Serebryakova
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432, Chernogolovka, Russia
| | - Sofya V Lushchekina
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432, Chernogolovka, Russia.,Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, 119334, Moscow, Russia
| | - Tatiana Y Astakhova
- Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, 119334, Moscow, Russia
| | - Ekaterina F Zhilina
- Postovsky Institute of Organic Synthesis, Urals Branch of Russian Academy of Sciences, 620990, Ekaterinburg, Russia
| | - Evgeny V Shchegolkov
- Postovsky Institute of Organic Synthesis, Urals Branch of Russian Academy of Sciences, 620990, Ekaterinburg, Russia
| | - Rudy J Richardson
- Departments of Environmental Health Sciences and Neurology, University of Michigan, 48109, Ann Arbor, MI, USA.,Center for Computational Medicine and Bioinformatics, University of Michigan, 48109, Ann Arbor, MI, USA
| | - Victor I Saloutin
- Postovsky Institute of Organic Synthesis, Urals Branch of Russian Academy of Sciences, 620990, Ekaterinburg, Russia
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Makhaeva GF, Kovaleva NV, Boltneva NP, Rudakova EV, Lushchekina SV, Astakhova TY, Serkov IV, Proshin AN, Radchenko EV, Palyulin VA, Korabecny J, Soukup O, Bachurin SO, Richardson RJ. Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: N-Functionalization Determines the Multitarget Anti-Alzheimer’s Activity Profile. Molecules 2022; 27:molecules27031060. [PMID: 35164325 PMCID: PMC8839189 DOI: 10.3390/molecules27031060] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/26/2022] [Accepted: 01/28/2022] [Indexed: 11/16/2022] Open
Abstract
Using two ways of functionalizing amiridine—acylation with chloroacetic acid chloride and reaction with thiophosgene—we have synthesized new homobivalent bis-amiridines joined by two different spacers—bis-N-acyl-alkylene (3) and bis-N-thiourea-alkylene (5) —as potential multifunctional agents for the treatment of Alzheimer’s disease (AD). All compounds exhibited high inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity for BChE. These new agents displayed negligible carboxylesterase inhibition, suggesting a probable lack of untoward drug–drug interactions arising from hydrolytic biotransformation. Compounds 3 with bis-N-acyl-alkylene spacers were more potent inhibitors of both cholinesterases compared to compounds 5 and the parent amiridine. The lead compounds 3a–c exhibited an IC50(AChE) = 2.9–1.4 µM, IC50(BChE) = 0.13–0.067 µM, and 14–18% propidium displacement at 20 μM. Kinetic studies of compounds 3a and 5d indicated mixed-type reversible inhibition. Molecular docking revealed favorable poses in both catalytic and peripheral AChE sites. Propidium displacement from the peripheral site by the hybrids suggests their potential to hinder AChE-assisted Aβ42 aggregation. Conjugates 3 had no effect on Aβ42 self-aggregation, whereas compounds 5c–e (m = 4, 5, 6) showed mild (13–17%) inhibition. The greatest difference between conjugates 3 and 5 was their antioxidant activity. Bis-amiridines 3 with N-acylalkylene spacers were nearly inactive in ABTS and FRAP tests, whereas compounds 5 with thiourea in the spacers demonstrated high antioxidant activity, especially in the ABTS test (TEAC = 1.2–2.1), in agreement with their significantly lower HOMO-LUMO gap values. Calculated ADMET parameters for all conjugates predicted favorable blood–brain barrier permeability and intestinal absorption, as well as a low propensity for cardiac toxicity. Thus, it was possible to obtain amiridine derivatives whose potencies against AChE and BChE equaled (5) or exceeded (3) that of the parent compound, amiridine. Overall, based on their expanded and balanced pharmacological profiles, conjugates 5c–e appear promising for future optimization and development as multitarget anti-AD agents.
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Affiliation(s)
- Galina F. Makhaeva
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Russia; (G.F.M.); (N.V.K.); (N.P.B.); (E.V.R.); (S.V.L.); (I.V.S.); (A.N.P.); (S.O.B.)
| | - Nadezhda V. Kovaleva
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Russia; (G.F.M.); (N.V.K.); (N.P.B.); (E.V.R.); (S.V.L.); (I.V.S.); (A.N.P.); (S.O.B.)
| | - Natalia P. Boltneva
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Russia; (G.F.M.); (N.V.K.); (N.P.B.); (E.V.R.); (S.V.L.); (I.V.S.); (A.N.P.); (S.O.B.)
| | - Elena V. Rudakova
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Russia; (G.F.M.); (N.V.K.); (N.P.B.); (E.V.R.); (S.V.L.); (I.V.S.); (A.N.P.); (S.O.B.)
| | - Sofya V. Lushchekina
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Russia; (G.F.M.); (N.V.K.); (N.P.B.); (E.V.R.); (S.V.L.); (I.V.S.); (A.N.P.); (S.O.B.)
- Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, 119334 Moscow, Russia;
| | - Tatiana Yu. Astakhova
- Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, 119334 Moscow, Russia;
| | - Igor V. Serkov
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Russia; (G.F.M.); (N.V.K.); (N.P.B.); (E.V.R.); (S.V.L.); (I.V.S.); (A.N.P.); (S.O.B.)
| | - Alexey N. Proshin
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Russia; (G.F.M.); (N.V.K.); (N.P.B.); (E.V.R.); (S.V.L.); (I.V.S.); (A.N.P.); (S.O.B.)
| | - Eugene V. Radchenko
- Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia; (E.V.R.); (V.A.P.)
| | - Vladimir A. Palyulin
- Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia; (E.V.R.); (V.A.P.)
| | - Jan Korabecny
- Biomedical Research Centre, University Hospital Hradec Kralove, 500 05 Hradec Kralove, Czech Republic; (J.K.); (O.S.)
| | - Ondrej Soukup
- Biomedical Research Centre, University Hospital Hradec Kralove, 500 05 Hradec Kralove, Czech Republic; (J.K.); (O.S.)
| | - Sergey O. Bachurin
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Russia; (G.F.M.); (N.V.K.); (N.P.B.); (E.V.R.); (S.V.L.); (I.V.S.); (A.N.P.); (S.O.B.)
| | - Rudy J. Richardson
- Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
- Center of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
- Michigan Institute for Computational Discovery and Engineering, University of Michigan, Ann Arbor, MI 48109, USA
- Correspondence: ; Tel.: +1-734-936-0769
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