Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: <i>N</i>-Functionalization Determines the Multitarget Anti-Alzheimer’s Activity Profile
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-<i>N</i>-acyl-alkylene (<b>3</b>) and bis-<i>N</i>-thiourea...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-02-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/3/1060 |
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| author | Galina F. Makhaeva Nadezhda V. Kovaleva Natalia P. Boltneva Elena V. Rudakova Sofya V. Lushchekina Tatiana Yu. Astakhova Igor V. Serkov Alexey N. Proshin Eugene V. Radchenko Vladimir A. Palyulin Jan Korabecny Ondrej Soukup Sergey O. Bachurin Rudy J. Richardson |
| author_facet | Galina F. Makhaeva Nadezhda V. Kovaleva Natalia P. Boltneva Elena V. Rudakova Sofya V. Lushchekina Tatiana Yu. Astakhova Igor V. Serkov Alexey N. Proshin Eugene V. Radchenko Vladimir A. Palyulin Jan Korabecny Ondrej Soukup Sergey O. Bachurin Rudy J. Richardson |
| author_sort | Galina F. Makhaeva |
| collection | DOAJ |
| description | 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-<i>N</i>-acyl-alkylene (<b>3</b>) and bis-<i>N</i>-thiourea-alkylene (<b>5</b>) —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 <b>3</b> with bis-<i>N</i>-acyl-alkylene spacers were more potent inhibitors of both cholinesterases compared to compounds <b>5</b> and the parent amiridine. The lead compounds <b>3a</b><b>–c</b> exhibited an IC<sub>50</sub>(AChE) = 2.9–1.4 µM, IC<sub>50</sub>(BChE) = 0.13–0.067 µM, and 14–18% propidium displacement at 20 μM. Kinetic studies of compounds <b>3a</b> and <b>5d</b> 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 Aβ<sub>42</sub> aggregation. Conjugates <b>3</b> had no effect on Aβ<sub>42</sub> self-aggregation, whereas compounds <b>5c</b>–<b>e</b> (<i>m</i> = 4, 5, 6) showed mild (13–17%) inhibition. The greatest difference between conjugates <b>3</b> and <b>5</b> was their antioxidant activity. Bis-amiridines <b>3</b> with <i>N</i>-acylalkylene spacers were nearly inactive in ABTS and FRAP tests, whereas compounds <b>5</b> 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 (<b>5</b>) or exceeded (<b>3</b>) that of the parent compound, amiridine. Overall, based on their expanded and balanced pharmacological profiles, conjugates <b>5c</b>–<b>e</b> appear promising for future optimization and development as multitarget anti-AD agents. |
| first_indexed | 2024-03-09T23:26:32Z |
| format | Article |
| id | doaj.art-90ae90fd4e9f4057a738309e4978db2b |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T23:26:32Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-90ae90fd4e9f4057a738309e4978db2b2023-11-23T17:16:57ZengMDPI AGMolecules1420-30492022-02-01273106010.3390/molecules27031060Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: <i>N</i>-Functionalization Determines the Multitarget Anti-Alzheimer’s Activity ProfileGalina F. Makhaeva0Nadezhda V. Kovaleva1Natalia P. Boltneva2Elena V. Rudakova3Sofya V. Lushchekina4Tatiana Yu. Astakhova5Igor V. Serkov6Alexey N. Proshin7Eugene V. Radchenko8Vladimir A. Palyulin9Jan Korabecny10Ondrej Soukup11Sergey O. Bachurin12Rudy J. Richardson13Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaEmanuel Institute of Biochemical Physics, Russian Academy of Sciences, 119334 Moscow, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaDepartment of Chemistry, Lomonosov Moscow State University, 119991 Moscow, RussiaDepartment of Chemistry, Lomonosov Moscow State University, 119991 Moscow, RussiaBiomedical Research Centre, University Hospital Hradec Kralove, 500 05 Hradec Kralove, Czech RepublicBiomedical Research Centre, University Hospital Hradec Kralove, 500 05 Hradec Kralove, Czech RepublicInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaDepartment of Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48109, USAUsing 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-<i>N</i>-acyl-alkylene (<b>3</b>) and bis-<i>N</i>-thiourea-alkylene (<b>5</b>) —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 <b>3</b> with bis-<i>N</i>-acyl-alkylene spacers were more potent inhibitors of both cholinesterases compared to compounds <b>5</b> and the parent amiridine. The lead compounds <b>3a</b><b>–c</b> exhibited an IC<sub>50</sub>(AChE) = 2.9–1.4 µM, IC<sub>50</sub>(BChE) = 0.13–0.067 µM, and 14–18% propidium displacement at 20 μM. Kinetic studies of compounds <b>3a</b> and <b>5d</b> 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 Aβ<sub>42</sub> aggregation. Conjugates <b>3</b> had no effect on Aβ<sub>42</sub> self-aggregation, whereas compounds <b>5c</b>–<b>e</b> (<i>m</i> = 4, 5, 6) showed mild (13–17%) inhibition. The greatest difference between conjugates <b>3</b> and <b>5</b> was their antioxidant activity. Bis-amiridines <b>3</b> with <i>N</i>-acylalkylene spacers were nearly inactive in ABTS and FRAP tests, whereas compounds <b>5</b> 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 (<b>5</b>) or exceeded (<b>3</b>) that of the parent compound, amiridine. Overall, based on their expanded and balanced pharmacological profiles, conjugates <b>5c</b>–<b>e</b> appear promising for future optimization and development as multitarget anti-AD agents.https://www.mdpi.com/1420-3049/27/3/1060amiridine<i>N</i>-acylamidethioureaacetylcholinesterase (AChE)butyrylcholinesterase (BChE)antioxidants |
| spellingShingle | Galina F. Makhaeva Nadezhda V. Kovaleva Natalia P. Boltneva Elena V. Rudakova Sofya V. Lushchekina Tatiana Yu. Astakhova Igor V. Serkov Alexey N. Proshin Eugene V. Radchenko Vladimir A. Palyulin Jan Korabecny Ondrej Soukup Sergey O. Bachurin Rudy J. Richardson Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: <i>N</i>-Functionalization Determines the Multitarget Anti-Alzheimer’s Activity Profile Molecules amiridine <i>N</i>-acylamide thiourea acetylcholinesterase (AChE) butyrylcholinesterase (BChE) antioxidants |
| title | Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: <i>N</i>-Functionalization Determines the Multitarget Anti-Alzheimer’s Activity Profile |
| title_full | Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: <i>N</i>-Functionalization Determines the Multitarget Anti-Alzheimer’s Activity Profile |
| title_fullStr | Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: <i>N</i>-Functionalization Determines the Multitarget Anti-Alzheimer’s Activity Profile |
| title_full_unstemmed | Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: <i>N</i>-Functionalization Determines the Multitarget Anti-Alzheimer’s Activity Profile |
| title_short | Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: <i>N</i>-Functionalization Determines the Multitarget Anti-Alzheimer’s Activity Profile |
| title_sort | bis amiridines as acetylcholinesterase and butyrylcholinesterase inhibitors i n i functionalization determines the multitarget anti alzheimer s activity profile |
| topic | amiridine <i>N</i>-acylamide thiourea acetylcholinesterase (AChE) butyrylcholinesterase (BChE) antioxidants |
| url | https://www.mdpi.com/1420-3049/27/3/1060 |
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