Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases
Abstract The development of remedies against the Alzheimer’s disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Schwarz, Stefan [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2014transfer abstract |
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| Schlagwörter: |
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| Umfang: |
9 |
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| Übergeordnetes Werk: |
Enthalten in: A theoretical model of cyberchondria development: Antecedents and intermediate processes - Zheng, Han ELSEVIER, 2021, a Tetrahedron publication for the rapid dissemination of full original research papers and critical reviews on bioorganic chemistry, medicinal chemistry, bioinorganic chemistry and related disciplines, Amsterdam [u.a.] |
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| Übergeordnetes Werk: |
volume:22 ; year:2014 ; number:13 ; day:1 ; month:07 ; pages:3370-3378 ; extent:9 |
| Links: |
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| DOI / URN: |
10.1016/j.bmc.2014.04.046 |
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ELV017785561 |
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| 245 | 1 | 0 | |a Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases |
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| 520 | |a Abstract The development of remedies against the Alzheimer’s disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of acetylcholine (ACh) decreases; hence, a therapy using inhibitors should be of some benefit to the patients. Drugs presently used for the treatment of AD inhibit the two ACh controlling enzymes, acetylcholinesterase as well as butyrylcholinesterase; hence, the design of selective inhibitors is called for. Glycyrrhetinic acid seems to be an interesting starting point for the development of selective inhibitors. Although its glycon, glycyrrhetinic acid is known for being an AChE activator, several derivatives, altered in position C-3 and C-30, exhibited remarkable inhibition constants in micro-molar range. Furthermore, five representative compounds were subjected to three more enzyme assays (on carbonic anhydrase II, papain and the lipase from Candida antarctica) to gain information about the selectivity of the compounds in comparison to other enzymes. In addition, photometric sulforhodamine B assays using murine embryonic fibroblasts (NiH 3T3) were performed to study the cytotoxicity of these compounds. Two derivatives, bearing either a 1,3-diaminopropyl or a 1H-benzotriazolyl residue, showed a BChE selective inhibition in the single-digit micro-molar range without being cytotoxic up to 30μM. In silico molecular docking studies on the active sites of AChE and BChE were performed to gain a molecular insight into the mode of action of these compounds and to explain the pronounced selectivity for BChE. | ||
| 520 | |a Abstract The development of remedies against the Alzheimer’s disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of acetylcholine (ACh) decreases; hence, a therapy using inhibitors should be of some benefit to the patients. Drugs presently used for the treatment of AD inhibit the two ACh controlling enzymes, acetylcholinesterase as well as butyrylcholinesterase; hence, the design of selective inhibitors is called for. Glycyrrhetinic acid seems to be an interesting starting point for the development of selective inhibitors. Although its glycon, glycyrrhetinic acid is known for being an AChE activator, several derivatives, altered in position C-3 and C-30, exhibited remarkable inhibition constants in micro-molar range. Furthermore, five representative compounds were subjected to three more enzyme assays (on carbonic anhydrase II, papain and the lipase from Candida antarctica) to gain information about the selectivity of the compounds in comparison to other enzymes. In addition, photometric sulforhodamine B assays using murine embryonic fibroblasts (NiH 3T3) were performed to study the cytotoxicity of these compounds. Two derivatives, bearing either a 1,3-diaminopropyl or a 1H-benzotriazolyl residue, showed a BChE selective inhibition in the single-digit micro-molar range without being cytotoxic up to 30μM. In silico molecular docking studies on the active sites of AChE and BChE were performed to gain a molecular insight into the mode of action of these compounds and to explain the pronounced selectivity for BChE. | ||
| 650 | 7 | |a Docking studies |2 Elsevier | |
| 650 | 7 | |a Cholinesterase inhibitors |2 Elsevier | |
| 650 | 7 | |a Glycyrrhetinic acid |2 Elsevier | |
| 650 | 7 | |a Ellman’s test |2 Elsevier | |
| 700 | 1 | |a Lucas, Susana Dias |4 oth | |
| 700 | 1 | |a Sommerwerk, Sven |4 oth | |
| 700 | 1 | |a Csuk, René |4 oth | |
| 773 | 0 | 8 | |i Enthalten in |n Elsevier |a Zheng, Han ELSEVIER |t A theoretical model of cyberchondria development: Antecedents and intermediate processes |d 2021 |d a Tetrahedron publication for the rapid dissemination of full original research papers and critical reviews on bioorganic chemistry, medicinal chemistry, bioinorganic chemistry and related disciplines |g Amsterdam [u.a.] |w (DE-627)ELV006510728 |
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10.1016/j.bmc.2014.04.046 doi GBVA2014016000015.pica (DE-627)ELV017785561 (ELSEVIER)S0968-0896(14)00311-3 DE-627 ger DE-627 rakwb eng 540 610 540 DE-600 610 DE-600 004 VZ 53.70 bkl 05.42 bkl 53.76 bkl 54.00 bkl Schwarz, Stefan verfasserin aut Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases 2014transfer abstract 9 nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Abstract The development of remedies against the Alzheimer’s disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of acetylcholine (ACh) decreases; hence, a therapy using inhibitors should be of some benefit to the patients. Drugs presently used for the treatment of AD inhibit the two ACh controlling enzymes, acetylcholinesterase as well as butyrylcholinesterase; hence, the design of selective inhibitors is called for. Glycyrrhetinic acid seems to be an interesting starting point for the development of selective inhibitors. Although its glycon, glycyrrhetinic acid is known for being an AChE activator, several derivatives, altered in position C-3 and C-30, exhibited remarkable inhibition constants in micro-molar range. Furthermore, five representative compounds were subjected to three more enzyme assays (on carbonic anhydrase II, papain and the lipase from Candida antarctica) to gain information about the selectivity of the compounds in comparison to other enzymes. In addition, photometric sulforhodamine B assays using murine embryonic fibroblasts (NiH 3T3) were performed to study the cytotoxicity of these compounds. Two derivatives, bearing either a 1,3-diaminopropyl or a 1H-benzotriazolyl residue, showed a BChE selective inhibition in the single-digit micro-molar range without being cytotoxic up to 30μM. In silico molecular docking studies on the active sites of AChE and BChE were performed to gain a molecular insight into the mode of action of these compounds and to explain the pronounced selectivity for BChE. Abstract The development of remedies against the Alzheimer’s disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of acetylcholine (ACh) decreases; hence, a therapy using inhibitors should be of some benefit to the patients. Drugs presently used for the treatment of AD inhibit the two ACh controlling enzymes, acetylcholinesterase as well as butyrylcholinesterase; hence, the design of selective inhibitors is called for. Glycyrrhetinic acid seems to be an interesting starting point for the development of selective inhibitors. Although its glycon, glycyrrhetinic acid is known for being an AChE activator, several derivatives, altered in position C-3 and C-30, exhibited remarkable inhibition constants in micro-molar range. Furthermore, five representative compounds were subjected to three more enzyme assays (on carbonic anhydrase II, papain and the lipase from Candida antarctica) to gain information about the selectivity of the compounds in comparison to other enzymes. In addition, photometric sulforhodamine B assays using murine embryonic fibroblasts (NiH 3T3) were performed to study the cytotoxicity of these compounds. Two derivatives, bearing either a 1,3-diaminopropyl or a 1H-benzotriazolyl residue, showed a BChE selective inhibition in the single-digit micro-molar range without being cytotoxic up to 30μM. In silico molecular docking studies on the active sites of AChE and BChE were performed to gain a molecular insight into the mode of action of these compounds and to explain the pronounced selectivity for BChE. Docking studies Elsevier Cholinesterase inhibitors Elsevier Glycyrrhetinic acid Elsevier Ellman’s test Elsevier Lucas, Susana Dias oth Sommerwerk, Sven oth Csuk, René oth Enthalten in Elsevier Zheng, Han ELSEVIER A theoretical model of cyberchondria development: Antecedents and intermediate processes 2021 a Tetrahedron publication for the rapid dissemination of full original research papers and critical reviews on bioorganic chemistry, medicinal chemistry, bioinorganic chemistry and related disciplines Amsterdam [u.a.] (DE-627)ELV006510728 volume:22 year:2014 number:13 day:1 month:07 pages:3370-3378 extent:9 https://doi.org/10.1016/j.bmc.2014.04.046 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U 53.70 Nachrichtentechnik Kommunikationstechnik: Allgemeines VZ 05.42 Telekommunikation VZ 53.76 Kommunikationsdienste Fernmeldetechnik VZ 54.00 Informatik: Allgemeines VZ AR 22 2014 13 1 0701 3370-3378 9 045F 540 |
| spelling |
10.1016/j.bmc.2014.04.046 doi GBVA2014016000015.pica (DE-627)ELV017785561 (ELSEVIER)S0968-0896(14)00311-3 DE-627 ger DE-627 rakwb eng 540 610 540 DE-600 610 DE-600 004 VZ 53.70 bkl 05.42 bkl 53.76 bkl 54.00 bkl Schwarz, Stefan verfasserin aut Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases 2014transfer abstract 9 nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Abstract The development of remedies against the Alzheimer’s disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of acetylcholine (ACh) decreases; hence, a therapy using inhibitors should be of some benefit to the patients. Drugs presently used for the treatment of AD inhibit the two ACh controlling enzymes, acetylcholinesterase as well as butyrylcholinesterase; hence, the design of selective inhibitors is called for. Glycyrrhetinic acid seems to be an interesting starting point for the development of selective inhibitors. Although its glycon, glycyrrhetinic acid is known for being an AChE activator, several derivatives, altered in position C-3 and C-30, exhibited remarkable inhibition constants in micro-molar range. Furthermore, five representative compounds were subjected to three more enzyme assays (on carbonic anhydrase II, papain and the lipase from Candida antarctica) to gain information about the selectivity of the compounds in comparison to other enzymes. In addition, photometric sulforhodamine B assays using murine embryonic fibroblasts (NiH 3T3) were performed to study the cytotoxicity of these compounds. Two derivatives, bearing either a 1,3-diaminopropyl or a 1H-benzotriazolyl residue, showed a BChE selective inhibition in the single-digit micro-molar range without being cytotoxic up to 30μM. In silico molecular docking studies on the active sites of AChE and BChE were performed to gain a molecular insight into the mode of action of these compounds and to explain the pronounced selectivity for BChE. Abstract The development of remedies against the Alzheimer’s disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of acetylcholine (ACh) decreases; hence, a therapy using inhibitors should be of some benefit to the patients. Drugs presently used for the treatment of AD inhibit the two ACh controlling enzymes, acetylcholinesterase as well as butyrylcholinesterase; hence, the design of selective inhibitors is called for. Glycyrrhetinic acid seems to be an interesting starting point for the development of selective inhibitors. Although its glycon, glycyrrhetinic acid is known for being an AChE activator, several derivatives, altered in position C-3 and C-30, exhibited remarkable inhibition constants in micro-molar range. Furthermore, five representative compounds were subjected to three more enzyme assays (on carbonic anhydrase II, papain and the lipase from Candida antarctica) to gain information about the selectivity of the compounds in comparison to other enzymes. In addition, photometric sulforhodamine B assays using murine embryonic fibroblasts (NiH 3T3) were performed to study the cytotoxicity of these compounds. Two derivatives, bearing either a 1,3-diaminopropyl or a 1H-benzotriazolyl residue, showed a BChE selective inhibition in the single-digit micro-molar range without being cytotoxic up to 30μM. In silico molecular docking studies on the active sites of AChE and BChE were performed to gain a molecular insight into the mode of action of these compounds and to explain the pronounced selectivity for BChE. Docking studies Elsevier Cholinesterase inhibitors Elsevier Glycyrrhetinic acid Elsevier Ellman’s test Elsevier Lucas, Susana Dias oth Sommerwerk, Sven oth Csuk, René oth Enthalten in Elsevier Zheng, Han ELSEVIER A theoretical model of cyberchondria development: Antecedents and intermediate processes 2021 a Tetrahedron publication for the rapid dissemination of full original research papers and critical reviews on bioorganic chemistry, medicinal chemistry, bioinorganic chemistry and related disciplines Amsterdam [u.a.] (DE-627)ELV006510728 volume:22 year:2014 number:13 day:1 month:07 pages:3370-3378 extent:9 https://doi.org/10.1016/j.bmc.2014.04.046 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U 53.70 Nachrichtentechnik Kommunikationstechnik: Allgemeines VZ 05.42 Telekommunikation VZ 53.76 Kommunikationsdienste Fernmeldetechnik VZ 54.00 Informatik: Allgemeines VZ AR 22 2014 13 1 0701 3370-3378 9 045F 540 |
| allfields_unstemmed |
10.1016/j.bmc.2014.04.046 doi GBVA2014016000015.pica (DE-627)ELV017785561 (ELSEVIER)S0968-0896(14)00311-3 DE-627 ger DE-627 rakwb eng 540 610 540 DE-600 610 DE-600 004 VZ 53.70 bkl 05.42 bkl 53.76 bkl 54.00 bkl Schwarz, Stefan verfasserin aut Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases 2014transfer abstract 9 nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Abstract The development of remedies against the Alzheimer’s disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of acetylcholine (ACh) decreases; hence, a therapy using inhibitors should be of some benefit to the patients. Drugs presently used for the treatment of AD inhibit the two ACh controlling enzymes, acetylcholinesterase as well as butyrylcholinesterase; hence, the design of selective inhibitors is called for. Glycyrrhetinic acid seems to be an interesting starting point for the development of selective inhibitors. Although its glycon, glycyrrhetinic acid is known for being an AChE activator, several derivatives, altered in position C-3 and C-30, exhibited remarkable inhibition constants in micro-molar range. Furthermore, five representative compounds were subjected to three more enzyme assays (on carbonic anhydrase II, papain and the lipase from Candida antarctica) to gain information about the selectivity of the compounds in comparison to other enzymes. In addition, photometric sulforhodamine B assays using murine embryonic fibroblasts (NiH 3T3) were performed to study the cytotoxicity of these compounds. Two derivatives, bearing either a 1,3-diaminopropyl or a 1H-benzotriazolyl residue, showed a BChE selective inhibition in the single-digit micro-molar range without being cytotoxic up to 30μM. In silico molecular docking studies on the active sites of AChE and BChE were performed to gain a molecular insight into the mode of action of these compounds and to explain the pronounced selectivity for BChE. Abstract The development of remedies against the Alzheimer’s disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of acetylcholine (ACh) decreases; hence, a therapy using inhibitors should be of some benefit to the patients. Drugs presently used for the treatment of AD inhibit the two ACh controlling enzymes, acetylcholinesterase as well as butyrylcholinesterase; hence, the design of selective inhibitors is called for. Glycyrrhetinic acid seems to be an interesting starting point for the development of selective inhibitors. Although its glycon, glycyrrhetinic acid is known for being an AChE activator, several derivatives, altered in position C-3 and C-30, exhibited remarkable inhibition constants in micro-molar range. Furthermore, five representative compounds were subjected to three more enzyme assays (on carbonic anhydrase II, papain and the lipase from Candida antarctica) to gain information about the selectivity of the compounds in comparison to other enzymes. In addition, photometric sulforhodamine B assays using murine embryonic fibroblasts (NiH 3T3) were performed to study the cytotoxicity of these compounds. Two derivatives, bearing either a 1,3-diaminopropyl or a 1H-benzotriazolyl residue, showed a BChE selective inhibition in the single-digit micro-molar range without being cytotoxic up to 30μM. In silico molecular docking studies on the active sites of AChE and BChE were performed to gain a molecular insight into the mode of action of these compounds and to explain the pronounced selectivity for BChE. Docking studies Elsevier Cholinesterase inhibitors Elsevier Glycyrrhetinic acid Elsevier Ellman’s test Elsevier Lucas, Susana Dias oth Sommerwerk, Sven oth Csuk, René oth Enthalten in Elsevier Zheng, Han ELSEVIER A theoretical model of cyberchondria development: Antecedents and intermediate processes 2021 a Tetrahedron publication for the rapid dissemination of full original research papers and critical reviews on bioorganic chemistry, medicinal chemistry, bioinorganic chemistry and related disciplines Amsterdam [u.a.] (DE-627)ELV006510728 volume:22 year:2014 number:13 day:1 month:07 pages:3370-3378 extent:9 https://doi.org/10.1016/j.bmc.2014.04.046 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U 53.70 Nachrichtentechnik Kommunikationstechnik: Allgemeines VZ 05.42 Telekommunikation VZ 53.76 Kommunikationsdienste Fernmeldetechnik VZ 54.00 Informatik: Allgemeines VZ AR 22 2014 13 1 0701 3370-3378 9 045F 540 |
| allfieldsGer |
10.1016/j.bmc.2014.04.046 doi GBVA2014016000015.pica (DE-627)ELV017785561 (ELSEVIER)S0968-0896(14)00311-3 DE-627 ger DE-627 rakwb eng 540 610 540 DE-600 610 DE-600 004 VZ 53.70 bkl 05.42 bkl 53.76 bkl 54.00 bkl Schwarz, Stefan verfasserin aut Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases 2014transfer abstract 9 nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Abstract The development of remedies against the Alzheimer’s disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of acetylcholine (ACh) decreases; hence, a therapy using inhibitors should be of some benefit to the patients. Drugs presently used for the treatment of AD inhibit the two ACh controlling enzymes, acetylcholinesterase as well as butyrylcholinesterase; hence, the design of selective inhibitors is called for. Glycyrrhetinic acid seems to be an interesting starting point for the development of selective inhibitors. Although its glycon, glycyrrhetinic acid is known for being an AChE activator, several derivatives, altered in position C-3 and C-30, exhibited remarkable inhibition constants in micro-molar range. Furthermore, five representative compounds were subjected to three more enzyme assays (on carbonic anhydrase II, papain and the lipase from Candida antarctica) to gain information about the selectivity of the compounds in comparison to other enzymes. In addition, photometric sulforhodamine B assays using murine embryonic fibroblasts (NiH 3T3) were performed to study the cytotoxicity of these compounds. Two derivatives, bearing either a 1,3-diaminopropyl or a 1H-benzotriazolyl residue, showed a BChE selective inhibition in the single-digit micro-molar range without being cytotoxic up to 30μM. In silico molecular docking studies on the active sites of AChE and BChE were performed to gain a molecular insight into the mode of action of these compounds and to explain the pronounced selectivity for BChE. Abstract The development of remedies against the Alzheimer’s disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of acetylcholine (ACh) decreases; hence, a therapy using inhibitors should be of some benefit to the patients. Drugs presently used for the treatment of AD inhibit the two ACh controlling enzymes, acetylcholinesterase as well as butyrylcholinesterase; hence, the design of selective inhibitors is called for. Glycyrrhetinic acid seems to be an interesting starting point for the development of selective inhibitors. Although its glycon, glycyrrhetinic acid is known for being an AChE activator, several derivatives, altered in position C-3 and C-30, exhibited remarkable inhibition constants in micro-molar range. Furthermore, five representative compounds were subjected to three more enzyme assays (on carbonic anhydrase II, papain and the lipase from Candida antarctica) to gain information about the selectivity of the compounds in comparison to other enzymes. In addition, photometric sulforhodamine B assays using murine embryonic fibroblasts (NiH 3T3) were performed to study the cytotoxicity of these compounds. Two derivatives, bearing either a 1,3-diaminopropyl or a 1H-benzotriazolyl residue, showed a BChE selective inhibition in the single-digit micro-molar range without being cytotoxic up to 30μM. In silico molecular docking studies on the active sites of AChE and BChE were performed to gain a molecular insight into the mode of action of these compounds and to explain the pronounced selectivity for BChE. Docking studies Elsevier Cholinesterase inhibitors Elsevier Glycyrrhetinic acid Elsevier Ellman’s test Elsevier Lucas, Susana Dias oth Sommerwerk, Sven oth Csuk, René oth Enthalten in Elsevier Zheng, Han ELSEVIER A theoretical model of cyberchondria development: Antecedents and intermediate processes 2021 a Tetrahedron publication for the rapid dissemination of full original research papers and critical reviews on bioorganic chemistry, medicinal chemistry, bioinorganic chemistry and related disciplines Amsterdam [u.a.] (DE-627)ELV006510728 volume:22 year:2014 number:13 day:1 month:07 pages:3370-3378 extent:9 https://doi.org/10.1016/j.bmc.2014.04.046 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U 53.70 Nachrichtentechnik Kommunikationstechnik: Allgemeines VZ 05.42 Telekommunikation VZ 53.76 Kommunikationsdienste Fernmeldetechnik VZ 54.00 Informatik: Allgemeines VZ AR 22 2014 13 1 0701 3370-3378 9 045F 540 |
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Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases |
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Abstract The development of remedies against the Alzheimer’s disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of acetylcholine (ACh) decreases; hence, a therapy using inhibitors should be of some benefit to the patients. Drugs presently used for the treatment of AD inhibit the two ACh controlling enzymes, acetylcholinesterase as well as butyrylcholinesterase; hence, the design of selective inhibitors is called for. Glycyrrhetinic acid seems to be an interesting starting point for the development of selective inhibitors. Although its glycon, glycyrrhetinic acid is known for being an AChE activator, several derivatives, altered in position C-3 and C-30, exhibited remarkable inhibition constants in micro-molar range. Furthermore, five representative compounds were subjected to three more enzyme assays (on carbonic anhydrase II, papain and the lipase from Candida antarctica) to gain information about the selectivity of the compounds in comparison to other enzymes. In addition, photometric sulforhodamine B assays using murine embryonic fibroblasts (NiH 3T3) were performed to study the cytotoxicity of these compounds. Two derivatives, bearing either a 1,3-diaminopropyl or a 1H-benzotriazolyl residue, showed a BChE selective inhibition in the single-digit micro-molar range without being cytotoxic up to 30μM. In silico molecular docking studies on the active sites of AChE and BChE were performed to gain a molecular insight into the mode of action of these compounds and to explain the pronounced selectivity for BChE. |
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Abstract The development of remedies against the Alzheimer’s disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of acetylcholine (ACh) decreases; hence, a therapy using inhibitors should be of some benefit to the patients. Drugs presently used for the treatment of AD inhibit the two ACh controlling enzymes, acetylcholinesterase as well as butyrylcholinesterase; hence, the design of selective inhibitors is called for. Glycyrrhetinic acid seems to be an interesting starting point for the development of selective inhibitors. Although its glycon, glycyrrhetinic acid is known for being an AChE activator, several derivatives, altered in position C-3 and C-30, exhibited remarkable inhibition constants in micro-molar range. Furthermore, five representative compounds were subjected to three more enzyme assays (on carbonic anhydrase II, papain and the lipase from Candida antarctica) to gain information about the selectivity of the compounds in comparison to other enzymes. In addition, photometric sulforhodamine B assays using murine embryonic fibroblasts (NiH 3T3) were performed to study the cytotoxicity of these compounds. Two derivatives, bearing either a 1,3-diaminopropyl or a 1H-benzotriazolyl residue, showed a BChE selective inhibition in the single-digit micro-molar range without being cytotoxic up to 30μM. In silico molecular docking studies on the active sites of AChE and BChE were performed to gain a molecular insight into the mode of action of these compounds and to explain the pronounced selectivity for BChE. |
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Abstract The development of remedies against the Alzheimer’s disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of acetylcholine (ACh) decreases; hence, a therapy using inhibitors should be of some benefit to the patients. Drugs presently used for the treatment of AD inhibit the two ACh controlling enzymes, acetylcholinesterase as well as butyrylcholinesterase; hence, the design of selective inhibitors is called for. Glycyrrhetinic acid seems to be an interesting starting point for the development of selective inhibitors. Although its glycon, glycyrrhetinic acid is known for being an AChE activator, several derivatives, altered in position C-3 and C-30, exhibited remarkable inhibition constants in micro-molar range. Furthermore, five representative compounds were subjected to three more enzyme assays (on carbonic anhydrase II, papain and the lipase from Candida antarctica) to gain information about the selectivity of the compounds in comparison to other enzymes. In addition, photometric sulforhodamine B assays using murine embryonic fibroblasts (NiH 3T3) were performed to study the cytotoxicity of these compounds. Two derivatives, bearing either a 1,3-diaminopropyl or a 1H-benzotriazolyl residue, showed a BChE selective inhibition in the single-digit micro-molar range without being cytotoxic up to 30μM. In silico molecular docking studies on the active sites of AChE and BChE were performed to gain a molecular insight into the mode of action of these compounds and to explain the pronounced selectivity for BChE. |
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Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases |
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https://doi.org/10.1016/j.bmc.2014.04.046 |
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Lucas, Susana Dias Sommerwerk, Sven Csuk, René |
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10.1016/j.bmc.2014.04.046 |
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