Fe(III)-catalyzed regioselective and faster synthesis of isocoumarins with 3-oxoalkyl moiety at C-4 : Identification of new inhibitors of PDE4
Copyright © 2022 Elsevier Inc. All rights reserved..
In search of potent and new anti-inflammatory agents, we explored a new class of isocoumarin derivatives possessing the 3-oxoalkyl moiety at C-4 position. These compounds were synthesized via the FeCl3 catalyzed construction of isocoumarin ring. The methodology involved coupling of 2-alkynyl benzamides with alkyl vinyl ketone and proceeded via a regioselective cyclization to give the desired compound as a result of formation of CO and CC bonds. A large number of isocoumarins were synthesized and assessed against PDE4B in vitro. While isocoumarins containing an aminosulfonyl moiety attached to the C-3 aryl ring showed encouraging inhibition of PDE4B, some of the derivatives devoid of aminosulfonyl moiety also showed considerable inhibition. According to the SAR analysis the C6H4NHSO2R2-m moiety at C-3 position of the isocoumarin ring was favorable when the R2 was chosen as an aryl or 2-thienyl group whereas the presence of F or OMe substituent at C-7 of the isocoumarin ring was found to be beneficial. The compound 5f with IC50 values 0.125 ± 0.032 and 0.43 ± 0.013 µM against PDE4B and 4D, respectively was identified as an initial hit. It showed in silico interaction with the PHE678 residue in the CR3 region of PDE4B and relatively less number of interactions with PDE4D. Besides showing the PDE4 selectivity over other PDEs and TNF-α inhibition in vitro the compound 5f at an intraperitoneal dose of 30 mg/kg demonstrated the protective effects against the development of arthritis and potent immunomodulatory activity in adjuvant induced arthritic (AIA) rats. Furthermore, no significant adverse effects were observed for this compound when evaluated in a systematic toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity) studies in zebrafish at various concentrations. Collectively, being a new, potent, moderately selective and safe inhibitor of PDE4B the isocoumarin 5f can be progressed into further pharmacological studies.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:121 |
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| Enthalten in: |
Bioorganic chemistry - 121(2022) vom: 30. Apr., Seite 105667 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Thirupataiah, B [VerfasserIn] |
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| Links: |
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| Themen: |
AIA rats |
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| Anmerkungen: |
Date Completed 19.04.2022 Date Revised 19.04.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bioorg.2022.105667 |
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| funding: |
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| 245 | 1 | 0 | |a Fe(III)-catalyzed regioselective and faster synthesis of isocoumarins with 3-oxoalkyl moiety at C-4 |b Identification of new inhibitors of PDE4 |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 Elsevier Inc. All rights reserved. | ||
| 520 | |a In search of potent and new anti-inflammatory agents, we explored a new class of isocoumarin derivatives possessing the 3-oxoalkyl moiety at C-4 position. These compounds were synthesized via the FeCl3 catalyzed construction of isocoumarin ring. The methodology involved coupling of 2-alkynyl benzamides with alkyl vinyl ketone and proceeded via a regioselective cyclization to give the desired compound as a result of formation of CO and CC bonds. A large number of isocoumarins were synthesized and assessed against PDE4B in vitro. While isocoumarins containing an aminosulfonyl moiety attached to the C-3 aryl ring showed encouraging inhibition of PDE4B, some of the derivatives devoid of aminosulfonyl moiety also showed considerable inhibition. According to the SAR analysis the C6H4NHSO2R2-m moiety at C-3 position of the isocoumarin ring was favorable when the R2 was chosen as an aryl or 2-thienyl group whereas the presence of F or OMe substituent at C-7 of the isocoumarin ring was found to be beneficial. The compound 5f with IC50 values 0.125 ± 0.032 and 0.43 ± 0.013 µM against PDE4B and 4D, respectively was identified as an initial hit. It showed in silico interaction with the PHE678 residue in the CR3 region of PDE4B and relatively less number of interactions with PDE4D. Besides showing the PDE4 selectivity over other PDEs and TNF-α inhibition in vitro the compound 5f at an intraperitoneal dose of 30 mg/kg demonstrated the protective effects against the development of arthritis and potent immunomodulatory activity in adjuvant induced arthritic (AIA) rats. Furthermore, no significant adverse effects were observed for this compound when evaluated in a systematic toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity) studies in zebrafish at various concentrations. Collectively, being a new, potent, moderately selective and safe inhibitor of PDE4B the isocoumarin 5f can be progressed into further pharmacological studies | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a AIA rats | |
| 650 | 4 | |a Fe-catalyst | |
| 650 | 4 | |a Inflammation | |
| 650 | 4 | |a Isocoumarin | |
| 650 | 4 | |a PDE-4 | |
| 650 | 7 | |a Ferric Compounds |2 NLM | |
| 650 | 7 | |a Isocoumarins |2 NLM | |
| 650 | 7 | |a Cyclic Nucleotide Phosphodiesterases, Type 4 |2 NLM | |
| 650 | 7 | |a EC 3.1.4.17 |2 NLM | |
| 700 | 1 | |a Bhuktar, Harshavardhan |e verfasserin |4 aut | |
| 700 | 1 | |a Mounika, Guntipally |e verfasserin |4 aut | |
| 700 | 1 | |a Reddy, Gangireddy Sujeevan |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Jetta Sandeep |e verfasserin |4 aut | |
| 700 | 1 | |a Shukla, Sharda |e verfasserin |4 aut | |
| 700 | 1 | |a Hossain, Kazi Amirul |e verfasserin |4 aut | |
| 700 | 1 | |a Medishetti, Raghavender |e verfasserin |4 aut | |
| 700 | 1 | |a Samarpita, Snigdha |e verfasserin |4 aut | |
| 700 | 1 | |a Rasool, Mahaboobkhan |e verfasserin |4 aut | |
| 700 | 1 | |a Jagadish, P C |e verfasserin |4 aut | |
| 700 | 1 | |a Shenoy, Gautham G |e verfasserin |4 aut | |
| 700 | 1 | |a Parsa, Kishore V L |e verfasserin |4 aut | |
| 700 | 1 | |a Pal, Manojit |e verfasserin |4 aut | |
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