Synthesis, Biological Evaluation, and Molecular Docking Studies of Novel Coumarin–Triazole–Isatin Hybrids as Selective Butyrylcholinesterase Inhibitors
A series of 21 novel coumarin–triazole–isatin hybrids was synthesized and evaluated for their potential as multitarget agents in Alzheimer’s disease (AD). The compounds featured variations in alkyl linker length that connects coumarin and triazole and substitution at the 5-position of the isatin rin...
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MDPI AG
2025-05-01
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| Online Access: | https://www.mdpi.com/1420-3049/30/10/2121 |
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| author | Aleksandar Dimkovski Vladimir Dobričić Milena R. Simić Maja Jurhar Pavlova Evgenija Mihajloska Zoran Sterjev Ana Poceva Panovska |
| author_facet | Aleksandar Dimkovski Vladimir Dobričić Milena R. Simić Maja Jurhar Pavlova Evgenija Mihajloska Zoran Sterjev Ana Poceva Panovska |
| author_sort | Aleksandar Dimkovski |
| collection | DOAJ |
| description | A series of 21 novel coumarin–triazole–isatin hybrids was synthesized and evaluated for their potential as multitarget agents in Alzheimer’s disease (AD). The compounds featured variations in alkyl linker length that connects coumarin and triazole and substitution at the 5-position of the isatin ring. Several derivatives showed potent butyrylcholinesterase (BChE) inhibition with selectivity over acetylcholinesterase (AChE). The lead compound, <b>6c1</b>, exhibited strong BChE inhibition (IC<sub>50</sub> = 1.74 μM), surpassing donepezil. Enzyme kinetics revealed a mixed-type mechanism, while molecular docking studies confirmed dual binding at catalytic and peripheral sites. Structure–activity relationship (SAR) analysis highlighted the influence of linker flexibility and steric/electronic effects of substituents. The observed BChE selectivity, combined with favorable in vitro profiles, identifies these hybrids as promising leads for AD drug development. |
| format | Article |
| id | doaj-art-631186ff1dfa4b9582729377d3d22e0a |
| institution | DOAJ |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj-art-631186ff1dfa4b9582729377d3d22e0a2025-08-20T03:14:42ZengMDPI AGMolecules1420-30492025-05-013010212110.3390/molecules30102121Synthesis, Biological Evaluation, and Molecular Docking Studies of Novel Coumarin–Triazole–Isatin Hybrids as Selective Butyrylcholinesterase InhibitorsAleksandar Dimkovski0Vladimir Dobričić1Milena R. Simić2Maja Jurhar Pavlova3Evgenija Mihajloska4Zoran Sterjev5Ana Poceva Panovska6Institute for Pharmaceutical Chemistry, Faculty of Pharmacy, Ss Cyril and Methodius University in Skopje, 1000 Skopje, North MacedoniaDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, SerbiaDepartment of Organic Chemistry, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, SerbiaInstitute for Microbiology and Parasitology, Faculty of Medicine, Ss Cyril and Methodius University in Skopje, 1000 Skopje, North MacedoniaInstitute for Pharmaceutical Chemistry, Faculty of Pharmacy, Ss Cyril and Methodius University in Skopje, 1000 Skopje, North MacedoniaInstitute for Pharmaceutical Chemistry, Faculty of Pharmacy, Ss Cyril and Methodius University in Skopje, 1000 Skopje, North MacedoniaInstitute for Applied Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy, Ss Cyril and Methodius University in Skopje, 1000 Skopje, North MacedoniaA series of 21 novel coumarin–triazole–isatin hybrids was synthesized and evaluated for their potential as multitarget agents in Alzheimer’s disease (AD). The compounds featured variations in alkyl linker length that connects coumarin and triazole and substitution at the 5-position of the isatin ring. Several derivatives showed potent butyrylcholinesterase (BChE) inhibition with selectivity over acetylcholinesterase (AChE). The lead compound, <b>6c1</b>, exhibited strong BChE inhibition (IC<sub>50</sub> = 1.74 μM), surpassing donepezil. Enzyme kinetics revealed a mixed-type mechanism, while molecular docking studies confirmed dual binding at catalytic and peripheral sites. Structure–activity relationship (SAR) analysis highlighted the influence of linker flexibility and steric/electronic effects of substituents. The observed BChE selectivity, combined with favorable in vitro profiles, identifies these hybrids as promising leads for AD drug development.https://www.mdpi.com/1420-3049/30/10/2121coumarin–trazole–isatin derivativesAlzheimer’s diseasecholinesterasehybrid moleculesmolecular docking |
| spellingShingle | Aleksandar Dimkovski Vladimir Dobričić Milena R. Simić Maja Jurhar Pavlova Evgenija Mihajloska Zoran Sterjev Ana Poceva Panovska Synthesis, Biological Evaluation, and Molecular Docking Studies of Novel Coumarin–Triazole–Isatin Hybrids as Selective Butyrylcholinesterase Inhibitors Molecules coumarin–trazole–isatin derivatives Alzheimer’s disease cholinesterase hybrid molecules molecular docking |
| title | Synthesis, Biological Evaluation, and Molecular Docking Studies of Novel Coumarin–Triazole–Isatin Hybrids as Selective Butyrylcholinesterase Inhibitors |
| title_full | Synthesis, Biological Evaluation, and Molecular Docking Studies of Novel Coumarin–Triazole–Isatin Hybrids as Selective Butyrylcholinesterase Inhibitors |
| title_fullStr | Synthesis, Biological Evaluation, and Molecular Docking Studies of Novel Coumarin–Triazole–Isatin Hybrids as Selective Butyrylcholinesterase Inhibitors |
| title_full_unstemmed | Synthesis, Biological Evaluation, and Molecular Docking Studies of Novel Coumarin–Triazole–Isatin Hybrids as Selective Butyrylcholinesterase Inhibitors |
| title_short | Synthesis, Biological Evaluation, and Molecular Docking Studies of Novel Coumarin–Triazole–Isatin Hybrids as Selective Butyrylcholinesterase Inhibitors |
| title_sort | synthesis biological evaluation and molecular docking studies of novel coumarin triazole isatin hybrids as selective butyrylcholinesterase inhibitors |
| topic | coumarin–trazole–isatin derivatives Alzheimer’s disease cholinesterase hybrid molecules molecular docking |
| url | https://www.mdpi.com/1420-3049/30/10/2121 |
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