Classical Paal-Knorr Cyclization for Synthesis of Pyrrole-Based Aryl Hydrazones and In Vitro/In Vivo Evaluation on Pharmacological Models of Parkinson’s Disease
Some studies performed in our laboratory on pyrrole and its derivatives pointed towards the enrichment of the evaluations of these promising chemical structures for the potential treatment of neurodegenerative conditions in general and Parkinson’s disease in particular. A classical Paal-Knorr cycliz...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-07-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/30/15/3154 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849405462678601728 |
|---|---|
| author | Maya Georgieva Martin Sharkov Emilio Mateev Diana Tzankova Georgi Popov Vasil Manov Alexander Zlatkov Rumyana Simeonova Magdalena Kondeva-Burdina |
| author_facet | Maya Georgieva Martin Sharkov Emilio Mateev Diana Tzankova Georgi Popov Vasil Manov Alexander Zlatkov Rumyana Simeonova Magdalena Kondeva-Burdina |
| author_sort | Maya Georgieva |
| collection | DOAJ |
| description | Some studies performed in our laboratory on pyrrole and its derivatives pointed towards the enrichment of the evaluations of these promising chemical structures for the potential treatment of neurodegenerative conditions in general and Parkinson’s disease in particular. A classical Paal-Knorr cyclization approach is applied to synthesize the basic hydrazine used for the formation of the designed series of hydrazones (<b>15a</b>–<b>15g</b>). The potential neurotoxic and neuroprotective effects of the newly synthesized derivatives were investigated in vitro using different models of induced oxidative stress at three subcellular levels (rat brain synaptosomes, mitochondria, and microsomes). The results identified as the least neurotoxic molecules, <b>15a</b>, <b>15d</b>, and <b>15f</b> applied at a concentration of 100 µM to the isolated fractions. In addition, the highest statistically significant neuroprotection was observed for <b>15a</b> and <b>15d</b> at a concentration of 100 µM using three different injury models on subcellular fractions, including 6-hydroxydopamine in rat brain synaptosomes, tert-butyl hydroperoxide in brain mitochondria, and non-enzyme-induced lipid peroxidation in brain microsomes. The <i>h</i>MAOA/MAOB inhibitory activity of the new compounds was studied at a concentration of 1 µM. The lack of a statistically significant <i>h</i>MAOA inhibitory effect was observed for all tested compounds, except for <b>15f</b>, which showed 40% inhibitory activity. The most prominent statistically significant <i>h</i>MAOB inhibitory effect was determined for <b>15a</b>, <b>15d</b>, and <b>15f</b>, comparable to that of selegiline. The corresponding selectivity index defined <b>15f</b> as a non-selective MAO inhibitor and all other new hydrazones as selective <i>h</i>MAOB inhibitors, with <b>15d</b> indicating the highest selectivity index of >471. The most active and least toxic representative (<b>15d</b>) was evaluated in vivo on Rotenone based model of Parkinson’s disease. The results revealed no microscopically visible alterations in the ganglion and glial cells in the animals treated with rotenone in combination with <b>15d</b>. |
| format | Article |
| id | doaj-art-3f40e1d7eaa04308b8836cab5adeb661 |
| institution | Kabale University |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj-art-3f40e1d7eaa04308b8836cab5adeb6612025-08-20T03:36:41ZengMDPI AGMolecules1420-30492025-07-013015315410.3390/molecules30153154Classical Paal-Knorr Cyclization for Synthesis of Pyrrole-Based Aryl Hydrazones and In Vitro/In Vivo Evaluation on Pharmacological Models of Parkinson’s DiseaseMaya Georgieva0Martin Sharkov1Emilio Mateev2Diana Tzankova3Georgi Popov4Vasil Manov5Alexander Zlatkov6Rumyana Simeonova7Magdalena Kondeva-Burdina8Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University Sofia, 1000 Sofia, BulgariaDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University Sofia, 1000 Sofia, BulgariaDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University Sofia, 1000 Sofia, BulgariaDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University Sofia, 1000 Sofia, BulgariaDepartment of Internal Non-Communicable Diseases, Pathology and Pharmacology, Faculty of Veterinary Medicine, University of Forestry, 10 St. Kliment Ohridski Blvd., 1797 Sofia, BulgariaDepartment of Internal Non-Communicable Diseases, Pathology and Pharmacology, Faculty of Veterinary Medicine, University of Forestry, 10 St. Kliment Ohridski Blvd., 1797 Sofia, BulgariaDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University Sofia, 1000 Sofia, BulgariaDepartment of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University Sofia, 1000 Sofia, BulgariaDepartment of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University Sofia, 1000 Sofia, BulgariaSome studies performed in our laboratory on pyrrole and its derivatives pointed towards the enrichment of the evaluations of these promising chemical structures for the potential treatment of neurodegenerative conditions in general and Parkinson’s disease in particular. A classical Paal-Knorr cyclization approach is applied to synthesize the basic hydrazine used for the formation of the designed series of hydrazones (<b>15a</b>–<b>15g</b>). The potential neurotoxic and neuroprotective effects of the newly synthesized derivatives were investigated in vitro using different models of induced oxidative stress at three subcellular levels (rat brain synaptosomes, mitochondria, and microsomes). The results identified as the least neurotoxic molecules, <b>15a</b>, <b>15d</b>, and <b>15f</b> applied at a concentration of 100 µM to the isolated fractions. In addition, the highest statistically significant neuroprotection was observed for <b>15a</b> and <b>15d</b> at a concentration of 100 µM using three different injury models on subcellular fractions, including 6-hydroxydopamine in rat brain synaptosomes, tert-butyl hydroperoxide in brain mitochondria, and non-enzyme-induced lipid peroxidation in brain microsomes. The <i>h</i>MAOA/MAOB inhibitory activity of the new compounds was studied at a concentration of 1 µM. The lack of a statistically significant <i>h</i>MAOA inhibitory effect was observed for all tested compounds, except for <b>15f</b>, which showed 40% inhibitory activity. The most prominent statistically significant <i>h</i>MAOB inhibitory effect was determined for <b>15a</b>, <b>15d</b>, and <b>15f</b>, comparable to that of selegiline. The corresponding selectivity index defined <b>15f</b> as a non-selective MAO inhibitor and all other new hydrazones as selective <i>h</i>MAOB inhibitors, with <b>15d</b> indicating the highest selectivity index of >471. The most active and least toxic representative (<b>15d</b>) was evaluated in vivo on Rotenone based model of Parkinson’s disease. The results revealed no microscopically visible alterations in the ganglion and glial cells in the animals treated with rotenone in combination with <b>15d</b>.https://www.mdpi.com/1420-3049/30/15/3154synthesispyrrolehydrazonein vivoParkinson’s |
| spellingShingle | Maya Georgieva Martin Sharkov Emilio Mateev Diana Tzankova Georgi Popov Vasil Manov Alexander Zlatkov Rumyana Simeonova Magdalena Kondeva-Burdina Classical Paal-Knorr Cyclization for Synthesis of Pyrrole-Based Aryl Hydrazones and In Vitro/In Vivo Evaluation on Pharmacological Models of Parkinson’s Disease Molecules synthesis pyrrole hydrazone in vivo Parkinson’s |
| title | Classical Paal-Knorr Cyclization for Synthesis of Pyrrole-Based Aryl Hydrazones and In Vitro/In Vivo Evaluation on Pharmacological Models of Parkinson’s Disease |
| title_full | Classical Paal-Knorr Cyclization for Synthesis of Pyrrole-Based Aryl Hydrazones and In Vitro/In Vivo Evaluation on Pharmacological Models of Parkinson’s Disease |
| title_fullStr | Classical Paal-Knorr Cyclization for Synthesis of Pyrrole-Based Aryl Hydrazones and In Vitro/In Vivo Evaluation on Pharmacological Models of Parkinson’s Disease |
| title_full_unstemmed | Classical Paal-Knorr Cyclization for Synthesis of Pyrrole-Based Aryl Hydrazones and In Vitro/In Vivo Evaluation on Pharmacological Models of Parkinson’s Disease |
| title_short | Classical Paal-Knorr Cyclization for Synthesis of Pyrrole-Based Aryl Hydrazones and In Vitro/In Vivo Evaluation on Pharmacological Models of Parkinson’s Disease |
| title_sort | classical paal knorr cyclization for synthesis of pyrrole based aryl hydrazones and in vitro in vivo evaluation on pharmacological models of parkinson s disease |
| topic | synthesis pyrrole hydrazone in vivo Parkinson’s |
| url | https://www.mdpi.com/1420-3049/30/15/3154 |
| work_keys_str_mv | AT mayageorgieva classicalpaalknorrcyclizationforsynthesisofpyrrolebasedarylhydrazonesandinvitroinvivoevaluationonpharmacologicalmodelsofparkinsonsdisease AT martinsharkov classicalpaalknorrcyclizationforsynthesisofpyrrolebasedarylhydrazonesandinvitroinvivoevaluationonpharmacologicalmodelsofparkinsonsdisease AT emiliomateev classicalpaalknorrcyclizationforsynthesisofpyrrolebasedarylhydrazonesandinvitroinvivoevaluationonpharmacologicalmodelsofparkinsonsdisease AT dianatzankova classicalpaalknorrcyclizationforsynthesisofpyrrolebasedarylhydrazonesandinvitroinvivoevaluationonpharmacologicalmodelsofparkinsonsdisease AT georgipopov classicalpaalknorrcyclizationforsynthesisofpyrrolebasedarylhydrazonesandinvitroinvivoevaluationonpharmacologicalmodelsofparkinsonsdisease AT vasilmanov classicalpaalknorrcyclizationforsynthesisofpyrrolebasedarylhydrazonesandinvitroinvivoevaluationonpharmacologicalmodelsofparkinsonsdisease AT alexanderzlatkov classicalpaalknorrcyclizationforsynthesisofpyrrolebasedarylhydrazonesandinvitroinvivoevaluationonpharmacologicalmodelsofparkinsonsdisease AT rumyanasimeonova classicalpaalknorrcyclizationforsynthesisofpyrrolebasedarylhydrazonesandinvitroinvivoevaluationonpharmacologicalmodelsofparkinsonsdisease AT magdalenakondevaburdina classicalpaalknorrcyclizationforsynthesisofpyrrolebasedarylhydrazonesandinvitroinvivoevaluationonpharmacologicalmodelsofparkinsonsdisease |