4,5-Dihydro-5-Oxo-Pyrazolo[1,5-a]Thieno[2,3-c]Pyrimidine: A Novel Scaffold Containing Thiophene Ring. Chemical Reactivity and In Silico Studies to Predict the Profile to GABA<sub>A</sub> Receptor Subtype
The isosteric replacement of the benzene with thiophene ring is a chemical modification widely applied in medicinal chemistry. Several drugs containing the thiophene ring are marketed for treating various pathologies (osteoporosis, peripheral artery disorder, psychosis, anxiety and convulsion). Taki...
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| Format: | Article |
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MDPI AG
2023-03-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/7/3054 |
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| author | Letizia Crocetti Gabriella Guerrini Fabrizio Melani Claudia Vergelli Maria Paola Giovannoni |
| author_facet | Letizia Crocetti Gabriella Guerrini Fabrizio Melani Claudia Vergelli Maria Paola Giovannoni |
| author_sort | Letizia Crocetti |
| collection | DOAJ |
| description | The isosteric replacement of the benzene with thiophene ring is a chemical modification widely applied in medicinal chemistry. Several drugs containing the thiophene ring are marketed for treating various pathologies (osteoporosis, peripheral artery disorder, psychosis, anxiety and convulsion). Taking into account this evidence and as a continuation of our study in the GABA<sub>A</sub> receptor modulators field, we designed and synthesized new compounds containing the thiophene ring with 4,5-dihydro-5-oxo-pyrazolo[1,5-a]thieno[2,3-c]pyrimidine and pyrazolo[1,5-a]thieno[2,3-c] pyrimidine scaffold. Moreover, these cores, never reported in the literature, are isosteres of pyrazolo[1,5-a]quinazolines (PQ), previously published by us as GABA<sub>A</sub>R subtype ligands. We introduced in the new scaffold those functions and groups (esters, ketones, alpha/beta-thiophene) that in our PQ derivatives were responsible for the activity, and at the same time, we have extensively investigated the reactivity of the new nucleus regarding the alkylation, reduction, halogenation and hydrolyses. On the six final designed compounds (<b>12c</b>–<b>f</b>, <b>22a,b</b>) molecular docking and dynamic simulation studies have been performed. The analysis of dynamic simulation, applying our reported model ‘Proximity Frequencies’, collocates with high probability <b>12c</b>, <b>22b</b>, in the agonist class towards α1β2γ2-GABA<sub>A</sub>R. |
| first_indexed | 2024-03-11T05:29:22Z |
| format | Article |
| id | doaj.art-0e06483d87c64f6582d77899b45ca2dc |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T05:29:22Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-0e06483d87c64f6582d77899b45ca2dc2023-11-17T17:12:51ZengMDPI AGMolecules1420-30492023-03-01287305410.3390/molecules280730544,5-Dihydro-5-Oxo-Pyrazolo[1,5-a]Thieno[2,3-c]Pyrimidine: A Novel Scaffold Containing Thiophene Ring. Chemical Reactivity and In Silico Studies to Predict the Profile to GABA<sub>A</sub> Receptor SubtypeLetizia Crocetti0Gabriella Guerrini1Fabrizio Melani2Claudia Vergelli3Maria Paola Giovannoni4Neurofarba, Pharmaceutical and Nutraceutical Section, University of Florence, 50019 Sesto Fiorentino, ItalyNeurofarba, Pharmaceutical and Nutraceutical Section, University of Florence, 50019 Sesto Fiorentino, ItalyNeurofarba, Pharmaceutical and Nutraceutical Section, University of Florence, 50019 Sesto Fiorentino, ItalyNeurofarba, Pharmaceutical and Nutraceutical Section, University of Florence, 50019 Sesto Fiorentino, ItalyNeurofarba, Pharmaceutical and Nutraceutical Section, University of Florence, 50019 Sesto Fiorentino, ItalyThe isosteric replacement of the benzene with thiophene ring is a chemical modification widely applied in medicinal chemistry. Several drugs containing the thiophene ring are marketed for treating various pathologies (osteoporosis, peripheral artery disorder, psychosis, anxiety and convulsion). Taking into account this evidence and as a continuation of our study in the GABA<sub>A</sub> receptor modulators field, we designed and synthesized new compounds containing the thiophene ring with 4,5-dihydro-5-oxo-pyrazolo[1,5-a]thieno[2,3-c]pyrimidine and pyrazolo[1,5-a]thieno[2,3-c] pyrimidine scaffold. Moreover, these cores, never reported in the literature, are isosteres of pyrazolo[1,5-a]quinazolines (PQ), previously published by us as GABA<sub>A</sub>R subtype ligands. We introduced in the new scaffold those functions and groups (esters, ketones, alpha/beta-thiophene) that in our PQ derivatives were responsible for the activity, and at the same time, we have extensively investigated the reactivity of the new nucleus regarding the alkylation, reduction, halogenation and hydrolyses. On the six final designed compounds (<b>12c</b>–<b>f</b>, <b>22a,b</b>) molecular docking and dynamic simulation studies have been performed. The analysis of dynamic simulation, applying our reported model ‘Proximity Frequencies’, collocates with high probability <b>12c</b>, <b>22b</b>, in the agonist class towards α1β2γ2-GABA<sub>A</sub>R.https://www.mdpi.com/1420-3049/28/7/30544,5-dihydro-5-oxo-pyrazolo[1,5-a]thieno[2,3-c]pyrimidinesnovel scaffoldthiophenemolecular dynamic studiesproximity frequencies (PF)GABA<sub>A</sub> receptor subtype |
| spellingShingle | Letizia Crocetti Gabriella Guerrini Fabrizio Melani Claudia Vergelli Maria Paola Giovannoni 4,5-Dihydro-5-Oxo-Pyrazolo[1,5-a]Thieno[2,3-c]Pyrimidine: A Novel Scaffold Containing Thiophene Ring. Chemical Reactivity and In Silico Studies to Predict the Profile to GABA<sub>A</sub> Receptor Subtype Molecules 4,5-dihydro-5-oxo-pyrazolo[1,5-a]thieno[2,3-c]pyrimidines novel scaffold thiophene molecular dynamic studies proximity frequencies (PF) GABA<sub>A</sub> receptor subtype |
| title | 4,5-Dihydro-5-Oxo-Pyrazolo[1,5-a]Thieno[2,3-c]Pyrimidine: A Novel Scaffold Containing Thiophene Ring. Chemical Reactivity and In Silico Studies to Predict the Profile to GABA<sub>A</sub> Receptor Subtype |
| title_full | 4,5-Dihydro-5-Oxo-Pyrazolo[1,5-a]Thieno[2,3-c]Pyrimidine: A Novel Scaffold Containing Thiophene Ring. Chemical Reactivity and In Silico Studies to Predict the Profile to GABA<sub>A</sub> Receptor Subtype |
| title_fullStr | 4,5-Dihydro-5-Oxo-Pyrazolo[1,5-a]Thieno[2,3-c]Pyrimidine: A Novel Scaffold Containing Thiophene Ring. Chemical Reactivity and In Silico Studies to Predict the Profile to GABA<sub>A</sub> Receptor Subtype |
| title_full_unstemmed | 4,5-Dihydro-5-Oxo-Pyrazolo[1,5-a]Thieno[2,3-c]Pyrimidine: A Novel Scaffold Containing Thiophene Ring. Chemical Reactivity and In Silico Studies to Predict the Profile to GABA<sub>A</sub> Receptor Subtype |
| title_short | 4,5-Dihydro-5-Oxo-Pyrazolo[1,5-a]Thieno[2,3-c]Pyrimidine: A Novel Scaffold Containing Thiophene Ring. Chemical Reactivity and In Silico Studies to Predict the Profile to GABA<sub>A</sub> Receptor Subtype |
| title_sort | 4 5 dihydro 5 oxo pyrazolo 1 5 a thieno 2 3 c pyrimidine a novel scaffold containing thiophene ring chemical reactivity and in silico studies to predict the profile to gaba sub a sub receptor subtype |
| topic | 4,5-dihydro-5-oxo-pyrazolo[1,5-a]thieno[2,3-c]pyrimidines novel scaffold thiophene molecular dynamic studies proximity frequencies (PF) GABA<sub>A</sub> receptor subtype |
| url | https://www.mdpi.com/1420-3049/28/7/3054 |
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