: 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 these evidences and as a continuation of our study in the GABAA 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 pyrazo-lo[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 GABAAR sub-type ligands. We introduced in the new scaffold those functions and groups (esters, ketones, al-pha/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 alkyla-tion, reduction, halogenation and hydrolyses. On the six final designed compounds (12c-f, 22a, b) molecular docking and dynamic simulation studies have been performed. The analysis of dy-namic simulation, applying our reported model 'Proximity Frequencies', collocates with high probability 12c, 22b, in the agonist class towards α1β2γ2-GABAAR.

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 GABAA Receptor Subtype / Crocetti, Letizia; Guerrini, Gabriella; Melani, Fabrizio; Vergelli, Claudia; Giovannoni, Maria Paola. - In: MOLECULES. - ISSN 1420-3049. - ELETTRONICO. - 28:(2023), pp. 3054-3074. [10.3390/molecules28073054]

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 GABAA Receptor Subtype

Crocetti, Letizia;Guerrini, Gabriella
;
Melani, Fabrizio;Vergelli, Claudia;Giovannoni, Maria Paola
2023

Abstract

: 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 these evidences and as a continuation of our study in the GABAA 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 pyrazo-lo[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 GABAAR sub-type ligands. We introduced in the new scaffold those functions and groups (esters, ketones, al-pha/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 alkyla-tion, reduction, halogenation and hydrolyses. On the six final designed compounds (12c-f, 22a, b) molecular docking and dynamic simulation studies have been performed. The analysis of dy-namic simulation, applying our reported model 'Proximity Frequencies', collocates with high probability 12c, 22b, in the agonist class towards α1β2γ2-GABAAR.
2023
28
3054
3074
Goal 3: Good health and well-being
Crocetti, Letizia; Guerrini, Gabriella; Melani, Fabrizio; Vergelli, Claudia; Giovannoni, Maria Paola
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1303280
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