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_A Receptor Subtype

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 this evidence 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 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 GABAAR 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 (12c–f, 22a,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 12c, 22b, in the agonist class towards α1β2γ2-GABAAR.

Keywords

• 4,5-dihydro-5-oxo-pyrazolo[1,5-a]thieno[2,3-c]pyrimidines
• novel scaffold
• thiophene
• molecular dynamic studies
• proximity frequencies (PF)
• GABA_A receptor subtype