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

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.

Anti-Inflammatory Activity of Pyrazolo[1,5-a]quinazolines

“…We report here the procedures for the synthesis of 65 new compounds that were included in the screening library. For the 15 compounds in screening library that were already published, we provide the appropriate reference (chemical structures of all compounds and relevant references are presented in Supplementary Tables S1–S3 ) [ 29 , 30 , 31 , 32 ]. As mentioned above, most of the compounds selected for this study are tricycles with a pyrazolo[1,5- a ]quinazoline scaffold (abbreviated below as PQ), and their synthesis is outlined in Scheme 1 , Scheme 2 , Scheme 3 , Scheme 4 , Scheme 5 , Scheme 6 , Scheme 7 , Scheme 8 and Scheme 9 .…”