Synthesis of Thieno[3,2-d]pyrimidine Derivatives through Sequential SNAr and Suzuki Reactions as Selective h-NTPDase Inhibitors

Abstract

In this study various of thieno[3,2-d]pyrimidine derivatives have been synthesized by treating different secondary amines through aromatic nucleophilic substitution reaction (SNAr) followed by Suzuki reaction with aryl and heteroaryl boronic acids. A bis-Suzuki coupling was also performed to generate bis-aryl thienopyrimidine derivatives. The synthesized compounds were screened for the hydrolytic activity of h-NTPdase1, h-NTPdase2, h-NTPdase3, and h-NTPdase8. The compound N-benzyl-N-methyl-7-phenylthieno[3,2-d]pyrimidin-4-amine 3 j selectively inhibits the activity of h-NTPdase1 with IC50 value of 0.62±0.02 μM whereas, the compound 4 d was the most potent inhibitor of h-NTPdase2 with sub-micromolar IC50 value of 0.33±0.09 μM. Similarly, compounds 4 c and 3 b were found to be selective inhibitors for isozymes h-NTPdase3 (IC50=0.13±0.06 μM) and h-NTPdase8 (IC50=0.32±0.10 μM), respectively. The molecular docking study of the compounds with the highest potency and selectivity revealed the interactions with the important amino acid residues.