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

The thienopyrimidine scaffold has shown promising selective inhibition of four isoforms of ectonucleoside triphosphate diphosphohydrolases (NTPDases). Modifications to the core thienopyrimidine were accomplished by S_NAr and Suzuki coupling. These modifications correspond to selective inhibition of h-NTPDase1, h-NTPDase2, h-NTPDase3, and h-NTPDase8. The in vitro results against enzymes were supported by molecular docking studies.

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 (S_NAr) 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.

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