Synthesis of Thieno[3,2‐d]pyrimidine Derivatives through Sequential S_NAr 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.

Synthesis and biological evaluation of sulfamoyl benzamide derivatives as selective inhibitors for h-NTPDases

“…The binding site of the protein h -NTPDase8 is comprised of the important amino acid residues such as Phe57, Tyr59, Tyr178, Gly179, Gly435, Ile438, Val436, Thr441, and Leu442 comprising. 26,29 The oxygen and hydrogen atoms of the carboxylic group were involved in the H-bond formation with the residues Trp440, Thr441, and Leu442, moreover, the hydrogen atom attached with the nitrogen atom of the sulfamoyl group was also connected via H-bond interaction with the amino acid Ile438. A π–π stacked connection was found between the aromatic ring and the Phe57, a π-alkyl interaction was observed among the chlorine atom of the chlorophenyl ring and the Tyr59, and an alkyl bridge was located between the chlorine atom and the residue Val436.…”

“…Considering our interest in finding new inhibitors for h -NTPDases, 26,27 and owing to the diverse biological profile of sulfamoyl-carboxamide, synthesis of planned derivatives of sulfamoyl-benzamides was carried out to identify their potential against the activity of the h -NTPDase-1, -2, -3, and -8 to develop more effective inhibitors of h -NTPDases for the potential treatment of the pathological conditions associated with the unwanted function of the h -NTPDases.…”