Identification of thienopyrimidine glycinates as selective inhibitors for h-NTPDases

• Published in: Bioorganic chemistry 2022-12, Vol.129, p.106196-106196, Article 106196
• Main Authors: Begum, Zahra, Ullah, Saif, Akram, Muhammad, Uzair, Muhammad, Ullah, Farman, Ahsanullah, Pelletier, Julie, Sévigny, Jean, Iqbal, Jamshed, Hassan, Abbas
• Format: Article
• Language: English
• Subjects: Human nucleoside triphosphate diphosphohydrolases (h-NTPDases); Molecular docking studies; Structure-activity relationship; Suzuki coupling; Thienopyrimidine
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2022.106196

[Display omitted] •Several physiological conditions are associated with abnormal activity of the NTPDases.•7-Arylthieno[3,2-d]pyrimidine N-glycinates were designed as NTPDases inhibitors.•The compound 4a selectively inhibits the activity of h-NTPDase2 with IC50 = 0.13 ± 0.05 µM.•Compound 3k (IC50 = 2.88 ± 0.13 µM) selective inhibitor against h-NTPDase3.•Compound 3d (IC50 = 0.64 ± 0.52 µM) was found most active against h-NTPDase8. The h-NTPDases is an essential family of ectonucleotidases that consists of eight isozymes with various physiological functions. The undesired activity of the h-NTPDases leads to pathological conditions such as cancer, diabetes, inflammation, and thrombosis. In the present study, a series of thienopyrimidines was synthesized employing a sequential SNAr and Suzuki coupling to synthesize diverse aryl substituted thienopyrimidine glycinate derivatives. The synthesized compounds constituted electron donating, electron-deficient, heteroaryl, and fluorinated substituents. The thienopyrimidines were screened against h-NTPDases to determine the effect on the activity of the h-NTPDases-1, -2, -3, and -8. The compound 3j selectively blocked the isozyme h-NTPDases1, while the compounds 3e, 3m, and 4a were selective inhibitors of h-NTPDases2. The activity of the isozyme h-NTPDases3 was selectively reduced by inhibitor 3k whereas, the compound 3d was found as the most active inhibitor against isozyme h-NTPDase8. The molecular docking study interpreted the interactions of the potent inhibitors of the respective isozymes with important amino acid residues i.e., Asp54, Ser57, His59, Ser58, His59, Asp213, and Phe360 of h-NTPDases1 protein; residues Arg 392, Ala393, Ala347, Tye350 and Arg245 of h-NTPDases2; amino acids Arg67, Ser65, Ala323, Gly222, and Tyr375 of h-NTPDases3 whereas in case of h-NTPDases8, the residues Val436, Gln74, Gly179, and Val71 were involved in interaction with the inhibitors docked into the active sites of these isozymes.