Benzo[4,5]thieno[2,3‐d]pyrimidine phthalimide derivative, one of the rare noncompetitive inhibitors of dipeptidyl peptidase‐4

• Published in: Archiv der Pharmazie (Weinheim) 2020-01, Vol.353 (1), p.e1900238-n/a
• Main Authors: Tomovic, Katarina, Ilic, Budimir S., Miljkovic, Marija, Dimov, Stefan, Yancheva, Denitsa, Kojic, Milan, Mavrova, Anelia T., Kocic, Gordana, Smelcerovic, Andrija
• Format: Article
• Language: English
• Subjects: dipeptidyl peptidase‐4; molecular dynamics; noncompetitive DPP‐4 inhibition; phthalimide
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.201900238

A small library of benzo[4,5]thieno[2,3‐d]pyrimidine phthalimide and amine derivatives was evaluated for inhibitory activity against dipeptidyl peptidase‐4 (DPP‐4). The phthalimide derivatives exhibited better activity than the amine precursors, with 2‐(2‐(3‐chlorobenzyl)‐5,6,7,8‐tetrahydrobenzo[4,5]thieno[2,3‐d]pyrimidin‐4‐yl)isoindoline‐1,3‐dione (compound 14) as the most effective inhibitor (IC50 = 34.17 ± 5.11 μM). The five most potent selected inhibitors did not show cytotoxicity to a greater extent on Caco‐2 cells, even at a concentration of 250 μM. Compound 14 is considered as a novel representative of the rare noncompetitive DPP‐4 inhibitors. Molecular docking and dynamics simulation indicated the importance of the Tyr547, Lys554, and Trp629 residues of DPP‐4 in the formation of the enzyme–inhibitor complex. These observations could be potentially utilized for the rational design and optimization of novel (structurally similar, with phthalimide moiety, or different) noncompetitive DPP‐4 inhibitors, which are anyway rare, but favorable in terms of the saturation of substrate competition. 2‐(2‐(3‐Chlorobenzyl)‐5,6,7,8‐tetrahydrobenzo[4,5]thieno[2,3‐d]pyrimidin‐4‐yl)isoindoline‐1,3‐dione is one of the rare noncompetitive dipeptidyl peptidase‐4 (DPP‐4) inhibitors, with the phthalimide and phenyl moieties being important for the interaction with the DPP‐4 residues Tyr547, Lys554, and Trp629, without interactions with exosite substrate‐binding residues. It could be utilized for the rational design of novel noncompetitive DPP‐4 inhibitors.