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Benzo[4,5]thieno[2,3‐ d ]pyrimidine phthalimide derivative, one of the rare noncompetitive inhibitors of dipeptidyl peptidase‐4
Author(s) -
Tomovic Katarina,
Ilic Budimir S.,
Miljkovic Marija,
Dimov Stefan,
Yancheva Denitsa,
Kojic Milan,
Mavrova Anelia T.,
Kocic Gordana,
Smelcerovic Andrija
Publication year - 2020
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201900238
Subject(s) - phthalimide , chemistry , stereochemistry , pyrimidine , non competitive inhibition , moiety , isoindoline , docking (animal) , enzyme , ic50 , dipeptidyl peptidase , amine gas treating , active site , combinatorial chemistry , biochemistry , medicinal chemistry , organic chemistry , in vitro , medicine , nursing
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 (IC 50 = 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.