Benzo[4,5]thieno[2,3-d]pyrimidine phthalimide derivative, one of the rare noncompetitive inhibitors of dipeptidyl peptidase-4
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2019
Authors
Tomović, KatarinaIlić, Budimir S.
Miljković, Marija
Dimov, Stefan
Yancheva, Denitsa
Kojić, Milan
Mavrova, Anelia T.
Kocić, Gordana
Smelcerović, Andrija
Article (Published version)
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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 mu M). The five most potent selected inhibitors did not show cytotoxicity to a greater extent on Caco-2 cells, even at a concentration of 250 mu M. 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) nonco...mpetitive DPP-4 inhibitors, which are anyway rare, but favorable in terms of the saturation of substrate competition.
Keywords:
phthalimide / noncompetitive DPP-4 inhibition / molecular dynamics / dipeptidyl peptidase-4Source:
Archiv Der Pharmazie, 2019, 353, 1Publisher:
- Wiley-V C H Verlag Gmbh, Weinheim
Funding / projects:
- Faculty of Medicine of the University of Nis [4]
- The electrical breakdown of gases, surface processes and applications (RS-MESTD-Basic Research (BR or ON)-171025)
- Obtaining, physicochemical characterization, analysis and biological activity of pharmacologically active compounds (RS-MESTD-Basic Research (BR or ON)-172044)
- Genes and molecular mechanisms promoting probiotic activity of lactic acid bacteria from Western Balkan (RS-MESTD-Basic Research (BR or ON)-173019)
- Production of new dietetic milk products for risk populations based on qualitative and quantitative analysis of health risk markers in milk consumption (RS-MESTD-Technological Development (TD or TR)-31060)
DOI: 10.1002/ardp.201900238
ISSN: 0365-6233
PubMed: 31710123
WoS: 000495566900001
Scopus: 2-s2.0-85075069596
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Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Tomović, Katarina AU - Ilić, Budimir S. AU - Miljković, Marija AU - Dimov, Stefan AU - Yancheva, Denitsa AU - Kojić, Milan AU - Mavrova, Anelia T. AU - Kocić, Gordana AU - Smelcerović, Andrija PY - 2019 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/1396 AB - 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 mu M). The five most potent selected inhibitors did not show cytotoxicity to a greater extent on Caco-2 cells, even at a concentration of 250 mu M. 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. PB - Wiley-V C H Verlag Gmbh, Weinheim T2 - Archiv Der Pharmazie T1 - Benzo[4,5]thieno[2,3-d]pyrimidine phthalimide derivative, one of the rare noncompetitive inhibitors of dipeptidyl peptidase-4 IS - 1 VL - 353 DO - 10.1002/ardp.201900238 ER -
@article{ author = "Tomović, Katarina and Ilić, Budimir S. and Miljković, Marija and Dimov, Stefan and Yancheva, Denitsa and Kojić, Milan and Mavrova, Anelia T. and Kocić, Gordana and Smelcerović, Andrija", year = "2019", abstract = "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 mu M). The five most potent selected inhibitors did not show cytotoxicity to a greater extent on Caco-2 cells, even at a concentration of 250 mu M. 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.", publisher = "Wiley-V C H Verlag Gmbh, Weinheim", journal = "Archiv Der Pharmazie", title = "Benzo[4,5]thieno[2,3-d]pyrimidine phthalimide derivative, one of the rare noncompetitive inhibitors of dipeptidyl peptidase-4", number = "1", volume = "353", doi = "10.1002/ardp.201900238" }
Tomović, K., Ilić, B. S., Miljković, M., Dimov, S., Yancheva, D., Kojić, M., Mavrova, A. T., Kocić, G.,& Smelcerović, A.. (2019). Benzo[4,5]thieno[2,3-d]pyrimidine phthalimide derivative, one of the rare noncompetitive inhibitors of dipeptidyl peptidase-4. in Archiv Der Pharmazie Wiley-V C H Verlag Gmbh, Weinheim., 353(1). https://doi.org/10.1002/ardp.201900238
Tomović K, Ilić BS, Miljković M, Dimov S, Yancheva D, Kojić M, Mavrova AT, Kocić G, Smelcerović A. Benzo[4,5]thieno[2,3-d]pyrimidine phthalimide derivative, one of the rare noncompetitive inhibitors of dipeptidyl peptidase-4. in Archiv Der Pharmazie. 2019;353(1). doi:10.1002/ardp.201900238 .
Tomović, Katarina, Ilić, Budimir S., Miljković, Marija, Dimov, Stefan, Yancheva, Denitsa, Kojić, Milan, Mavrova, Anelia T., Kocić, Gordana, Smelcerović, Andrija, "Benzo[4,5]thieno[2,3-d]pyrimidine phthalimide derivative, one of the rare noncompetitive inhibitors of dipeptidyl peptidase-4" in Archiv Der Pharmazie, 353, no. 1 (2019), https://doi.org/10.1002/ardp.201900238 . .