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Benzo[4,5]thieno[2,3‐ d ]pyrimidine phthalimide derivative, one of the rare noncompetitive inhibitors of dipeptidyl peptidase‐4
Archiv der Pharmazie ( IF 4.3 ) Pub Date : 2019-11-11 , DOI: 10.1002/ardp.201900238 Katarina Tomovic 1 , Budimir S Ilic 2 , Marija Miljkovic 3 , Stefan Dimov 4 , Denitsa Yancheva 5 , Milan Kojic 3 , Anelia T Mavrova 4 , Gordana Kocic 6 , Andrija Smelcerovic 2
Archiv der Pharmazie ( IF 4.3 ) Pub Date : 2019-11-11 , DOI: 10.1002/ardp.201900238 Katarina Tomovic 1 , Budimir S Ilic 2 , Marija Miljkovic 3 , Stefan Dimov 4 , Denitsa Yancheva 5 , Milan Kojic 3 , Anelia T Mavrova 4 , Gordana Kocic 6 , Andrija Smelcerovic 2
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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 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.
中文翻译：
苯并[4,5]噻吩并[2,3-d]嘧啶邻苯二甲酰亚胺衍生物，二肽基肽酶-4的罕见非竞争性抑制剂之一
评估了苯并[4,5]噻吩并[2,3-d]嘧啶邻苯二甲酰亚胺和胺衍生物的小型文库对二肽基肽酶-4（DPP-4）的抑制活性。邻苯二甲酰亚胺衍生物表现出比胺前体更好的活性，2-(2-(3-氯苄基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶-4-基)isoindoline-1,3-dione (化合物 14) 作为最有效的抑制剂 (IC50 = 34.17 ± 5.11 μM)。五种最有效的选定抑制剂对 Caco-2 细胞没有更大程度的细胞毒性，即使浓度为 250 μM。化合物 14 被认为是罕见的非竞争性 DPP-4 抑制剂的新代表。分子对接和动力学模拟表明 DPP-4 的 Tyr547、Lys554 和 Trp629 残基在酶-抑制剂复合物形成中的重要性。
更新日期：2019-11-11
中文翻译：
苯并[4,5]噻吩并[2,3-d]嘧啶邻苯二甲酰亚胺衍生物，二肽基肽酶-4的罕见非竞争性抑制剂之一
评估了苯并[4,5]噻吩并[2,3-d]嘧啶邻苯二甲酰亚胺和胺衍生物的小型文库对二肽基肽酶-4（DPP-4）的抑制活性。邻苯二甲酰亚胺衍生物表现出比胺前体更好的活性，2-(2-(3-氯苄基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶-4-基)isoindoline-1,3-dione (化合物 14) 作为最有效的抑制剂 (IC50 = 34.17 ± 5.11 μM)。五种最有效的选定抑制剂对 Caco-2 细胞没有更大程度的细胞毒性，即使浓度为 250 μM。化合物 14 被认为是罕见的非竞争性 DPP-4 抑制剂的新代表。分子对接和动力学模拟表明 DPP-4 的 Tyr547、Lys554 和 Trp629 残基在酶-抑制剂复合物形成中的重要性。
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