Towards discovery of novel scaffold with potent antiangiogenic activity; design, synthesis of pyridazine based compounds, impact of hinge interaction, and accessibility of their bioactive conformation on VEGFR-2 activities.
Towards discovery of novel scaffold with potent antiangiogenic activity; design, synthesis of pyridazine based compounds, impact of hinge interaction, and accessibility of their bioactive conformation on VEGFR-2 activities.
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DOI：
10.1080/14756366.2019.1651723
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发表时间：
2019-12-01
影响因子：
5.6
通讯作者：
Abouzid, Khaled A M
中科院分区：
文献类型：
--
作者：
Jaballah, Maiy Y;Serya, Rabah A T;Abouzid, Khaled A M
哒嗪支架被认为是与其新奇、化学稳定性和合成可行性有关的特权结构。在我们对开发具有抗血管生成活性的有效抑制血管内皮生长2（VEGFR-2）的新型支架的探索中，设计并合成了四种新型系列的哒嗪。五种合成的化合物，即（8 c、8 f、15、18 b和18 c）表现出有效的VEGFR-2抑制效力（>80%）; IC 50值范围从低微摩尔至纳摩尔范围;即化合物8 c、8 f、15、18 c分别具有（1.8M、1.3M、1.4M、107 nM）。此外，3-[4-{（6-氧代-1，6-二氢哒嗪-3-基）氧基}苯基]脲衍生物（18 b）对VEGFR-2表现出纳摩尔效力（60.7 nM）。在细胞试验中，上述化合物在10 μ M浓度下对VEGF刺激的人脐静脉内皮细胞增殖表现出良好的抑制作用。最后，进行了广泛的分子模拟研究，以研究与VEGFR-2可能的相互作用。
Pyridazine scaffolds are considered privileged structures pertaining to its novelty, chemical stability, and synthetic feasibility. In our quest towards the development of novel scaffolds for effective vascular endothelial growth 2 (VEGFR-2) inhibition with antiangiogenic activity, four novel series of pyridazines were designed and synthesised. Five of the synthesised compounds; namely (8c, 8f, 15, 18b, and 18c) exhibited potent VEGFR-2 inhibitory potency (>80%); with IC50 values ranging from low micromolar to nanomolar range; namely compounds 8c, 8f, 15, 18c with (1.8M, 1.3M, 1.4M, 107nM), respectively. Moreover, 3-[4-{(6-oxo-1,6-dihydropyridazin-3-yl)oxy}phenyl]urea derivative (18b) exhibited nanomolar potency towards VEGFR-2 (60.7nM). In cellular assay, the above compounds showed excellent inhibition of VEGF-stimulated proliferation of human umbilical vein endothelial cells at 10muM concentration. Finally, an extensive molecular simulation study was performed to investigate the probable interaction with VEGFR-2.