Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470, Eskişehir, Turkey.
Central Analysis Laboratory, Faculty of Pharmacy, Anadolu University, 26470, Eskişehir, Turkey.
Chem Biodivers. 2023 Sep;20(9):e202300944. doi: 10.1002/cbdv.202300944. Epub 2023 Aug 21.
In this study, 12 novel 2-((1-(4-(1H-imidazol-1-yl)phenyl)ethylidene)hydrazineylidene)-3-ethyl-4-(substitutephenyl)-2,3-dihydrothiazole derivatives were obtained. Among these compounds, 2-((1-(4-(1H-imidazol-1-yl)phenyl)ethylidene)hydrazineylidene)-4-([1,1'-biphenyl]-4-yl)-3-ethyl-2,3-dihydrothiazole (4h) was chosen as the most active derivative in the series. According to the MTT results, compounds 4h and 4k showed activity with IC =4.566±0.246 μM and IC =4.537±0.463 μM, respectively. Unlike other derivatives, compound 4h carries a phenyl ring in the 4th position of the phenyl ring. This bulky group allowed the compound to settle in the enzyme active site. Dynamic studies show that the stability of the compound does not change over 40 ns. RMSD, RMSF and Rg parameters all remained within acceptable limits. The uninterrupted aromatic hydrogen bonding of the enzyme active site with the important amino acids Cys919, Glu885 and Asp1046 proves the inhibitory potential of compound 4h on the VEGFR-2 enzyme. It is thought that more active compounds will be reached with the derivatives to be synthesized starting from compound 4h.
在这项研究中，得到了 12 种新型 2-((1-(4-(1H-咪唑-1-基)苯基)亚乙基)腙基)-3-乙基-4-(取代苯基)-2,3-二氢噻唑衍生物。在这些化合物中，2-((1-(4-(1H-咪唑-1-基)苯基)亚乙基)腙基)-4-([1,1'-联苯]-4-基)-3-乙基-2,3-二氢噻唑（4h）被选为该系列中最活跃的衍生物。根据 MTT 结果，化合物 4h 和 4k 的活性分别为 IC =4.566±0.246 μM 和 IC =4.537±0.463 μM。与其他衍生物不同，化合物 4h 在苯环的 4 位带有一个苯基。这个大体积基团使化合物能够在酶的活性部位中稳定下来。动态研究表明，化合物的稳定性在 40 ns 内没有变化。RMSD、RMSF 和 Rg 参数均保持在可接受的范围内。酶活性部位与重要氨基酸 Cys919、Glu885 和 Asp1046 的不间断芳香氢键证明了化合物 4h 对 VEGFR-2 酶的抑制潜力。可以认为，从化合物 4h 开始合成的衍生物将得到更活跃的化合物。
