Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt.
Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
Molecules. 2022 Nov 3;27(21):7540. doi: 10.3390/molecules27217540.
A novel derivative of ibuprofen and salicylaldehyde N'-(4-hydroxybenzylidene)-2-(4-isobutylphenyl) propane hydrazide (HL) was synthesized, followed by its complexation with Cu, Ni, Co, Gd, and Sm. The compounds obtained were characterized by HNMR, mass spectrometry, UV-Vis spectroscopy, FT-IR spectroscopy, thermal analysis (DTA and TGA), conductivity measurements, and magnetic susceptibility measurements. The results indicate that the complexes formed were [Cu(L)(HO)]Cl·2HO, [Ni(L)], [Co(L)]·HO, Gd(L)(HO)·2HO and Sm(L)(HO)·2HO. The surface characteristics of the produced compounds were evaluated by DFT calculations using the MOE environment. The docking was performed against the COX2 targeting protein (PDB code: 5IKT Homo sapiens). The binding energies were -7.52, -9.41, -9.51, -8.09, -10.04, and -8.05 kcal/mol for HL and the Co, Ni, Cu, Sm, and Gd complexes, respectively, which suggests the enhancement of anti-inflammatory behaviors compared with the binding energy of ibuprofen (-5.38 kcal/mol). The anti-inflammatory properties of the new compounds were assessed in vitro using the western blot analysis method and the enzyme-linked immunosorbent assay (ELISA), consistent with the outcomes obtained from docking. The half-maximal inhibitory concentration (IC) values are 4.9, 1.7, 3.7, 5.6, 2.9, and 2.3 µM for HL and the Co, Ni, Cu, Sm, and Gd complexes, respectively, showing that they are more effective inhibitors of COX2 than ibuprofen (IC = 31.4 µM). The brain or intestinal estimated permeation method (BOILED-Egg) showed that HL and its Co complex have high gastrointestinal absorption, while only the free ligand has high brain penetration. The binding constants of Co, Cu, and Gd complexes with DNA were recorded as 2.20 × 10, 2.27 × 10 and 4.46 × 10 M, respectively, indicating the intercalator behavior of interaction. The newly synthesized ibuprofen derivative and its metal complexes showed greater anti-inflammatory activity than ibuprofen.
一种新型的布洛芬和水杨醛 N'-(4-羟基苄叉)-2-(4-异丁基苯基)丙酰肼（HL）衍生物被合成，并与 Cu、Ni、Co、Gd 和 Sm 配位。所得化合物通过 HNMR、质谱、紫外可见光谱、FT-IR 光谱、热分析（DTA 和 TGA）、电导率测量和磁化率测量进行了表征。结果表明，形成的配合物为[Cu(L)(HO)]Cl·2HO、[Ni(L)]、[Co(L)]·HO、Gd(L)(HO)·2HO 和Sm(L)(HO)·2HO。通过 MOE 环境下的 DFT 计算评估了所生成化合物的表面特性。对接是针对 COX2 靶向蛋白（PDB 代码：5IKT 智人）进行的。HL 和 Co、Ni、Cu、Sm 和 Gd 配合物的结合能分别为-7.52、-9.41、-9.51、-8.09、-10.04 和-8.05 kcal/mol，表明与布洛芬（-5.38 kcal/mol）相比，抗炎行为得到增强。通过 Western blot 分析方法和酶联免疫吸附测定（ELISA）在体外评估了新化合物的抗炎特性，与对接结果一致。HL 和 Co、Ni、Cu、Sm 和 Gd 配合物的半最大抑制浓度（IC）值分别为 4.9、1.7、3.7、5.6、2.9 和 2.3 µM，表明它们是 COX2 的更有效的抑制剂比布洛芬（IC = 31.4 µM）。脑或肠估计渗透法（BOILED-Egg）表明 HL 和其 Co 配合物具有较高的胃肠道吸收，而只有游离配体具有较高的脑穿透性。Co、Cu 和 Gd 配合物与 DNA 的结合常数分别记录为 2.20×10、2.27×10 和 4.46×10 M，表明相互作用具有嵌入剂行为。新合成的布洛芬衍生物及其金属配合物表现出比布洛芬更强的抗炎活性。
