耐多药结核病治疗药物及潜在药物的结构和性质计算

目的：比较分析耐多药结核病（MDR-TB）临床治疗药物和潜在药物结构与性质差异,为开发新药提供参考。方法：运用密度泛函理论M06-2X/6-311+G（2d,p）方法,对噁唑烷酮类MDR-TB治疗药物利奈唑胺（Lin）,临床试验药物舒特唑胺（Sut）、德帕唑胺（Del）、TBI-223（223）及新近合成化合物19c的药效构象、几何和电子结构、红外（IR）、紫外-可见（UV-Vis）、电子圆二色（ECD）谱进行计算比较,并借助概念密度泛函理论进行分子全局反应指数分析,使用药物代谢动力学平台开展成药性和ADME/Tox评估。结果：计算显示19c增加一个手性中心明显减少了药效构象,在不同溶剂环境中,五种化合物药效结构几何参数值相近,计算值与晶体参数吻合较好。极性环境使Del极性改变最大。计算红外光谱特征与实验吻合。Lin计算的紫外最大吸收波数与实验完全一致,Del紫外吸收光谱以HOMO电子向LUMO跃迁为主,其他均以HOMO向LUMO+2跃迁为主,都具有双峰曲线。Sut计算ECD峰与实验相吻合。19c、Sut和Lin静电势分布主要集中在噁唑烷酮端,而Del和223则另一端呈电势负性。五种化合物反应指数彼此数值接近。类药性评价显示Del分布系数与其他差别大,整体彼此相近。动力学参数五种化合物比较一致,但临床用药Lin的参数更优。结论：新化合物19c较MDR-TB临床治疗药物及临床试验药物具有优势,存在进一步开发的价值。

Theoretical study on the structures and properties of multidrug-resistant tuberculosis drug and potential drugs in oxazolidinone derivatives

Objective: To compare the differences in the structures and properties of clinical drug and potential drugs for treatment multidrug-resistant tuberculosis (MDR-TB) so as to provide a reference for the development of new drugs. Methods: The pharmacophoric conformation, geometric and electronic structures, IR, UV-Vis and ECD spectra for Linezolid (Lin), the current treatment of MDR-TB and clinical trials of Sutezolid (Sut), Delpazolid (Del), TBI-223 (223), and the newly synthesized compound 19c in oxazolidinone derivatives were calculated and compared by using density functional theory M06-2X/6-311+G (2d, p). The molecular global reactivity index analysis was carried out with the aid of conceptual density functional theory, and the pharmacodynamic platform was used to calculate ADME/Tox and evaluate the druggability. Results: The data showed that the addition of a chiral center in 19c greatly reduced the pharmacophoric conformation. In different solvent environments, the geometric parameters of the pharmacophoric core in the five compounds were basically the same, and the calculated bond length values were in good agreement with the crystal parameters. Polar solvent environment caused maximum polarity change of Del. The calculated characteristics of infrared were in agreement with the experimental measurements. The theoretical maximum wavenumber of UV-Vis absorption of Lin was exactly the same as the experiment. Except that the UV-Vis absorption spectrum of Del transited from HOMO electron to LUMO, the others were HOMO→LUMO+2 transition, and all UV-Vis spectra were twin-peak curves. The ECD spectrum calculated of Sut coincided with the experiment. The electrostatic potential distribution of 19c, Sut and Lin were mainly concentrated at the oxazolidinone end, while the Del and 223 were negative at the other end. The reactivity index of the five compounds was close to each other. Drug evaluation showed that the distribution coefficient of Del was different from others, and the whole was similar to each other. Pharmacokinetic parameters of 5 compounds were consistent, but the parameters of clinical drug Lin were better. Conclusion: The new compound 19c has more advantages over clinical treatment drug and clinical trial drugs for MDR-TB, and has greater value for development.