耐多药结核病治疗药物及潜在药物的结构和性质计算

doi:10.3969/j.issn.2095-9400.2021.06.006

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Abstract 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.

Key words： multidrug-resistant tuberculosis linezolid density functional theory index

Received: 15 February 2021

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	LI Zhenyue
	WENG Yueyue
	HUANG Luoyi
	WANG Chaojie

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https://xb.wmu.edu.cn/EN/10.3969/j.issn.2095-9400.2021.06.006 OR https://xb.wmu.edu.cn/EN/Y2021/V51/I6/459

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