Design, Synthesis, and Biological Evaluation of 5,8-Dimethyl Shikonin Oximes as SARS-CoV-2 M<sup>pro</sup> Inhibitors
We have designed, synthesized, and characterized a small library of shikonin derivatives and demonstrated their inhibitory activity against the main protease, M<sup>pro</sup>, of SARS-CoV-2. One analog, 5,8-dimethyl shikonin oxime (<b>15</b>), exhibited the highest activity a...
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MDPI AG
2025-03-01
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| author | Jiahua Cui Shouyan Xiang Qijing Zhang Shangqing Xiao Gaoyang Yuan Chenwu Liu Shaoshun Li |
| author_facet | Jiahua Cui Shouyan Xiang Qijing Zhang Shangqing Xiao Gaoyang Yuan Chenwu Liu Shaoshun Li |
| author_sort | Jiahua Cui |
| collection | DOAJ |
| description | We have designed, synthesized, and characterized a small library of shikonin derivatives and demonstrated their inhibitory activity against the main protease, M<sup>pro</sup>, of SARS-CoV-2. One analog, 5,8-dimethyl shikonin oxime (<b>15</b>), exhibited the highest activity against SARS-CoV-2 M<sup>pro</sup> with an IC<sub>50</sub> value of 12.53 ± 3.59 μM. It exhibited much less toxicity as compared with the parent compound, shikonin, in both in vitro and in vivo models. Structure–activity relationship analysis indicated that the oxime moieties on the naphthalene ring and the functional groups attached to the oxygen atom on the side chain play a pivotal role in enzymatic inhibitory activity. Molecular docking results implied that the inhibitor <b>15</b> is perfectly settled in the core of the substrate-binding pocket of M<sup>pro</sup> by possibly interacting with three catalytic residues, His41, Cys145, and Met165. Overall, the shikonin oxime derivative <b>15</b> deserves further investigation as an antiviral agent against SARS-CoV-2. |
| format | Article |
| id | doaj-art-661efbe8f32a4645ad148c7a4ba18db6 |
| institution | DOAJ |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj-art-661efbe8f32a4645ad148c7a4ba18db62025-08-20T02:42:22ZengMDPI AGMolecules1420-30492025-03-01306132110.3390/molecules30061321Design, Synthesis, and Biological Evaluation of 5,8-Dimethyl Shikonin Oximes as SARS-CoV-2 M<sup>pro</sup> InhibitorsJiahua Cui0Shouyan Xiang1Qijing Zhang2Shangqing Xiao3Gaoyang Yuan4Chenwu Liu5Shaoshun Li6School of Pharmacy, Gannan Medical University, Ganzhou 341000, ChinaSchool of Pharmacy, Gannan Medical University, Ganzhou 341000, ChinaSchool of Pharmacy, Shanghai Jiaotong University, Shanghai 200240, ChinaSchool of Pharmacy, Gannan Medical University, Ganzhou 341000, ChinaSchool of Pharmacy, Gannan Medical University, Ganzhou 341000, ChinaSchool of Pharmacy, Gannan Medical University, Ganzhou 341000, ChinaSchool of Pharmacy, Shanghai Jiaotong University, Shanghai 200240, ChinaWe have designed, synthesized, and characterized a small library of shikonin derivatives and demonstrated their inhibitory activity against the main protease, M<sup>pro</sup>, of SARS-CoV-2. One analog, 5,8-dimethyl shikonin oxime (<b>15</b>), exhibited the highest activity against SARS-CoV-2 M<sup>pro</sup> with an IC<sub>50</sub> value of 12.53 ± 3.59 μM. It exhibited much less toxicity as compared with the parent compound, shikonin, in both in vitro and in vivo models. Structure–activity relationship analysis indicated that the oxime moieties on the naphthalene ring and the functional groups attached to the oxygen atom on the side chain play a pivotal role in enzymatic inhibitory activity. Molecular docking results implied that the inhibitor <b>15</b> is perfectly settled in the core of the substrate-binding pocket of M<sup>pro</sup> by possibly interacting with three catalytic residues, His41, Cys145, and Met165. Overall, the shikonin oxime derivative <b>15</b> deserves further investigation as an antiviral agent against SARS-CoV-2.https://www.mdpi.com/1420-3049/30/6/1321SARS-CoV-2 M<sup>pro</sup>shikonindimethyl shikonin oximesinhibitorsCOVID-19 |
| spellingShingle | Jiahua Cui Shouyan Xiang Qijing Zhang Shangqing Xiao Gaoyang Yuan Chenwu Liu Shaoshun Li Design, Synthesis, and Biological Evaluation of 5,8-Dimethyl Shikonin Oximes as SARS-CoV-2 M<sup>pro</sup> Inhibitors Molecules SARS-CoV-2 M<sup>pro</sup> shikonin dimethyl shikonin oximes inhibitors COVID-19 |
| title | Design, Synthesis, and Biological Evaluation of 5,8-Dimethyl Shikonin Oximes as SARS-CoV-2 M<sup>pro</sup> Inhibitors |
| title_full | Design, Synthesis, and Biological Evaluation of 5,8-Dimethyl Shikonin Oximes as SARS-CoV-2 M<sup>pro</sup> Inhibitors |
| title_fullStr | Design, Synthesis, and Biological Evaluation of 5,8-Dimethyl Shikonin Oximes as SARS-CoV-2 M<sup>pro</sup> Inhibitors |
| title_full_unstemmed | Design, Synthesis, and Biological Evaluation of 5,8-Dimethyl Shikonin Oximes as SARS-CoV-2 M<sup>pro</sup> Inhibitors |
| title_short | Design, Synthesis, and Biological Evaluation of 5,8-Dimethyl Shikonin Oximes as SARS-CoV-2 M<sup>pro</sup> Inhibitors |
| title_sort | design synthesis and biological evaluation of 5 8 dimethyl shikonin oximes as sars cov 2 m sup pro sup inhibitors |
| topic | SARS-CoV-2 M<sup>pro</sup> shikonin dimethyl shikonin oximes inhibitors COVID-19 |
| url | https://www.mdpi.com/1420-3049/30/6/1321 |
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