In Silico Driven Design and Synthesis of Rhodanine Derivatives as Novel Antibacterials Targeting the Enoyl Reductase InhA

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• 作者：Liudas Slepikas ; Gianpaolo Chiriano ; Remo Perozzo ; Sébastien Tardy ; Agata Kranjc ; Ophélie Patthey-Vuadens ; Hajer Ouertatani-Sakouhi ; Sébastien Kicka ; Christopher F. Harrison ; Tiziana Scrignari ; Karl Perron ; Hubert Hilbi ; Thierry Soldati ; Pierre Cosson ; Eduardas Tarasevicius ; Leonardo Scapozza
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：December 22, 2016
• 年：2016
• 卷：59
• 期：24
• 页码：10917-10928
• 全文大小：599K
• ISSN：1520-4804

文摘

Here, we report on the design, synthesis, and biological evaluation of 4-thiazolidinone (rhodanine) derivatives targeting Mycobacterial tuberculosis (Mtb) trans-2-enoyl-acyl carrier protein reductase (InhA). Compounds having bulky aromatic substituents at position 5 and a tryptophan residue at position N-3 of the rhodanine ring were the most active against InhA, with IC₅₀ values ranging from 2.7 to 30 μM. The experimental data showed consistent correlations with computational studies. Their antimicrobial activity was assessed against Mycobacterium marinum (Mm) (a model for Mtb), Pseudomonas aeruginosa (Pa), Legionella pneumophila (Lp), and Enterococcus faecalis (Ef) by using anti-infective, antivirulence, and antibiotic assays. Nineteen out of 34 compounds reduced Mm virulence at 10 μM. 33 exhibited promising antibiotic activity against Mm with a MIC of 0.21 μM and showed up to 89% reduction of Lp growth in an anti-infective assay at 30 μM. 32 showed high antibiotic activity against Ef, with a MIC of 0.57 μM.