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J Med Chem. 2016 Dec 22;59(24):10917-10928. doi: 10.1021/acs.jmedchem.5b01620. Epub 2016 Dec 9.

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

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School of Pharmaceutical Sciences, Department of Pharmaceutical Biochemistry, University of Geneva and University of Lausanne , 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland.
Faculty of Pharmacy, Lithuanian University of Health Sciences , LT 44307 Kaunas, Lithuania.
Department of Cell Physiology and Metabolism, CMU , Rue Michel-Servet 1 CH-1211 Geneva, Switzerland.
Department of Biochemistry, University of Geneva , 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland.
Max von Pettenkofer Institute, Department of Medicine, Ludwig-Maximilians University Munich , 80336 Munich, Germany.
Microbiology Unit, Department of Botany and Plant Biology, University of Geneva , CH-1211 Geneva, Switzerland.
Institute of Medical Microbiology, Department of Medicine, University of Zürich , Gloriastrasse 30/32, CH-8006 Zürich, Switzerland.


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.

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