In silico driven design and synthesis of rhodanine derivatives as novel antibacterials targeting the enoyl reductase InhA

Article Article scientifique Article In silico driven design and synthesis of rhodanine derivatives as novel antibacterials targeting the enoyl reductase InhA eng 2016 author Slepikas Liudas 742594 author Chiriano Gianpaolo 784524 author Perozzo Remo 625237 author Tardy Sébastien 784523 author Kranjc-Pietrucci Agata author Patthey-Vuadens Ophélie author Ouertatani-Sakouhi Hajer author Kicka Sébastien 736074 author Harrison Christopher F author Scrignari Tiziana 733530 author Perron Karl 45679 author Hilbi Hubert author Soldati Thierry 0000-0002-2056-7931 135632 author Cosson Pierre 0000-0002-4881-0358 119596 author Tarasevicius Eduardas author Scapozza Leonardo 600318 10917-10928 10.1021/acs.jmedchem.5b01620 26730986 0022-2623 Here, we report on the design, synthesis and biological evaluation of 4-thiazolidinone (rhodanine) de-rivatives 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 µM to 30 µM. The experimental data showed consistent correlations with computational studies. Their anti-microbial 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, anti-virulence and antibiotic assays. 19 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. Dewey 540 Dewey 580 Dewey 612 Dewey 615 39 Département de biochimie 144 45 Département des sciences végétales 163 31 Section des sciences pharmaceutiques 17 134 Département de physiologie cellulaire et métabolisme 21C false 111 Phagocytose 140 Journal of medicinal chemistry 59 24 9d2f491b-d714-4d20-960e-3c2f2ca350aa Article (Published version) Restricted acs%2Ejmedchem%2E5b01620.pdf 1404786 application/pdf restrictedAccess Faculté des sciences / Section de chimie et biochimie / Département de biochimie Faculté des sciences / Section de biologie / Département des sciences végétales Faculté des sciences / Section des sciences pharmaceutiques Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme

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In silico driven design and synthesis of rhodanine derivatives as novel antibacterials targeting the enoyl reductase InhA	Journal of medicinal chemistry			2016	680	6

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