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

Published inJournal of medicinal chemistry, vol. 59, no. 24, p. 10917-10928
Publication date2016
Abstract

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.

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SLEPIKAS, Liudas et al. In silico driven design and synthesis of rhodanine derivatives as novel antibacterials targeting the enoyl reductase InhA. In: Journal of medicinal chemistry, 2016, vol. 59, n° 24, p. 10917–10928. doi: 10.1021/acs.jmedchem.5b01620
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ISSN of the journal0022-2623
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