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


Slepikas, Liudas; Chiriano, Gianpaolo; Perozzo, Remo; Tardy, Sébastien; Kranjc, Agata; Patthey-Vuadens, Ophélie; Ouertatani-Sakouhi, Hajer; Kicka, Sébastien; Harrison, Christopher F; Scrignari, Tiziana; Perron, Karl; Hilbi, Hubert; Soldati, Thierry; Cosson, Pierre; Tarasevicius, Eduardas; Scapozza, Leonardo (2016). In silico driven design and synthesis of rhodanine derivatives as novel antibacterials targeting the enoyl reductase InhA. Journal of Medicinal Chemistry, 59(24):10917-10928.

Abstract

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.

Abstract

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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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Microbiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:9 December 2016
Deposited On:15 Dec 2016 10:25
Last Modified:22 Feb 2017 02:02
Publisher:American Chemical Society (ACS)
ISSN:0022-2623
Publisher DOI:https://doi.org/10.1021/acs.jmedchem.5b01620
PubMed ID:26730986

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