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

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

doi:10.1021/acs.jmedchem.5b01620

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

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

Authors

Liudas Slepikas^{1

2}, Gianpaolo Chiriano¹, Remo Perozzo¹, Sébastien Tardy¹, Agata Kranjc¹, Ophélie Patthey-Vuadens¹, Hajer Ouertatani-Sakouhi³, Sébastien Kicka⁴, Christopher F Harrison⁵, Tiziana Scrignari⁶, Karl Perron⁶, Hubert Hilbi^{5

7}, Thierry Soldati⁴, Pierre Cosson³, Eduardas Tarasevicius², Leonardo Scapozza¹

Affiliations

¹ School of Pharmaceutical Sciences, Department of Pharmaceutical Biochemistry, University of Geneva and University of Lausanne , 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland.
² Faculty of Pharmacy, Lithuanian University of Health Sciences , LT 44307 Kaunas, Lithuania.
³ Department of Cell Physiology and Metabolism, CMU , Rue Michel-Servet 1 CH-1211 Geneva, Switzerland.
⁴ Department of Biochemistry, University of Geneva , 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland.
⁵ Max von Pettenkofer Institute, Department of Medicine, Ludwig-Maximilians University Munich , 80336 Munich, Germany.
⁶ Microbiology Unit, Department of Botany and Plant Biology, University of Geneva , CH-1211 Geneva, Switzerland.
⁷ Institute of Medical Microbiology, Department of Medicine, University of Zürich , Gloriastrasse 30/32, CH-8006 Zürich, Switzerland.

PMID: 26730986
DOI: 10.1021/acs.jmedchem.5b01620

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.

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / isolation & purification
Bacterial Proteins / metabolism
Dose-Response Relationship, Drug
Drug Design*
Enterococcus faecalis / drug effects
Legionella pneumophila / drug effects
Microbial Sensitivity Tests
Models, Molecular
Molecular Structure
Mycobacterium marinum / drug effects
Oxidoreductases / antagonists & inhibitors*
Oxidoreductases / isolation & purification
Oxidoreductases / metabolism
Pseudomonas aeruginosa / drug effects
Rhodanine / chemical synthesis
Rhodanine / chemistry
Rhodanine / pharmacology*
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Bacterial Proteins
Rhodanine
Oxidoreductases
InhA protein, Mycobacterium