title: In Silico Driven Design and Synthesis of Rhodanine Derivatives as Novel Antibacterials Targeting the Enoyl Reductase InhA.
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 IC50values 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.
authors.affiliation: 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.
authors.forename: Liudas
authors.initials: L
authors.lastname: Slepikas
authors.affiliation: School of Pharmaceutical Sciences, Department of Pharmaceutical Biochemistry, University of Geneva and University of Lausanne , 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland.
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Chiriano
authors.affiliation: School of Pharmaceutical Sciences, Department of Pharmaceutical Biochemistry, University of Geneva and University of Lausanne , 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland.
authors.forename: Remo
authors.initials: R
authors.lastname: Perozzo
authors.affiliation: School of Pharmaceutical Sciences, Department of Pharmaceutical Biochemistry, University of Geneva and University of Lausanne , 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Tardy
authors.affiliation: School of Pharmaceutical Sciences, Department of Pharmaceutical Biochemistry, University of Geneva and University of Lausanne , 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland.
authors.forename: Agata
authors.initials: A
authors.lastname: Kranjc
authors.affiliation: School of Pharmaceutical Sciences, Department of Pharmaceutical Biochemistry, University of Geneva and University of Lausanne , 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland.
authors.forename: Ophélie
authors.initials: O
authors.lastname: Patthey-Vuadens
authors.affiliation: Department of Cell Physiology and Metabolism, CMU , Rue Michel-Servet 1 CH-1211 Geneva, Switzerland.
authors.forename: Hajer
authors.initials: H
authors.lastname: Ouertatani-Sakouhi
authors.affiliation: Department of Biochemistry, University of Geneva , 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Kicka
authors.affiliation: Max von Pettenkofer Institute, Department of Medicine, Ludwig-Maximilians University Munich , 80336 Munich, Germany.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Harrison
authors.affiliation: Microbiology Unit, Department of Botany and Plant Biology, University of Geneva , CH-1211 Geneva, Switzerland.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Scrignari
authors.affiliation: Microbiology Unit, Department of Botany and Plant Biology, University of Geneva , CH-1211 Geneva, Switzerland.
authors.forename: Karl
authors.initials: K
authors.lastname: Perron
authors.affiliation: Max von Pettenkofer Institute, Department of Medicine, Ludwig-Maximilians University Munich , 80336 Munich, Germany.|Institute of Medical Microbiology, Department of Medicine, University of Zürich , Gloriastrasse 30/32, CH-8006 Zürich, Switzerland.
authors.forename: Hubert
authors.initials: H
authors.lastname: Hilbi
authors.affiliation: Department of Biochemistry, University of Geneva , 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland.
authors.forename: Thierry
authors.initials: T
authors.lastname: Soldati
authors.affiliation: Department of Cell Physiology and Metabolism, CMU , Rue Michel-Servet 1 CH-1211 Geneva, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cosson
authors.affiliation: Faculty of Pharmacy, Lithuanian University of Health Sciences , LT 44307 Kaunas, Lithuania.
authors.forename: Eduardas
authors.initials: E
authors.lastname: Tarasevicius
authors.affiliation: School of Pharmaceutical Sciences, Department of Pharmaceutical Biochemistry, University of Geneva and University of Lausanne , 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Scapozza
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D013293:Enterococcus faecalis / Q000187:drug effects; D016952:Legionella pneumophila / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D019910:Mycobacterium marinum / Q000187:drug effects; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D012236:Rhodanine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D012236:Rhodanine; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium