Oxadiazolone derivatives, new promising multi-target inhibitors against M. tuberculosis. 2018

Phuong Chi Nguyen, and Vincent Delorme, and Anaïs Bénarouche, and Alexandre Guy, and Valérie Landry, and Stéphane Audebert, and Matthieu Pophillat, and Luc Camoin, and Céline Crauste, and Jean-Marie Galano, and Thierry Durand, and Priscille Brodin, and Stéphane Canaan, and Jean-François Cavalier
Aix-Marseille Univ, CNRS, LISM, Institut de Microbiologie de la Méditerranée, Marseille, France.

A set of 19 oxadiazolone (OX) derivatives have been investigated for their antimycobacterial activity against two pathogenic slow-growing mycobacteria, Mycobacterium marinum and Mycobacterium bovis BCG, and the avirulent Mycobacterium tuberculosis (M. tb) mc26230. The encouraging minimal inhibitory concentrations (MIC) values obtained prompted us to test them against virulent M. tb H37Rv growth either in broth medium or inside macrophages. The OX compounds displayed a diversity of action and were found to act either on extracellular M. tb growth only with moderated MIC50, or both intracellularly on infected macrophages as well as extracellularly on bacterial growth. Of interest, all OX derivatives exhibited very low toxicity towards host macrophages. Among the six potential OXs identified, HPOX, a selective inhibitor of extracellular M. tb growth, was selected and further used in a competitive labelling/enrichment assay against the activity-based probe Desthiobiotin-FP, in order to identify its putative target(s). This approach, combined with mass spectrometry, identified 18 potential candidates, all being serine or cysteine enzymes involved in M. tb lipid metabolism and/or in cell wall biosynthesis. Among them, Ag85A, CaeA, TesA, KasA and MetA have been reported as essential for in vitro growth of M. tb and/or its survival and persistence inside macrophages. Overall, our findings support the assumption that OX derivatives may represent a novel class of multi-target inhibitors leading to the arrest of M. tb growth through a cumulative inhibition of a large number of Ser- and Cys-containing enzymes involved in various important physiological processes.

UI MeSH Term Description Entries
D008264 Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood MONOCYTES. Main types are PERITONEAL MACROPHAGES; ALVEOLAR MACROPHAGES; HISTIOCYTES; KUPFFER CELLS of the liver; and OSTEOCLASTS. They may further differentiate within chronic inflammatory lesions to EPITHELIOID CELLS or may fuse to form FOREIGN BODY GIANT CELLS or LANGHANS GIANT CELLS. (from The Dictionary of Cell Biology, Lackie and Dow, 3rd ed.) Bone Marrow-Derived Macrophages,Monocyte-Derived Macrophages,Macrophage,Macrophages, Monocyte-Derived,Bone Marrow Derived Macrophages,Bone Marrow-Derived Macrophage,Macrophage, Bone Marrow-Derived,Macrophage, Monocyte-Derived,Macrophages, Bone Marrow-Derived,Macrophages, Monocyte Derived,Monocyte Derived Macrophages,Monocyte-Derived Macrophage
D008826 Microbial Sensitivity Tests Any tests that demonstrate the relative efficacy of different chemotherapeutic agents against specific microorganisms (i.e., bacteria, fungi, viruses). Bacterial Sensitivity Tests,Drug Sensitivity Assay, Microbial,Minimum Inhibitory Concentration,Antibacterial Susceptibility Breakpoint Determination,Antibiogram,Antimicrobial Susceptibility Breakpoint Determination,Bacterial Sensitivity Test,Breakpoint Determination, Antibacterial Susceptibility,Breakpoint Determination, Antimicrobial Susceptibility,Fungal Drug Sensitivity Tests,Fungus Drug Sensitivity Tests,Sensitivity Test, Bacterial,Sensitivity Tests, Bacterial,Test, Bacterial Sensitivity,Tests, Bacterial Sensitivity,Viral Drug Sensitivity Tests,Virus Drug Sensitivity Tests,Antibiograms,Concentration, Minimum Inhibitory,Concentrations, Minimum Inhibitory,Inhibitory Concentration, Minimum,Inhibitory Concentrations, Minimum,Microbial Sensitivity Test,Minimum Inhibitory Concentrations,Sensitivity Test, Microbial,Sensitivity Tests, Microbial,Test, Microbial Sensitivity,Tests, Microbial Sensitivity
D009169 Mycobacterium tuberculosis A species of gram-positive, aerobic bacteria that produces TUBERCULOSIS in humans, other primates, CATTLE; DOGS; and some other animals which have contact with humans. Growth tends to be in serpentine, cordlike masses in which the bacilli show a parallel orientation. Mycobacterium tuberculosis H37Rv
D010069 Oxadiazoles Compounds containing five-membered heteroaromatic rings containing two carbons, two nitrogens, and one oxygen atom which exist in various regioisomeric forms. Oxadiazole
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000067996 RAW 264.7 Cells A transformed macrophage cell line isolated from ASCITES of mice infected with ABELSON MURINE LEUKEMIA VIRUS. RAW 264.7 Cell Line,264.7 Cell, RAW,264.7 Cells, RAW,Cell, RAW 264.7,Cells, RAW 264.7,RAW 264.7 Cell
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000995 Antitubercular Agents Drugs used in the treatment of tuberculosis. They are divided into two main classes: "first-line" agents, those with the greatest efficacy and acceptable degrees of toxicity used successfully in the great majority of cases; and "second-line" drugs used in drug-resistant cases or those in which some other patient-related condition has compromised the effectiveness of primary therapy. Anti-Tuberculosis Agent,Anti-Tuberculosis Agents,Anti-Tuberculosis Drug,Anti-Tuberculosis Drugs,Antitubercular Agent,Antitubercular Drug,Tuberculostatic Agent,Tuberculostatic Agents,Antitubercular Drugs,Agent, Anti-Tuberculosis,Agent, Antitubercular,Agent, Tuberculostatic,Anti Tuberculosis Agent,Anti Tuberculosis Agents,Anti Tuberculosis Drug,Anti Tuberculosis Drugs,Drug, Anti-Tuberculosis,Drug, Antitubercular
D014376 Tuberculosis Any of the infectious diseases of man and other animals caused by species of MYCOBACTERIUM TUBERCULOSIS. Koch's Disease,Kochs Disease,Mycobacterium tuberculosis Infection,Infection, Mycobacterium tuberculosis,Infections, Mycobacterium tuberculosis,Koch Disease,Mycobacterium tuberculosis Infections,Tuberculoses
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs

Related Publications

Phuong Chi Nguyen, and Vincent Delorme, and Anaïs Bénarouche, and Alexandre Guy, and Valérie Landry, and Stéphane Audebert, and Matthieu Pophillat, and Luc Camoin, and Céline Crauste, and Jean-Marie Galano, and Thierry Durand, and Priscille Brodin, and Stéphane Canaan, and Jean-François Cavalier
January 2015, The open microbiology journal,
Phuong Chi Nguyen, and Vincent Delorme, and Anaïs Bénarouche, and Alexandre Guy, and Valérie Landry, and Stéphane Audebert, and Matthieu Pophillat, and Luc Camoin, and Céline Crauste, and Jean-Marie Galano, and Thierry Durand, and Priscille Brodin, and Stéphane Canaan, and Jean-François Cavalier
January 2020, PloS one,
Phuong Chi Nguyen, and Vincent Delorme, and Anaïs Bénarouche, and Alexandre Guy, and Valérie Landry, and Stéphane Audebert, and Matthieu Pophillat, and Luc Camoin, and Céline Crauste, and Jean-Marie Galano, and Thierry Durand, and Priscille Brodin, and Stéphane Canaan, and Jean-François Cavalier
January 1996, Cleveland Clinic journal of medicine,
Phuong Chi Nguyen, and Vincent Delorme, and Anaïs Bénarouche, and Alexandre Guy, and Valérie Landry, and Stéphane Audebert, and Matthieu Pophillat, and Luc Camoin, and Céline Crauste, and Jean-Marie Galano, and Thierry Durand, and Priscille Brodin, and Stéphane Canaan, and Jean-François Cavalier
October 2004, Drug discovery today,
Phuong Chi Nguyen, and Vincent Delorme, and Anaïs Bénarouche, and Alexandre Guy, and Valérie Landry, and Stéphane Audebert, and Matthieu Pophillat, and Luc Camoin, and Céline Crauste, and Jean-Marie Galano, and Thierry Durand, and Priscille Brodin, and Stéphane Canaan, and Jean-François Cavalier
December 1990, Kekkaku : [Tuberculosis],
Phuong Chi Nguyen, and Vincent Delorme, and Anaïs Bénarouche, and Alexandre Guy, and Valérie Landry, and Stéphane Audebert, and Matthieu Pophillat, and Luc Camoin, and Céline Crauste, and Jean-Marie Galano, and Thierry Durand, and Priscille Brodin, and Stéphane Canaan, and Jean-François Cavalier
December 2021, Journal of enzyme inhibition and medicinal chemistry,
Phuong Chi Nguyen, and Vincent Delorme, and Anaïs Bénarouche, and Alexandre Guy, and Valérie Landry, and Stéphane Audebert, and Matthieu Pophillat, and Luc Camoin, and Céline Crauste, and Jean-Marie Galano, and Thierry Durand, and Priscille Brodin, and Stéphane Canaan, and Jean-François Cavalier
January 2021, Frontiers in microbiology,
Phuong Chi Nguyen, and Vincent Delorme, and Anaïs Bénarouche, and Alexandre Guy, and Valérie Landry, and Stéphane Audebert, and Matthieu Pophillat, and Luc Camoin, and Céline Crauste, and Jean-Marie Galano, and Thierry Durand, and Priscille Brodin, and Stéphane Canaan, and Jean-François Cavalier
January 2023, Current drug targets,
Phuong Chi Nguyen, and Vincent Delorme, and Anaïs Bénarouche, and Alexandre Guy, and Valérie Landry, and Stéphane Audebert, and Matthieu Pophillat, and Luc Camoin, and Céline Crauste, and Jean-Marie Galano, and Thierry Durand, and Priscille Brodin, and Stéphane Canaan, and Jean-François Cavalier
January 2006, Recent patents on anti-infective drug discovery,
Phuong Chi Nguyen, and Vincent Delorme, and Anaïs Bénarouche, and Alexandre Guy, and Valérie Landry, and Stéphane Audebert, and Matthieu Pophillat, and Luc Camoin, and Céline Crauste, and Jean-Marie Galano, and Thierry Durand, and Priscille Brodin, and Stéphane Canaan, and Jean-François Cavalier
December 2015, Chemical biology & drug design,
Copied contents to your clipboard!