title: Searching for New Leads for Tuberculosis: Design, Synthesis, and Biological Evaluation of Novel 2-Quinolin-4-yloxyacetamides.
abstract: In this study, a new series of more than 60 quinoline derivatives has been synthesized and evaluated against Mycobacterium tuberculosis (H37Rv). Apart from the SAR exploration around the initial hits, the optimization process focused on the improvement of the physicochemical properties, cytotoxicity, and metabolic stability of the series. The best compounds obtained exhibited MIC values in the low micromolar range, excellent intracellular antimycobacterial activity, and an improved physicochemical profile without cytotoxic effects. Further investigation revealed that the amide bond was the source for the poor blood stability observed, while some of the compounds exhibited hERG affinity. Compound 83 which contains a benzoxazole ring instead of the amide group was found to be a good alternative, with good blood stability and no hERG affinity, providing new opportunities for the series. Overall, the obtained results suggest that further optimization of solubility and microsomal stability of the series could provide a strong lead for a new anti-TB drug development program.
authors.affiliation: Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp , Universitieitsplein 1, B-2610 Wilrijk, Belgium.|Diseases of the Developing World (DDW), Tres Cantos Medicines Development Campus (TCMDC), GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos Madrid, Spain.
authors.forename: Eleni
authors.initials: E
authors.lastname: Pitta
authors.affiliation: Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp , Universitieitsplein 1, B-2610 Wilrijk, Belgium.|Diseases of the Developing World (DDW), Tres Cantos Medicines Development Campus (TCMDC), GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos Madrid, Spain.
authors.forename: Maciej K
authors.initials: MK
authors.lastname: Rogacki
authors.affiliation: Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp , Universitieitsplein 1, B-2610 Wilrijk, Belgium.|Diseases of the Developing World (DDW), Tres Cantos Medicines Development Campus (TCMDC), GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos Madrid, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Balabon
authors.affiliation: Diseases of the Developing World (DDW), Tres Cantos Medicines Development Campus (TCMDC), GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos Madrid, Spain.
authors.forename: Sophie
authors.initials: S
authors.lastname: Huss
authors.affiliation: Diseases of the Developing World (DDW), Tres Cantos Medicines Development Campus (TCMDC), GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos Madrid, Spain.
authors.forename: Fraser
authors.initials: F
authors.lastname: Cunningham
authors.affiliation: Diseases of the Developing World (DDW), Tres Cantos Medicines Development Campus (TCMDC), GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos Madrid, Spain.
authors.forename: Eva Maria
authors.initials: EM
authors.lastname: Lopez-Roman
authors.affiliation: Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp , Universitieitsplein 1, B-2610 Wilrijk, Belgium.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Joossens
authors.affiliation: Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp , Universitieitsplein 1, B-2610 Wilrijk, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Augustyns
authors.affiliation: Diseases of the Developing World (DDW), Tres Cantos Medicines Development Campus (TCMDC), GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos Madrid, Spain.
authors.forename: Lluis
authors.initials: L
authors.lastname: Ballell
authors.affiliation: Diseases of the Developing World (DDW), Tres Cantos Medicines Development Campus (TCMDC), GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos Madrid, Spain.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bates
authors.affiliation: Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp , Universitieitsplein 1, B-2610 Wilrijk, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Van der Veken
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000620013:2-quinolin-4-yloxyacetamide; D000995:Antitubercular Agents; D001583:Benzoxazoles; D011804:Quinolines