title: N-Benzyl-4-((heteroaryl)methyl)benzamides: A New Class of Direct NADH-Dependent 2-trans Enoyl-Acyl Carrier Protein Reductase (InhA) Inhibitors with Antitubercular Activity.
abstract: Isoniazid (INH) remains one of the cornerstones of antitubercular chemotherapy for drug-sensitive strains of M. tuberculosis bacteria. However, the increasing prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains containing mutations in the KatG enzyme, which is responsible for the activation of INH into its antitubercular form, have rendered this drug of little or no use in many cases of drug-resistant tuberculosis. Presented herein is a novel family of antitubercular direct NADH-dependent 2-trans enoyl-acyl carrier protein reductase (InhA) inhibitors based on an N-benzyl-4-((heteroaryl)methyl)benzamide template; unlike INH, these do not require prior activation by KatG. Given their direct InhA target engagement, these compounds should be able to circumvent KatG-related resistance in the clinic. The lead molecules were shown to be potent inhibitors of InhA and showed activity against M. tuberculosis bacteria. This new family of inhibitors was found to be chemically tractable, as exemplified by the facile synthesis of analogues and the establishment of structure-activity relationships. Furthermore, a co-crystal structure of the initial hit with the enzyme is disclosed, providing valuable information toward the design of new InhA inhibitors for the treatment of MDR/XDR tuberculosis.
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain. ana.a.guardia@gsk.com.
authors.forename: Ana
authors.identifier: http://orcid.org/0000-0001-9532-9850
authors.initials: A
authors.lastname: Guardia
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, 300 Olsen Boulevard College Station, TX, 77843-2128, USA.
authors.forename: Gulcin
authors.initials: G
authors.lastname: Gulten
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Fernandez
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Gómez
authors.affiliation: California Institute for Biomedical Research (Calibr), 11119 North Torrey Pines Road, La Jolla, CA, 92037, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Molecular Discovery Research, GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
authors.forename: Maire
authors.initials: M
authors.lastname: Convery
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Delia
authors.initials: D
authors.lastname: Blanco
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Martínez
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Pérez-Herrán
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Alonso
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Fátima
authors.initials: F
authors.lastname: Ortega
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Rullás
authors.affiliation: Centro de Investigación Básica, Platform Technologies and Science, GlaxoSmithKline, Parque Tecnológico de Madrid, 28760 Tres Cantos, Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Calvo
authors.affiliation: Centro de Investigación Básica, Platform Technologies and Science, GlaxoSmithKline, Parque Tecnológico de Madrid, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Lydia
authors.initials: L
authors.lastname: Mata
authors.affiliation: Molecular Discovery Research, GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Young
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, 300 Olsen Boulevard College Station, TX, 77843-2128, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Sacchettini
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Mendoza-Losana
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Modesto
authors.initials: M
authors.lastname: Remuiñán
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Lluís
authors.initials: L
authors.lastname: Ballell Pages
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Julia
authors.initials: J
authors.lastname: Castro-Pichel
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D007265:Inhibins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D009243:NAD / Q000378:metabolism*; D013329:Structure-Activity Relationship; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000201:enzymology
chemical_list: D000995:Antitubercular Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; C094377:inhibin-alpha subunit; D009243:NAD; D007265:Inhibins
keywords: InhA; antimycobacterials; benzamides; drug discovery; medicinal chemistry; tuberculosis