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 |
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Authors: | Ana Guardia Dr Gulcin Gulten Dr Raquel Fernandez Jesus Gómez Dr Feng Wang Dr Maire Convery Delia Blanco María Martínez Dr Esther Pérez‐Herrán Marta Alonso Dr Fátima Ortega Dr Joaquín Rullás Dr David Calvo Lydia Mata Dr Robert Young Prof James C Sacchettini Dr Alfonso Mendoza‐Losana Dr Modesto Remuiñán Dr Lluís Ballell?Pages Dr Julia Castro‐Pichel |
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Affiliation: | 1. Diseases of the Developing World, GlaxoSmithKline, Madrid, Spain;2. Department of Biochemistry and Biophysics, Texas A&M University, TX, USA;3. California Institute for Biomedical Research (Calibr), La Jolla, CA, USA;4. Molecular Discovery Research, GSK Medicines Research Centre, Stevenage, UK;5. Centro de Investigación Básica, Platform Technologies and Science, GlaxoSmithKline, Madrid, Spain |
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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. |
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Keywords: | antimycobacterials benzamides drug discovery InhA medicinal chemistry tuberculosis |
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