Exploring the plasticity of the InhA substrate-binding site using new diaryl ether inhibitors.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a worldwide scourge with more than 10 million people affected yearly. Among the proteins essential for the survival of Mtb, InhA has been and is still clinically validated as a therapeutic target. A new family of direct diaryl ether inhibitors, not requiring prior activation by the catalase peroxidase enzyme KatG, has been designed with the ambition of fully occupying the InhA substrate-binding site. Thus, eleven compounds, featuring three pharmacophores within the same molecule, were synthesized. One of them, 5-(((4-(2-hydroxyphenoxy)benzyl)(octyl)amino)methyl)-2-phenoxyphenol (compound 21), showed good inhibitory activity against InhA with IC50 of 0.70 µM. The crystal structure of compound 21 in complex with InhA/NAD+ showed how the molecule fills the substrate-binding site as well as the minor portal of InhA. This study represents a further step towards the design of new inhibitors of InhA. Copyright © 2023 Elsevier Inc. All rights reserved.

Citation

Rasoul Tamhaev, Emeline Grosjean, Hikmat Ahamed, Mélina Chebaiki, Frédéric Rodriguez, Deborah Recchia, Giulia Degiacomi, Maria Rosalia Pasca, Laurent Maveyraud, Lionel Mourey, Christian Lherbet. Exploring the plasticity of the InhA substrate-binding site using new diaryl ether inhibitors. Bioorganic chemistry. 2024 Feb;143:107032

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PMID: 38128204

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