Structure-Based Design and Synthesis of Piperidinol-Containing Molecules as New Mycobacterium abscessus Inhibitors |
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Authors: | Dr Jérôme de Ruyck Dr Christian Dupont Elodie Lamy Dr Vincent Le Moigne Prof Christophe Biot Dr Yann Guérardel Prof Jean-Louis Herrmann Dr Mickaël Blaise Dr Stanislas Grassin-Delyle Dr Laurent Kremer Dr Faustine Dubar |
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Institution: | 1. Univ. Lille, CNRS UMR 8576 – UGSF – Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France;2. IRIM Institut de Recherche en Infectiologie de Montpellier – UMR9004-CNRS/UM, 1919 route de Mende, 34293 Montpellier, France;3. Infection et inflammation – Laboratoire 2I UMD1173-INSERM/UVSQ, Versailles, 2 Avenue de la source de la Bièvres, 78180 Montigny le Bretonneux, France;4. Infection et inflammation – Laboratoire 2I UMD1173-INSERM/UVSQ, Versailles, 2 Avenue de la source de la Bièvres, 78180 Montigny le Bretonneux, France
Hôpital Foch, Département des maladies des voies respiratoires, 92150 Suresnes, France |
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Abstract: | Non-tuberculous mycobacterium (NTM) infections, such as those caused by Mycobacterium abscessus, are increasing globally. Due to their intrinsic drug resistance, M. abscessus pulmonary infections are often difficult to cure using standard chemotherapy. We previously demonstrated that a piperidinol derivative, named PIPD1, is an efficient molecule both against M. abscessus and Mycobacterium tuberculosis, the agent of tuberculosis, by targeting the mycolic acid transporter MmpL3. These results prompted us to design and synthesize a series of piperidinol derivatives and to determine the biological activity against M. abscessus. Structure-activity relationship (SAR) studies pointed toward specific sites on the scaffold that can tolerate slight modifications. Overall, these results identified FMD-88 as a new promising active analogue against M. abscessus. Also, we determined the pharmacokinetics properties of PIPD1 and showed that intraperitoneal administration of this compound resulted in promising serum concentration and an elimination half-life of 3.2 hours. |
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Keywords: | mycobacterium abscessus molecular modeling structure-activity relationship phenotypic screening piperidinol derivatives |
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