Structure-Based Design and Synthesis of Piperidinol-Containing Molecules as New Mycobacterium abscessus Inhibitors.

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.

• Authors: Jérôme de Ruyck, Christian Dupont, Elodie Lamy, Vincent Le Moigne, Christophe Biot, Yann Guérardel, Jean-Louis Herrmann, Mickaël Blaise, Stanislas Grassin-Delyle, Laurent Kremer, Faustine Dubar
• Journal: ChemistryOpen (ChemistryOpen) Vol. 9 Issue 3 Pg. 351-365 (03 2020) ISSN: 2191-1363 [Print] Germany
• PMID: 32211280 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Chemical References

• Antitubercular Agents
• Membrane Transport Proteins
• Mycolic Acids

Topics

• Antitubercular Agents (chemistry, pharmacokinetics)
• Biological Transport
• Humans
• Membrane Transport Proteins (chemistry, metabolism)
• Microbial Sensitivity Tests
• Models, Molecular
• Mycobacterium abscessus (drug effects)
• Mycolic Acids (metabolism)
• Structure-Activity Relationship
• Tuberculosis (drug therapy)