Identification and Optimization of a Series of 8‑Hydroxy Naphthyridines with Potent In Vitro Antileishmanial Activity: Initial SAR and Assessment of In Vivo Activity

Visceral leishmaniasis (VL) is a parasitic infection that results in approximately 26 000–65 000 deaths annually. The available treatments are hampered by issues such as toxicity, variable efficacy, and unsuitable dosing options. The need for new treatments is urgent and led to a collaboration betwe...

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Published in:Journal of medicinal chemistry 2020-09, Vol.63 (17), p.9523-9539
Main Authors: Thomas, Michael G, De Rycker, Manu, Wall, Richard J, Spinks, Daniel, Epemolu, Ola, Manthri, Sujatha, Norval, Suzanne, Osuna-Cabello, Maria, Patterson, Stephen, Riley, Jennifer, Simeons, Frederick R. C, Stojanovski, Laste, Thomas, John, Thompson, Stephen, Naylor, Claire, Fiandor, Jose M, Wyatt, Paul G, Marco, Maria, Wyllie, Susan, Read, Kevin D, Miles, Timothy J, Gilbert, Ian H
Format: Article
Language:English
Subjects:
Animals
Antiprotozoal Agents - chemistry
Antiprotozoal Agents - pharmacology
Drug Design
Inhibitory Concentration 50
Leishmania - drug effects
Mice
Naphthyridines - chemistry
Naphthyridines - pharmacology
Solubility
Structure-Activity Relationship
Water - chemistry
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Summary:Visceral leishmaniasis (VL) is a parasitic infection that results in approximately 26 000–65 000 deaths annually. The available treatments are hampered by issues such as toxicity, variable efficacy, and unsuitable dosing options. The need for new treatments is urgent and led to a collaboration between the Drugs for Neglected Diseases initiative (DNDi), GlaxoSmithKline (GSK), and the University of Dundee. An 8-hydroxynaphthyridine was identified as a start point, and an early compound demonstrated weak efficacy in a mouse model of VL but was hampered by glucuronidation. Efforts to address this led to the development of compounds with improved in vitro profiles, but these were poorly tolerated in vivo. Investigation of the mode of action (MoA) demonstrated that activity was driven by sequestration of divalent metal cations, a mechanism which was likely to drive the poor tolerability. This highlights the importance of investigating MoA and pharmacokinetics at an early stage for phenotypically active series.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.0c00705