Identification of Phenylphthalazinones as a New Class of Leishmania infantum Inhibitors

Maarten Sijm, Erik de Heuvel, An Matheeussen, Guy Caljon, Louis Maes, Geert Jan Sterk, Iwan J.P. de Esch, Rob Leurs*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

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Abstract

Leishmaniasis is a neglected parasitic disease caused by over 20 different Leishmania species. Current treatments often rely on harsh regimes of pentavalent antimonials such as sodium stibogluconate, while more recent drugs suffer other shortcomings such as low stability and rapid emergence of treatment failure, amongst others. Furthermore, the effectiveness of drugs varies depending on the infecting Leishmania species, thus there is an urgent need for new and effective anti-leishmanial drugs. Screening of an in-house compound library identified the hexahydrophthalazinone NPD-2942 as a low micromolar hit with a pIC50 of 5.8 against L. infantum and a pIC50 of 4.6 for cytotoxicity against human MRC-5 fibroblasts. To derive structure–activity relationships, we modified the cyclohexyl ring of the hexahydrophthalazinone scaffold and 1,2,3-triazoles were attempted as replacement for the pyrazole ring, amongst others. Ultimately, the 2,3-pyrazole-substituted hexahydrophthalazinone NPD-1289 was identified as the most potent analogue in this series with a pIC50 of 6.3, although some cytotoxicity toward MRC-5 cells (pIC50=5.1) was recorded as well. Replacement of the unsubstituted 2,3-pyrazole with 1,2,3-triazoles led to compounds with lower anti-leishmanial activity. The current scaffold is a valuable new starting point for optimization toward novel anti-leishmanial drugs.

Original languageEnglish
Pages (from-to)219-227
Number of pages9
JournalChemMedChem
Volume15
Issue number2
Early online date22 Nov 2019
DOIs
Publication statusPublished - 17 Jan 2020

Funding

The authors thank H. Custers and A. van der Stolpe for their technical assistance. The PDE4NPD project was funded by the European Union under the FP‐7‐Health program, project ID: 602666.

FundersFunder number
FP-7-Health program
Seventh Framework Programme602666
European Commission

    Keywords

    • antiprotozoal agents
    • leishmania infantum
    • leishmaniasis
    • phenylphthalazinones
    • structure-activity relationships

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