TY - JOUR
T1 - Identification of Phenylphthalazinones as a New Class of Leishmania infantum Inhibitors
AU - Sijm, Maarten
AU - de Heuvel, Erik
AU - Matheeussen, An
AU - Caljon, Guy
AU - Maes, Louis
AU - Sterk, Geert Jan
AU - de Esch, Iwan J.P.
AU - Leurs, Rob
PY - 2020/1/17
Y1 - 2020/1/17
N2 - 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.
AB - 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.
KW - antiprotozoal agents
KW - leishmania infantum
KW - leishmaniasis
KW - phenylphthalazinones
KW - structure-activity relationships
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U2 - 10.1002/cmdc.201900538
DO - 10.1002/cmdc.201900538
M3 - Article
C2 - 31756285
AN - SCOPUS:85076759744
VL - 15
SP - 219
EP - 227
JO - ChemMedChem
JF - ChemMedChem
SN - 1860-7179
IS - 2
ER -