{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T16:58:04Z","timestamp":1761238684032,"version":"build-2065373602"},"reference-count":24,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,12,9]],"date-time":"2019-12-09T00:00:00Z","timestamp":1575849600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2020,1,17]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Leishmaniasis is a neglected parasitic disease caused by over 20 different <jats:italic>Leishmania<\/jats:italic> 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 <jats:italic>Leishmania<\/jats:italic> species, thus there is an urgent need for new and effective anti\u2010leishmanial drugs. Screening of an in\u2010house compound library identified the hexahydrophthalazinone NPD\u20102942 as a low micromolar hit with a pIC<jats:sub>50<\/jats:sub> of 5.8 against <jats:italic>L. infantum<\/jats:italic> and a pIC<jats:sub>50<\/jats:sub> of 4.6 for cytotoxicity against human MRC\u20105 fibroblasts. To derive structure\u2013activity relationships, we modified the cyclohexyl ring of the hexahydrophthalazinone scaffold and 1,2,3\u2010triazoles were attempted as replacement for the pyrazole ring, amongst others. Ultimately, the 2,3\u2010pyrazole\u2010substituted hexahydrophthalazinone NPD\u20101289 was identified as the most potent analogue in this series with a pIC<jats:sub>50<\/jats:sub> of 6.3, although some cytotoxicity toward MRC\u20105 cells (pIC<jats:sub>50<\/jats:sub>=5.1) was recorded as well. Replacement of the unsubstituted 2,3\u2010pyrazole with 1,2,3\u2010triazoles led to compounds with lower anti\u2010leishmanial activity. The current scaffold is a valuable new starting point for optimization toward novel anti\u2010leishmanial drugs.<\/jats:p>","DOI":"10.1002\/cmdc.201900538","type":"journal-article","created":{"date-parts":[[2019,11,22]],"date-time":"2019-11-22T15:11:27Z","timestamp":1574435487000},"page":"219-227","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Identification of Phenylphthalazinones as a New Class of <i>Leishmania infantum<\/i> Inhibitors"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9104-8485","authenticated-orcid":false,"given":"Maarten","family":"Sijm","sequence":"first","affiliation":[{"name":"Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS) Vrije Universiteit Amsterdam  De Boelelaan 1108 1081 HZ Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erik","family":"de Heuvel","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS) Vrije Universiteit Amsterdam  De Boelelaan 1108 1081 HZ Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"An","family":"Matheeussen","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology, Parasitology and Hygiene (LMPH) University of Antwerp  Universiteitsplein 1 2610 Antwerpen Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guy","family":"Caljon","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology, Parasitology and Hygiene (LMPH) University of Antwerp  Universiteitsplein 1 2610 Antwerpen Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louis","family":"Maes","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology, Parasitology and Hygiene (LMPH) University of Antwerp  Universiteitsplein 1 2610 Antwerpen Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geert\u2010Jan","family":"Sterk","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS) Vrije Universiteit Amsterdam  De Boelelaan 1108 1081 HZ Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iwan J. 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