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However, as a systemic antifungal, KTZ\u2032 efficacy and safety no longer justify its use as a first\u2010line treatment. Azole conjugates often display higher solubility and better antifungal activities than their parent azoles. Accordingly, we aimed at developing suitable linkers for clickable azole conjugation with a second antifungal molecule, and targeted drug delivery towards improving antifungal activity. For its low price and high availability, we selected KTZ as a molecular scaffold to introduce such chemical modifications. We prepared a series of piperazine\u2010modified KTZ derivatives and we evaluated their <jats:italic>in\u2005vitro<\/jats:italic> antifungal and antitrypanosomal activity against fourteen strains of pathogenic fungi and two strains of <jats:italic>Trypanosoma<\/jats:italic> parasites. Several compounds were more effective against the pathogens than KTZ. Compound <jats:bold>5<\/jats:bold> was 24\u2005times more potent against <jats:italic>Aspergillus flavus<\/jats:italic> and 8\u2005times more potent against <jats:italic>A. fumigatus<\/jats:italic> than KTZ, with similarly low cytotoxicity to HEK cells up to 100\u2005\u03bcM. Derivative <jats:bold>6<\/jats:bold> had 9\u2010 and 7\u2010fold higher activity against <jats:italic>T. brucei gambiense<\/jats:italic> and <jats:italic>T. brucei brucei<\/jats:italic> than KTZ, respectively, and inhibited trypanosoma growth at single micromolar EC<jats:sub>50<\/jats:sub> values. Combined, our findings will foster further research of piperazine\u2010modified KTZs as promising antifungal and antiparasitic drugs towards enhancing the properties of both KTZ and other azole derivatives.<\/jats:p>","DOI":"10.1002\/cmdc.202200385","type":"journal-article","created":{"date-parts":[[2022,9,17]],"date-time":"2022-09-17T13:13:18Z","timestamp":1663420398000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Piperazine\u2010Modified Ketoconazole Derivatives Show Increased Activity against Fungal and Trypanosomatid Pathogens"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0195-0003","authenticated-orcid":false,"given":"Ond\u0159ej","family":"\u0160t\u011bp\u00e1nek","sequence":"first","affiliation":[{"name":"Department of Organic Chemistry Faculty of Science Charles University  Hlavova 2030\/8 128 43 Prague Czech 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