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Piperazine-Modified Ketoconazole Derivatives Show Increased Activity against Fungal and Trypanosomatid Pathogens

The result's identifiers

  • Result code in IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60077344%3A_____%2F22%3A00563879" target="_blank" >RIV/60077344:_____/22:00563879 - isvavai.cz</a>

  • Alternative codes found

    RIV/61388971:_____/22:00563879 RIV/61388963:_____/22:00563879 RIV/00216208:11310/22:10451252

  • Result on the web

    <a href="https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202200385" target="_blank" >https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202200385</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1002/cmdc.202200385" target="_blank" >10.1002/cmdc.202200385</a>

Alternative languages

  • Result language

    angličtina

  • Original language name

    Piperazine-Modified Ketoconazole Derivatives Show Increased Activity against Fungal and Trypanosomatid Pathogens

  • Original language description

    Ketoconazole (KTZ) is an imidazole drug applied topically to treat numerous skin infections. However, as a systemic antifungal, KTZ ' efficacy and safety no longer justify its use as a first-line 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-modified KTZ derivatives and we evaluated their in vitro antifungal and antitrypanosomal activity against fourteen strains of pathogenic fungi and two strains of Trypanosoma parasites. Several compounds were more effective against the pathogens than KTZ. Compound 5 was 24 times more potent against Aspergillus flavus and 8 times more potent against A. fumigatus than KTZ, with similarly low cytotoxicity to HEK cells up to 100 mu M. Derivative 6 had 9- and 7-fold higher activity against T. brucei gambiense and T. brucei brucei than KTZ, respectively, and inhibited trypanosoma growth at single micromolar EC50 values. Combined, our findings will foster further research of piperazine-modified KTZs as promising antifungal and antiparasitic drugs towards enhancing the properties of both KTZ and other azole derivatives.

  • Czech name

  • Czech description

Classification

  • Type

    J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database

  • CEP classification

  • OECD FORD branch

    10401 - Organic chemistry

Result continuities

  • Project

    Result was created during the realization of more than one project. More information in the Projects tab.

  • Continuities

    I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Others

  • Publication year

    2022

  • Confidentiality

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Data specific for result type

  • Name of the periodical

    ChemMedChem

  • ISSN

    1860-7179

  • e-ISSN

    1860-7187

  • Volume of the periodical

    17

  • Issue of the periodical within the volume

    21

  • Country of publishing house

    DE - GERMANY

  • Number of pages

    14

  • Pages from-to

    e202200385

  • UT code for WoS article

    000861544000001

  • EID of the result in the Scopus database

    2-s2.0-85138932580