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

0563879 - MBÚ 2023 RIV DE eng J - Článek v odborném periodiku
Štěpánek, O. - Čmoková, Adéla - Procházková, Eliška - Grobárová, V. - Černý, J. - Slapničková, Martina - Zíková, Alena - Kolařík, Miroslav - Baszczyňski, O.
Piperazine-Modified Ketoconazole Derivatives Show Increased Activity against Fungal and Trypanosomatid Pathogens.
ChemMedChem. Roč. 17, č. 21 (2022), č. článku e202200385. ISSN 1860-7179. E-ISSN 1860-7187
Grant CEP: GA ČR(CZ) GA19-07707S; GA MZd(CZ) NU21-05-00681; GA MŠMT(CZ) EF16_019/0000759
Grant ostatní: AV ČR JFS20ST-127; AV ČR JFS20ST-127
Program: SEA-Europe JFS; SEA-Europe JFS
Institucionální podpora: RVO:61388971 ; RVO:61388963 ; RVO:60077344
Klíčová slova: Ketoconazole * Antifungal agents * Aspergillus * Trypanosoma
Obor OECD: Microbiology; Analytical chemistry (UOCHB-X); Organic chemistry (BC-A)
Impakt faktor: 3.4, rok: 2022
Způsob publikování: Omezený přístup
https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202200385

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.
Trvalý link: https://hdl.handle.net/11104/0335666