2. Academic Validation
  3. Targeting yeast topoisomerase II by imidazo and triazoloacridinone derivatives resulting in their antifungal activity

Targeting yeast topoisomerase II by imidazo and triazoloacridinone derivatives resulting in their antifungal activity

  • Sci Rep. 2024 Feb 13;14(1):3594. doi: 10.1038/s41598-024-54252-0.
Kamila Rząd 1,  Iwona Gabriel 2,  Ewa Paluszkiewicz 2,  Aleksandra Kuplińska 2,  Mateusz Olszewski 2,  Agnieszka Chylewska 3,  Aleksandra M Dąbrowska 3,  Katarzyna Kozłowska-Tylingo 2
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry and BioTechMed Center, Gdansk University of Technology, 11/12 Narutowicza Str., 80-233, Gdansk, Poland. [email protected].
  • 2 Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry and BioTechMed Center, Gdansk University of Technology, 11/12 Narutowicza Str., 80-233, Gdansk, Poland.
  • 3 Department of Bioinorganic Chemistry, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308, Gdansk, Poland.
PMID: 38351313 DOI: 10.1038/s41598-024-54252-0
Abstract

Fungal pathogens are considered as serious factors for deadly diseases and are a case of medical concern. Invasive Fungal infections also complicate the clinical course of COVID-19, leading to a significant increase in mortality. Furthermore, Fungal strains' multidrug resistance has increased the demand for antifungals with a different mechanism of action. The present study aimed to identify Antifungal compounds targeting yeast Topoisomerase II (yTOPOII) derived from well-known human Topoisomerase II (hTOPOII) poisons C-1305 and C-1311. Two sets of derivatives: triazoloacridinones (IKE1-8) and imidazoacridinones (IKE9-14) were synthetized and evaluated with a specific emphasis on the molecular mechanism of action. Our results indicated that their effectiveness as Enzyme inhibitors was not solely due to intercalation ability but also as a result of influence on catalytic activity by the formation of covalent complexes between plasmid DNA and yTOPOII. Lysine conjunction increased the strength of the compound's interaction with DNA and improved penetration into the Fungal cells. Triazoloacridinone derivatives in contrast to starting compound C-1305 exhibited moderate Antifungal activity and at least twice lower cytotoxicity. Importantly, compounds (IKE5-8) were not substrates for multidrug ABC transporters whereas a derivative conjugated with lysine (IKE7), showed the ability to overcome C. glabrata fluconazole-resistance (MIC 32-64 µg mL-1).

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