2. Academic Validation
  3. Synthesis of a New Purine Analogue Class with Antifungal Activity and Improved Potency against Fungal IP3-4K

Synthesis of a New Purine Analogue Class with Antifungal Activity and Improved Potency against Fungal IP3-4K

  • ACS Infect Dis. 2025 Apr 11;11(4):940-953. doi: 10.1021/acsinfecdis.4c00975.
Desmarini Desmarini 1 2,  Daniel Truong 3,  Pooja Sethiya 1 2,  Guizhen Liu 4 5,  Bethany Bowring 1 2,  Henning Jessen 4 5,  Hue Dinh 6,  Amy K Cain 6,  Philip E Thompson 3,  Julianne T Djordjevic 1 2 7
Affiliations

Affiliations

  • 1 Centre for Infectious Diseases and Microbiology, Westmead Institute for Medical Research, Westmead, NSW 2145, Australia.
  • 2 Sydney Institute for Infectious Diseases, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia.
  • 3 Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
  • 4 Institute of Organic Chemistry, University of Freiburg, Albertstrasse 21, 79104 Freiburg i.B, Germany.
  • 5 CIBSS-Centre for Integrative Biological Signaling Studies, University of Freiburg, Schänzlestraße 18, 79104 Freiburg im Breisgau, Germany.
  • 6 ARC Centre of Excellence in Synthetic Biology, School of Natural Sciences, Macquarie University, North Ryde, NSW 2019, Australia.
  • 7 Westmead Hospital, Westmead, NSW 2145, Australia.
PMID: 40164150 DOI: 10.1021/acsinfecdis.4c00975
Abstract

New antifungals are urgently needed to treat deadly Fungal infections. Targeting the Fungal inositol polyphosphate kinases IP3-4K (Arg1) and IP6K (Kcs1) is a promising strategy as it has been validated genetically to be crucial for Fungal virulence but never pharmacologically. We now report the synthesis of DT-23, an analogue of N2-(m-trifluorobenzylamino)-N6-(p-nitrobenzylamino)purine (TNP), and demonstrate that it more potently inhibits recombinant Arg1 from the priority pathogen Cryptococcus neoformans (Cn) (IC50 = 0.6 μM) than previous analogues (IC50 = 10-30 μM). DT-23 also inhibits recombinant Kcs1 with similar potency (IC50 = 0.68 μM) and Arg1 and Kcs1 activity in vivo. Unlike previous analogues, DT-23 inhibits Fungal growth (MIC50 = 15 μg/mL) and only 1.5 μg/mL synergizes with Amphotericin B to kill Cn in vitro. DT-23/Amphotericin B is also more protective against Cn Infection in an insect model compared to each drug alone. Transcription profiling shows that DT-23 impacts early stages in IP synthesis and cellular functions impacted by IPK gene deletion, consistent with its targeted effect. This study establishes the first pharmacological link between inhibiting IPK activity and Antifungal activity, providing tools for studying IPK function and a foundation to potentially develop a new class of Antifungal drug.

Keywords

Cryptococcus neoformans; IP3K; IP6K; antifungal drug; inositol polyphosphate kinase; purine analogue.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-173452
    Antifungal Agent