biostudies-literatureDesmarini DNSW HealthVolkswagen FoundationDeutsche ForschungsgemeinschaftNational Health and Medical Research CouncilUniversity of SydneyAustralian Research Council940-953https://www.ebi.ac.uk/biostudies/studies/S-EPMC11997995biostudies-literatureUnknown11(4)New antifungals are urgently needed to treat deadly fungal infections. Targeting the fungal inositol polyphosphate kinases IP<sub>3-4</sub>K (Arg1) and IP<sub>6</sub>K (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 <b>DT-23</b>, an analogue of <i>N</i>2-(<i>m</i>-trifluorobenzylamino)-<i>N</i>6-(<i>p</i>-nitrobenzylamino)purine (<b>TNP</b>), and demonstrate that it more potently inhibits recombinant Arg1 from the priority pathogen <i>Cryptococcus neoformans</i> (<i>Cn</i>) (IC<sub>50</sub> = 0.6 μM) than previous analogues (IC<sub>50</sub> = 10-30 μM). <b>DT-23</b> also inhibits recombinant Kcs1 with similar potency (IC<sub>50</sub> = 0.68 μM) and Arg1 and Kcs1 activity <i>inACS infectious diseasesSynthesis of a New Purine Analogue Class with Antifungal Activity and Improved Potency against Fungal IP<sub>3-4</sub>K.PMC11997995APP1183939FT220100152APP105877998604390939984Jessen HDinh HThompson PECain AKDjordjevic JTTruong DSethiya PDesmarini DBowring BLiu GfalseSynthesis of a New Purine Analogue Class with Antifungal Activity and Improved Potency against Fungal IP<sub>3-4</sub>K.New antifungals are urgently needed to treat deadly fungal infections. Targeting the fungal inositol polyphosphate kinases IP<sub>3-4</sub>K (Arg1) and IP<sub>6</sub>K (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 <b>DT-23</b>, an analogue of <i>N</i>2-(<i>m</i>-trifluorobenzylamino)-<i>N</i>6-(<i>p</i>-nitrobenzylamino)purine (<b>TNP</b>), and demonstrate that it more potently inhibits recombinant Arg1 from the priority pathogen <i>Cryptococcus neoformans</i> (<i>Cn</i>) (IC<sub>50</sub> = 0.6 μM) than previous analogues (IC<sub>50</sub> = 10-30 μM). <b>DT-23</b> also inhibits recombinant Kcs1 with similar potency (IC<sub>50</sub> = 0.68 μM) and Arg1 and Kcs1 activity <i>in2025-01-01T00:00:00Z2025 Apr2026-06-02T04:31:00.822Z2026-04-14T03:13:25.901ZS-EPMC119979954016415010.1021/acsinfecdis.4c00975