biostudies-literatureDonlin MJNational Institute of Neurological Disorders and StrokeNational Institute of Allergy and Infectious DiseasesNIAID NIH HHSSaint Louis UniversityNINDS NIH HHSNational Institute of General Medical SciencesNIGMS NIH HHS774-781https://www.ebi.ac.uk/biostudies/studies/S-EPMC8155264biostudies-literatureUnknown12(5)Opportunistic infections from pathogenic fungi present a major challenge to healthcare because of a very limited arsenal of antifungal drugs, an increasing population of immunosuppressed patients, and increased prevalence of resistant clinical strains due to overuse of the few available antifungals. Cryptococcal meningitis is a life-threatening opportunistic fungal infection caused by one of two species in the <i>Cryptococcus</i> genus, <i>Cryptococcus neoformans</i> and <i>Cryptococcus gattii</i>. Eighty percent of cryptococcosis diseases are caused by <i>C. neoformans</i> that is endemic in the environment. The standard of care is limited to old antifungals, and under a high standard of care, mortality remains between 10 and 30%. We have identified a series of 5-nitro-6-thiocyanatopyrimidine antifungal drug candidates using <i>in vitro</i> and computational machine learning approaches. These compounds can inhibit <i>C. neoformans</i> growth at submicromolar levels, are effective against fluconazole-resistant <i>C. neoformans</i> and a clinical strain of <i>C. gattii</i>, and are not antagonistic with currently approved antifungals.ACS medicinal chemistry lettersDiscovery of 5-Nitro-6-thiocyanatopyrimidines as Inhibitors of <i>Cryptococcus neoformans</i> and <i>Cryptococcus gattii</i>.PMC8155264R01 AI123407R01 NS102164R44GM122196-02A11R01NS102164-01R44 GM122196R01AI123407Riabova OEkins SMakarov VLepioshkin AXu ELin JDonlin MJLane TRfalseDiscovery of 5-Nitro-6-thiocyanatopyrimidines as Inhibitors of <i>Cryptococcus neoformans</i> and <i>Cryptococcus gattii</i>.Opportunistic infections from pathogenic fungi present a major challenge to healthcare because of a very limited arsenal of antifungal drugs, an increasing population of immunosuppressed patients, and increased prevalence of resistant clinical strains due to overuse of the few available antifungals. Cryptococcal meningitis is a life-threatening opportunistic fungal infection caused by one of two species in the <i>Cryptococcus</i> genus, <i>Cryptococcus neoformans</i> and <i>Cryptococcus gattii</i>. Eighty percent of cryptococcosis diseases are caused by <i>C. neoformans</i> that is endemic in the environment. The standard of care is limited to old antifungals, and under a high standard of care, mortality remains between 10 and 30%. We have identified a series of 5-nitro-6-thiocyanatopyrimidine antifungal drug candidates using <i>in vitro</i> and computational machine learning approaches. These compounds can inhibit <i>C. neoformans</i> growth at submicromolar levels, are effective against fluconazole-resistant <i>C. neoformans</i> and a clinical strain of <i>C. gattii</i>, and are not antagonistic with currently approved antifungals.2021-01-01T00:00:00Z2021 May2025-04-04T20:15:48.371Z2025-04-04T20:15:48.371ZS-EPMC81552643405522510.1021/acsmedchemlett.1c00038