Antifungal Drugs Discovered Through Synthetic Chemistry and Introduced for Human Use from 1895 to September 2026

Fungal diseases range from common superficial infections to life-threatening invasive mycoses, yet treatment options remain constrained by host toxicity, drug interactions, pharmacokinetic limitations and antifungal resistance. This review provides a historical and chemical account of 70 synthetic antifungal therapeutic entities, including mixtures and fixed-dose combinations, introduced or approved for human use from approximately 1895 to September 2026. These entities are organised into 19 structural classes, including hydroxyquinolines, diamidines, azoles, thiocarbamates, hydroxypyridones, benzylamines, morpholines and oxaboroles. Azoles constitute the largest class, comprising 31 agents across four subclasses: one benzimidazole, 20 imidazoles, nine triazoles and one tetrazole. For each entity, we summarise its first documented introduction or approval, clinical indications, routes of administration, use status, mode(s) of action, resistance mechanisms and relevant medicinal-chemistry context. Early synthetic antifungals were predominantly topical antiseptics used for dermatological or mucosal infections. Subsequent development delivered oral and intravenous agents suitable for systemic and invasive mycoses. From 1970 onwards, azoles predominated, accounting for 30 of the 43 synthetic entities first introduced or approved for human use. Broad-spectrum activity and the availability of oral and, for selected agents, intravenous formulations transformed antifungal therapy; however, the widespread use of azoles also concentrated treatment around inhibition of fungal ergosterol biosynthesis. Many early agents are classified as discontinued, whereas azoles and selected mechanistically distinct classes remain clinically important. This review highlights the enduring contribution of synthetic medicinal chemistry to antifungal therapy and the continuing need for safer agents with new chemical scaffolds and fungal targets, reliable exposure at sites of infection and reduced vulnerability to resistance.