We identified a new series of azole antifungal agents bearing a pyrrolotriazinone scaffold. These compounds exhibited a broad in vitro antifungal activity against pathogenic Candida spp. (fluconazole-susceptible and fluconazole-resistant) and were 10- to 100-fold more active than voriconazole against two Candida albicans isolates with known mechanisms of azole resistance (overexpression of efflux pumps and/or specific point substitutions in the Erg11p/CYP51 enzyme). Our lead compound 12 also displayed promising in vitro antifungal activity against some filamentous fungi such as Aspergillus fumigatus and the zygomycetes Rhizopus oryzae and Mucor circinelloides and an in vivo efficiency against two murine models of lethal systemic infections caused by Candida albicans. Display omitted •New triazole antifungal agents with a pyrrolotriazinone scaffold (lead compound 12).•In vitro antifungal activity against Candidaspp. and filamentous fungi (A. fumigatus and some zygomycetes).•In vivo antifungal efficiency in two lethal systemic infections caused by C. albicans (FLC- and VOR-resistant).