Marhiah C. Montoya, Louis DiDone, Richard F. Heier, Marvin J. Meyers, Damian J. Krysan

New classes of antifungal drugs are an urgent un-met clinical need. One approach to the challenge of developing new antifungal drugs is to optimize the antifungal properties of currently used drugs with favorable pharmacologic properties, so-called drug or scaffold repurposing. New therapies for cryptococcal meningitis are particularly important given its world-wide burden of disease and limited therapeutic options. We report the first systematic structure-activity study of the anti-cryptococcal properties of the phenothiazines. We also show that the antifungal activity of the phenothiazine scaffold correlates well with its calmodulin antagonism properties and, thereby, provides the first insights into the mechanism of its antifungal properties. Guided by this mechanism, we have generated improved trifluoperazine derivatives with increased anti-cryptococcal activity and, importantly, reduced affinity for receptors that modulate undesired neurological effects. Taken together, these data suggest that phenothiazines represent a potentially useful scaffold for further optimization in the search for new antifungal drugs.