Fungal infections remain a critical unmet medical need with millions of infections occurring annually. With only three classes of antifungal drugs available, drug resistance and modest activity toward some fungi represent threats to human health. To address this, optimization of the antifungal properties of approved drugs with appropriate pharmacokinetic properties represents an attractive strategy. Here, we have shown that the antifungal activity of phenothiazine-based extends to include fluconazole-resistant , , and , filamentous molds such as , spp., and , endemic human fungal pathogens , , and spp. Thus, phenothiazines (PTZs) have consistent antifungal activity toward a broad range of medically relevant fungi, including organisms that range from difficult to nearly impossible to treat with current drugs. Unfortunately, did not exhibit in vivo efficacy in either or mouse infection models, necessitating an effort to optimize the scaffold further. Toward this end, synthesis and minimum inhibitory concentration (MIC) values are reported for 15 novel PTZ analogs to extend structure-activity relationships (SARs). Six analogs were identified as 2- to 4-fold more potent. Azaphenothiazines (aza-PTZs) were tolerated and resulted in potent antifungals with moderate reduction in lipophilicity and more facile chemical synthesis. One analog displayed modest selectivity improvement against the serotonin 5HT receptor versus , but its overall selectivity profile versus a panel of other serotonin and dopamine receptors did not improve. Overall, the broad-spectrum antifungal activity and reduced neuroreceptor affinity of PTZ-based analogs encourages continued optimization to develop a novel antifungal therapeutic drug.