Antifungal Phenothiazines: Optimization, Characterization of Mechanism, and Modulation of Neuroreceptor Activity

Abstract

New classes of antifungal drugs are an urgent unmet 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 worldwide burden of disease and limited therapeutic options. We report the first systematic structure-activity study of the anticryptococcal 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 anticryptococcal 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.

Docusate-Based Ionic Liquids of Anthelmintic Benzimidazoles Show Improved Pharmaceutical Processability, Lipid Solubility, and in Vitro Activity against Cryptococcus neoformans

“…The majority of these cases are seen in patients with HIV/AIDS. Furthermore, mortality associated with CM shows a health disparity with a mortality rate of only 20% in developed countries and 40% in middle-income countries but 70% in low-income countries in sub-Saharan Africa. − …”

Development of Phenothiazine Hybrids with Potential Medicinal Interest: A Review

“…It was further demonstrated that the hybrid 62 led to an additive inhibition with fluconazole (2-fold reduction) against C. albicans with mutations in its efflux pump, which makes the strain more resistant to fluconazole. Antagonism of calmodulin by the phenothiazine scaffold correlates well with its antifungal activity [ 84 ].…”

S100 proteins as therapeutic targets

“…Notably, the architectures of the TFP-binding pockets, the number of bound TFP molecules, and the orientation of the TFP molecules are quite different between S100A4, troponin C, and calmodulin (Cook et al 1994;Feldkamp et al 2015;Malashkevich et al 2010;Vandonselaar et al 1994;Vertessy et al 1998). Given the differences in TFP-binding modes and the large number of phenothiazine derivatives that are available, it may be possible to selectively target these proteins with appropriate phenothiazine analogs (Brem et al 2017;Montoya et al 2018;Pluta et al 2017).…”