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ACS Infect Dis. 2018 Apr 13;4(4):499-507. doi: 10.1021/acsinfecdis.7b00157. Epub 2017 Nov 2.

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

Author information

1
Clinical and Translational Science Institute , University of Rochester School of Medicine and Dentistry , 601 Elmwood Avenue , Rochester , New York 14642 , United States.
2
Department of Pediatrics , University of Rochester School of Medicine and Dentistry , 601 Elmwood Avenue , Rochester , New York 14642 , United States.
3
Department of Pharmacology and Physiology , Saint Louis University School of Medicine , 1402 South Grand Blvd. , St. Louis , Missouri 63104 , United States.
4
Department of Chemistry , Saint Louis University , 1402 South Grand Blvd. , St. Louis , Missouri 63104 , United States.
5
Department of Microbiology and Immunology , University of Rochester School of Medicine and Dentistry , 601 Elmwood Avenue , Rochester , New York 14642 , United States.

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.

KEYWORDS:

Candida; Cryptococcus neoformans; antifungal; phenothiazine; repurposing

PMID:
29058407
DOI:
10.1021/acsinfecdis.7b00157
[Indexed for MEDLINE]

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