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

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

doi:10.1021/acsinfecdis.7b00157

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Journal article

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

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

ACS infectious diseases, Vol.4(4), pp.499-507

04/13/2018

DOI: 10.1021/acsinfecdis.7b00157

PMID: 29058407

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https://www.ncbi.nlm.nih.gov/pmc/articles/8994671View

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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.

Antifungal Agents - pharmacology

Antifungal Agents - chemistry

Structure-Activity Relationship

Antipsychotic Agents - chemical synthesis

Cryptococcus neoformans - drug effects

Microbial Sensitivity Tests

Phenothiazines - chemical synthesis

Antipsychotic Agents - chemistry

Candida albicans - drug effects

Phenothiazines - chemistry

Phenothiazines - pharmacology

Drug Repositioning - methods

Inhibitory Concentration 50

Molecular Structure

Sensory Receptor Cells - metabolism

Antipsychotic Agents - pharmacology

Details

Title: Subtitle: Antifungal Phenothiazines: Optimization, Characterization of Mechanism, and Modulation of Neuroreceptor Activity
Creators: Marhiah C Montoya - Clinical and Translational Science Institute , University of Rochester School of Medicine and Dentistry , 601 Elmwood Avenue , Rochester , New York 14642 , United States
Louis DiDone - Department of Pediatrics , University of Rochester School of Medicine and Dentistry , 601 Elmwood Avenue , Rochester , New York 14642 , United States
Richard F Heier - Department of Pharmacology and Physiology , Saint Louis University School of Medicine , 1402 South Grand Blvd. , St. Louis , Missouri 63104 , United States
Marvin J Meyers - Department of Chemistry , Saint Louis University , 1402 South Grand Blvd. , St. Louis , Missouri 63104 , United States
Damian J Krysan - Department of Microbiology and Immunology , University of Rochester School of Medicine and Dentistry , 601 Elmwood Avenue , Rochester , New York 14642 , United States
Resource Type: Journal article
Publication Details: ACS infectious diseases, Vol.4(4), pp.499-507
DOI: 10.1021/acsinfecdis.7b00157
PMID: 29058407
NLM abbreviation: ACS Infect Dis
ISSN: 2373-8227
eISSN: 2373-8227
Grant note: DOI: 10.13039/100000060, name: National Institute of Allergy and Infectious Diseases, award: 1R01AI097142, R21AI125094
Language: English
Date published: 04/13/2018
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
Record Identifier: 9984093223502771

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