title: Synthesis and antifungal activity of substituted 2,4,6-pyrimidinetrione carbaldehyde hydrazones.
abstract: Opportunistic fungal infections caused by the Candida spp. are the most common human fungal infections, often resulting in severe systemic infections-a significant cause of morbidity and mortality in at-risk populations. Azole antifungals remain the mainstay of antifungal treatment for candidiasis, however development of clinical resistance to azoles by Candida spp. limits the drugs' efficacy and highlights the need for discovery of novel therapeutics. Recently, it has been reported that simple hydrazone derivatives have the capability to potentiate antifungal activities in vitro. Similarly, pyrimidinetrione analogs have long been explored by medicinal chemists as potential therapeutics, with more recent focus being on the potential for pyrimidinetrione antimicrobial activity. In this work, we present the synthesis of a class of novel hydrazone-pyrimidinetrione analogs using novel synthetic procedures. In addition, structure-activity relationship studies focusing on fungal growth inhibition were also performed against two clinically significant fungal pathogens. A number of derivatives, including phenylhydrazones of 5-acylpyrimidinetrione exhibited potent growth inhibition at or below 10μM with minimal mammalian cell toxicity. In addition, in vitro studies aimed at defining the mechanism of action of the most active analogs provide preliminary evidence that these compound decrease energy production and fungal cell respiration, making this class of analogs promising novel therapies, as they target pathways not targeted by currently available antifungals.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido St., New Orleans, LA 70112, United States; Department of Ophthalmology, LSUHSC, New Orleans, United States. Electronic address: dneum1@lsuhsc.edu.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Neumann
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido St., New Orleans, LA 70112, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Cammarata
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido St., New Orleans, LA 70112, United States.
authors.forename: Gregory
authors.initials: G
authors.lastname: Backes
authors.affiliation: Department of Microbiology, Immunology and Parasitology, LSUHSC-New Orleans, United States.
authors.forename: Glen E
authors.initials: GE
authors.lastname: Palmer
authors.affiliation: Department of Chemistry, University of New Orleans, New Orleans, LA 70148, United States; STEPHARM, LLC., P.O. Box 24220, New Orleans, LA 70184, United States.
authors.forename: Branko S
authors.initials: BS
authors.lastname: Jursic
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002175:Candida / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D056945:Hep G2 Cells; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014709:Vero Cells / Q000166:cytology / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D006835:Hydrazones; D011744:Pyrimidinones
keywords: Antifungal; Carbaldehyde; Hydrazine; Hydrazones; Pyrimidinetrione