title: Potent antimicrobial agents against azole-resistant fungi based on pyridinohydrazide and hydrazomethylpyridine structural motifs.
abstract: Schiff base derivatives have recently been shown to possess antimicrobial activity, and these derivatives include a limited number of salicylaldehyde hydrazones. To further explore this structure-activity relationship between salicylaldehyde hydrazones and antifungal activity, we previously synthesized and analyzed a large series of salicylaldehyde and formylpyridinetrione hydrazones for their ability to inhibit fungal growth of both azole-susceptible and azole-resistant species of Candida. While many of these analogs showed excellent growth inhibition with low mammalian cell toxicity, their activity did not extend to azole-resistant species of Candida. To further dissect the structural features necessary to inhibit azole-resistant fungal species, we synthesized a new class of modified salicylaldehyde derivatives and subsequently identified a series of modified pyridine-based hydrazones that had potent fungicidal antifungal activity against multiple Candida spp. Here we would like to present our synthetic procedures as well as the results from fungal growth inhibition assays, mammalian cell toxicity assays, time-kill assays and synergy studies of these novel pyridine-based hydrazones on both azole-susceptible and azole-resistant fungal species.
authors.affiliation: Louisiana State University Health Sciences Center, Department of Pharmacology and Experimental Therapeutics, 1901 Perdido St., New Orleans, LA 70112, United States.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Backes
authors.affiliation: Department of Chemistry, University of New Orleans, New Orleans, LA 70148, United States; STEPHARM, LLC., PO Box 24220, New Orleans, LA 70184, United States.
authors.forename: Branko S
authors.initials: BS
authors.lastname: Jursic
authors.affiliation: Louisiana State University Health Sciences Center, Department of Pharmacology and Experimental Therapeutics, 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
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001393:Azoles / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects* / Q000254:growth & development; D041221:Candida glabrata / Q000187:drug effects* / Q000254:growth & development; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D025141:Drug Resistance, Fungal; D056945:Hep G2 Cells; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D006834:Hydrazines; D011725:Pyridines
keywords: Antifungals; Fungal infections; Schiff base derivatives; Triazole resistant; Yeasts