Synthesis and evaluation of thiophene-based guanylhydrazones (iminoguanidines) efficient against panel of voriconazole-resistant fungal isolates

Abstract

A series of new thiophene-based guanylhydrazones (iminoguanidines) were synthesized in high yields using a straightforward two-step procedure. The antifungal activity of compounds was evaluated against a wide range of medicaly important fungal strains including yeasts, molds, and dermatophytes in comparison to clinically used drug voriconazole. Cytotoxic properties of compounds were also determined using human lung fibroblast cell line and hemolysis assay. All guanylhydrazones showed significant activity against broad spectrum of clinically important species of Candida spp., Aspergillus fumigatus, Fusarium oxysporum, Microsporum canis and Trichophyton mentagrophytes, which was in some cases comparable or better than activity of voriconazole. More importantly, compounds 10, 11, 13, 14, 18 and 21 exhibited excellent activity against voriconazole-resistant Candida albicans CA5 with very low minimal inhibitory concentration (MIC) values <2 μg mL(-1). Derivative 14, bearing bromine on the phenyl ring, was the most effective compound with MICs ranging from 0.25 to 6.25 μg mL(-1). However, bis-guanylhydrazone 18 showed better selectivity in terms of therapeutic index values. In vivo embryotoxicity on zebrafish (Danio rerio) showed improved toxicity profile of 11, 14 and 18 in comparison to that of voriconazole. Most guanylhydrazones also inhibited C. albicans yeast to hyphal transition, essential for its biofilm formation, while 11 and 18 were able to disperse preformed Candida biofilms. All guanylhydrazones showed the equal potential to interact with genomic DNA of C. albicans in vitro, thus indicating a possible mechanism of their action, as well as possible mechanism of observed cytotoxic effects. Tested compounds did not have significant hemolytic effect and caused low liposome leakage, which excluded the cell membrane as a primary target. On the basis of computational docking experiments using both human and cytochrome P450 from Candida it was concluded that the most active guanylhydrazones had minimal structural prerequisites to interact with the cytochrome P450 14α-demethylase (CYP51). Promising guanylhydrazone derivatives also showed satisfactory pharmacokinetic profile based on molecular calculations.

Aromatic Guanylhydrazones for the Control of Heme-Induced Antibody Polyreactivity

“…Previous studies have demonstrated that this class of compounds is moderately toxic. 25 Here, the antiproliferative activity of two most potent inhibitors was tested on human lung fibroblasts by the MTT assay. The concentration of the compound inhibiting cell growth by 50% (IC 50 ) was 6.8 μM for compound 3 , and 8.4 μM for compound 4 .…”

Synthesis and anti‐Candida activity of novel benzothiepino[3,2‐c]pyridine derivatives

“…The sheep red blood cells and thiepines were co‐incubated in buffer at physiologic pH whereby erythrocyte membrane served as a model for the lipid bilayer. The percent of red blood cell disruption was quantified relative to positive control samples lysed with a Triton‐X detergent as described previously . Low hemolysis of up to 10% at physiologic pH (7.4) was observed using 4 , 16 , and VOR at determined C. albicans MIC concentrations (Figure A).…”

Copper(II) and Zinc(II) Complexes with the Clinically Used Fluconazole: Comparison of Antifungal Activity and Therapeutic Potential

“…The highest concentration used was 200 µg/mL. Candida strains used in this study included: Candida albicans ATCC 10231, C. parapsilosis ATCC 22019, C. krusei ATCC 6258, and clinical isolates from veterinary and human samples C. albicans 1c, C. albicans 1f [67], C. albicans 11, C. albicans 13 [68] and recombinant C. albicans SC5314 RFP and C. albicans SC5314 GFP [69]. For the MIC assessment, the inoculums were 1 × 10 5 colony forming units (cfu)/mL.…”