From Antidiabetic to Antifungal: Discovery of Highly Potent Triazole–Thiazolidinedione Hybrids as Novel Antifungal Agents

Abstract

In an attempt to discover a new generation of triazole antifungal agents, a series of triazole-thiazolidinedione hybrids were designed and synthesized by molecular hybridization of the antifungal agent fluconazole and rosiglitazone (an antidiabetic). Most of the target compounds showed good to excellent inhibitory activity against a variety of clinically important fungal pathogens. In particular, compounds (Z)-5-(2,4-dichlorobenzylidene)-3-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)thiazolidine-2,4-dione) (15 c), (Z)-3-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-5-(furan-3-ylmethylene)thiazolidine-2,4-dione (15 j), and (Z)-3-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-5-(furan-3-ylmethylene)thiazolidine-2,4-dione (15 r) were highly active against Candida albicans, with MIC80 values in the range of 0.03-0.15 μM. Moreover, compounds 15 j and 15 r were found to be effective against four fluconazole-resistant clinical isolates; these two compounds are particularly promising antifungal leads for further optimization. Molecular docking studies revealed that the hydrogen bonding interactions between thiazolidinedione and CYP51 from C. albicans are important for antifungal activity. This study also demonstrates the effectiveness of molecular hybridization in antifungal drug discovery.

3,5-Disubstituted Thiazolidine-2,4-Diones: Design, Microwave-Assisted Synthesis, Antifungal Activity, and ADMET Screening

“…Heterocyclic compounds containing nitrogen, oxygen, and sulfur atoms are known for exhibiting a wide spectrum of pharmacological activities. [1][2][3][4][5] Since the anticonvulsant, antimicrobial, and antihyperglycemic potential of several thiazolidine-2,4-dione-bearing compounds was reported, this moiety has been intensively studied in the last decades. 3 Thiazolidine-2,4-dione derivatives have been also identified as potential inhibitors of lanosterol 14α-demethylase.…”

“…3 Thiazolidine-2,4-dione derivatives have been also identified as potential inhibitors of lanosterol 14α-demethylase. 4…”

In VivoAnti-CandidaActivity of Phenolic Extracts and Compounds: Future Perspectives Focusing on Effective Clinical Interventions

“…The most prominent situation is the acquired-resistance to azoles, mainly by enhancement of its efflux through upregulation of multidrug transporter genes on yeast cells, besides changes in the ergosterol biosynthesis and occurrence of mutations. The new synthetic drugs seem to be effective against the majority of insidious- and resistant- Candida species [ 35 – 40 ], but the problem of their side effects and related toxicity still remains.…”

Efficient and Chemoselective Procedure for Conversion of Rhodanine Derivatives into 1,3‐Thiazolidine‐2,4‐diones via 1,3‐Dipolar Cycloaddition Reaction and Rearrangement Sequences

“…TZDs possess anti‐inflammatory, [16–17] antibacterial, [18] antihyperglycemic, [19] antiarthritic, [20] antioxidant, [21] anticonvulsant, [22] antimicrobial, [23] antimalarial, [24] antiviral, [25] antifungal, [26] and anticancer activities [27–28] . In addition, these compounds are identified as inhibitors of aldose‐reductase enzyme and lanosterol 14 α ‐demethylase, glycogen synthase kinase‐3 (GSK‐3), 15‐hydroxyprostaglandin dehydrogenase and also as activators of PPARγ receptors and antidiabetic drugs (glitazones) [29–34] . The first TZD was synthesized in an aqueous medium using monochloroacetic acid and thiourea [35] .…”