Synthesis of Eugenol Derivatives and Evaluation of their Antifungal Activity Against Fusarium solani f. sp. piperis

Abstract

<jats:sec> <jats:title>Background:</jats:title> <jats:p>Fusarium solani f. sp. piperis is a phytopathogen that causes one of the most destructive diseases in black pepper crops, resulting in significant economic and crop production losses. Consequently, the control of this fungal disease is a matter of current and relevant interest in agriculture.</jats:p> </jats:sec> <jats:sec> <jats:title>Objective:</jats:title> <jats:p>The objective was to synthesize eugenol derivatives with antifungal activity.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>In this study, using bimolecular nucleophilic substitution and click chemistry approaches, four new and three known eugenol derivatives were obtained. The eugenol derivatives were characterized and their antifungal and cytotoxic effects were evaluated.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>Eugenol derivative 4 (2-(4-allyl-2-methoxyphenoxy)-3-chloronaphthalene-1,4-dione) was the most active against F. solani f. sp. piperis and showed acceptable cytotoxicity. Compound 4 was two-fold more effective than tebuconazole in an antifungal assay and presented similar cytotoxicity in macrophages. The in silico study of β-glucosidase suggests a potential interaction of 4 with amino acid residues by a cation-π interaction with residue Arg177 followed by a hydrogen bond with Glu596, indicating an important role in the interactions with 4, justifying the antifungal action of this compound. In addition, the cytotoxicity after metabolism was evaluated as a mimic assay with the S9 fraction in HepG2 cells. Compound 4 demonstrated maintenance of cytotoxicity, showing IC50 values of 11.18 ± 0.5 and 9.04 ± 0.2 μg mL-1 without and with the S9 fraction, respectively. In contrast, eugenol (257.9 ± 0.4 and 133.5 ± 0.8 μg mL-1), tebuconazole (34.94 ± 0.2 and 26.76 ± 0.17 μg mL-1) and especially carbendazim (251.0 ± 0.30 and 34.7 ± 0.10 μg mL-1) showed greater cytotoxicity after hepatic biotransformation.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p>The results suggest that 4 is a potential candidate for use in the design of new and effective compounds that could control this pathogen.</jats:p> </jats:sec>

Anti‐Candida, docking studies, and in vitro metabolism‐mediated cytotoxicity evaluation of Eugenol derivatives

“…We used the eugenol phenol group for structural modifications by bimolecular nucleophilic substitution approaches and copper(I)‐catalyzed azide‐alkyne cycloaddition (CuAAC) reaction. The synthesis and spectroscopic characterization of compound 1a‐d were recently reported (Maximino et al, 2020). We used spectrometric and spectroscopic methods such as uni‐ and bidimensional NMR and FT‐IR to characterize the chemical structures of new compounds ( 2f‐m ) (Data shown in Supplementary material; Figure S1).…”

“…The system remained for 30 min in this condition. Commercial halides (1.5 equivalent) ( a – c, e are bromides and d is chloride) were then added, and the system was kept at room temperature under stirring for 12 h. The reactions solutions were concentrated under reduced pressure and the final products purified by column chromatography using silica gel as the stationary phase and hexane: acetate (7:3, v/v) as mobile phase to obtain compounds 1a–e (Maximino et al, 2020).…”

“…Subsequently, the tube was sealed, and microwave irradiated at 150 W, 80°C for 5–10 min (Scheme 1). The reaction solution was concentrated under reduced pressure by a rotary evaporator, the final products ( 2‐f‐m ) were purified by column chromatography using silica gel as the stationary phase, and several mobile phases depending on each triazole obtained (Maximino et al, 2020).…”

Cellular apoptosis and cell cycle arrest as potential therapeutic targets for eugenol derivatives in Candida auris

“…It also displays low chemical stability and is sensitive to oxidation and various chemical interactions [ 13 ]. To mitigate these side effects and to improve the biological profile of this molecules, various modifications of the structure of this molecule have been carried out [ 13 , 23 ]. In a previous study, it was reported that eugenol tosylate and its congeners, prepared by the functionalization of the hydroxyl group of eugenol with different sulfonyl chlorides under basic conditions, showed promising antifungal activities compared to eugenol.…”

Design and Synthesis of Eugenol Derivatives Bearing a 1,2,3-Triazole Moiety for Papaya Protection against Colletotrichum gloeosporioides

“…Its derivatives exhibit leishmanicidal, insecticidal, anti-inflammatory, antibacterial, antioxidant properties. Notably, extensive chemical modification of eugenol has resulted in substances with antifungal activity. − …”