Crop Protection and Treatment: Studying Fungal Membrane Damage by Tetrahydroacridine Derivatives

Background: The widespread use of antibiotics has led to the emergence of drug-resistant strains, posing a significant challenge to global public health. Inspired by natural products, this study synthesized three series of tetrahydroacridine derivatives. Their antifungal potential was evaluated. The compounds were screened against the phytopathogenic fungi Rhizoctonia solani , Botrytis cinerea , Gibberella zeae , Ampelomyces humuli , and Candida albicans . Methods: Three series of tetrahydroacridine derivatives – acridones, acridines, and hydroxylated acridines (32 compounds total) – were efficiently synthesized through a synergistic iron/citric acid-catalyzed one-pot cyclization and subsequent reduction steps. Initial antifungal screening against five pathogenic fungi identified the most promising candidates, which were further evaluated through mycelial growth inhibition, fluorescence staining, and in vivo assays. Results: At 200 μg/mL, three compounds (6j, 5e, and 5l) showed significant inhibitory activity (up to 95.77%). Compound 5e exhibited potent activity against B. cinerea , with inhibition rates of 40.94% (25 μg/mL), 57.50% (50 μg/mL), and 91.04% (100 μg/mL), yielding an EC 50 (Half-maximal Effective Concentration) value of 2.610 μg/mL. This activity was superior to the positive controls famoxadone (EC 50 = 4.734 ± 1.7 μg/mL), chlorothalonil (EC 50 = 12.893 ± 0.9 μg/mL), and carbendazim (EC 50 = 11.265 ± 1.4 μg/mL). Importantly, in vivo studies confirmed its dual activity, showing 97.46% protective efficacy and 63.79% curative efficacy at 100 μg/mL. Mechanistic studies revealed that 5e (100 μg/mL) induced significant membrane damage (87.60%) in B. cinerea . Conclusions: These results establish the tetrahydroacridine scaffold as a promising lead candidate for further development and modification into potential antibacterial agents.