Synthesis of 9-substituted Acridine Derivatives and Evaluation of their Antifungal Activity against Phytopathogenic Fungi

Background: The emergence of pesticide resistance in phytopathogenic fungi significantly impacts global crop yields. In this study, three series of 39 9-substituted acridine derivatives were synthesized (13 each of 9-methyl, 9-formyl, and 9-formaldehyde oxime derivatives), and their in vitro and in vivo antifungal activities against plant pathogenic fungi were evaluated. Methods: Three series of 39 9-substituted acridine derivatives were synthesized through Ullmann coupling, intramolecular cyclization, oxidation, and oximation reactions. Primary screening via antifungal rate determination against four phytopathogenic fungi identified promising candidate. Selected compound subsequently underwent antifungal evaluation employing mycelial growth rate assays, fluorescent staining, and in vivo experiments, while exploring its potential mechanism of action. Results: Three series of 39 9-substituted acridine derivatives were synthesized using 2-aminoacetophenone and various substituted iodobenzenes as starting materials. At 50 μg/mL, four compounds (5j, 4g, 5i, 4h) exhibited significant inhibitory activity. Notably, compound 4h demonstrated potent inhibition against Ampelomyces humuli . The half-maximal effect concentration value for 4h was 1.227 μg/mL, comparable to the positive control chlorothalonil (1.615 μg/mL) and superior to Famoxadone (14.11 μg/mL) and Carbendazim (20.03 μg/mL). Using the mycelial growth rate method, inhibition rates were 65.47% at 50 μg/mL. Mechanistic studies revealed that 4h (100 μg/mL) induced significant membrane damage (90.95%) in A. humuli and concomitantly suppressed its sporulation. In addition, in vivo studies confirmed that compound 4h exerts both curative and protective effects against A. humuli infection in plants. Conclusions: These results collectively establish the acridine scaffold as a promising candidate for developing novel antifungal agents.