Synthesis and antifungal and antitumor activities of acridine-containing tetrahydronaphthalene spiroisoxazoline derivatives

Abstract

To develop novel functional molecules with both antifungal and antitumor activities, this study rationally designed and synthesized 11 acridine-containing tetrahydronaphthalene spiroisoxazoline derivatives based on the bioactive fragment characteristics of isoxazoline, acridine, tetrahydronaphthalene, and spirocycle moieties. Using o-aminoacetophenone and other reagents as starting materials, the target compounds were prepared via a multi-step synthetic route involving copper-catalyzed Ullmann coupling, Wittig reaction, and Huisgen cycloaddition. The results of biological activity assays demonstrated that these compounds exerted definite antifungal effects against a variety of fungi, especially Ampelomyces humuli. Among them, compound 10a displayed the half-maximal effective concentration value of 0.9768 µg/mL against Ampelomyces humuli, which was superior to that of the positive controls Chlorothalonil (1.767 µg/mL), Famoxadone (13.87 µg/mL), and Carbendazim (27.02 µg/mL). The mycelial growth rate method indicated that its inhibitory effect on the mycelial growth of Ampelomyces humuli was concentration-dependent. Fluorescence staining experiments revealed that this compound could induce damage to fungal cell membranes and inhibit fungal spore secretion. In vitro experiments confirmed that it possessed certain protective and curative effects on corn leaves infected by Ampelomyces humuli. In addition, cytotoxicity studies showed that these compounds exhibited relatively high toxicity against normal cells while exerting significant antiproliferative activity against human colorectal cancer cells; notably, compound 10e had the half-maximal inhibitory concentration value of 2.53 µM, which was higher than that of the positive controls Cisplatin (36.00 µM) and Doxorubicin (10.43 µM). These findings suggest that the novel acridine-containing tetrahydronaphthalene spiroisoxazoline derivatives with multiple active fragments hold promise as candidates for the development of new antifungal agents and antitumor drugs.

Keywords: Acridine; Antifungal; Antitumor; Isoxazoline; Spirocyclic compound; Tetrahydronaphthalene.