Design and synthesis of small molecular 2-aminobenzoxazoles as potential antifungal agents against phytopathogenic fungi

Abstract

In order to discover novel antifungal agents, three series of simple 2-aminobenzoxazole derivatives were designed, synthesized and evaluated for their antifungal activities against eight phytopathogenic fungi. The in vitro antifungal results showed that most of the target compounds exhibited excellent and broad-spectrum antifungal activities to all the tested fungi. Particularly, the six compounds 3a, 3b, 3c, 3e, 3m and 3v displayed the most potent antifungal activity, with EC₅₀ value of 1.48-16.6 µg/mL, which were much superior to the positive control hymexazol. The in vivo study further confirmed that compounds 3a, 3c, 3e and 3m displayed good preventative effect against Botrytis cinerea at the concentration of 100 µg/mL. The structure-activity relationships research provides significant reference for the further structural optimization of 2-aminobenzoxazole as potential fungicides. Forty-four 2-aminobenzoxazole derivatives were designed and synthesized as agricultural antifungal agents, the in vitro and in vivo antifungal experiments showed that compounds 3a, 3b, 3c, 3e, 3m and 3v exhibited excellent and broad-spectrum antifungal activities compare with the commercial fungicide hymexazol.

Keywords: 2-Aminobenzoxazole derivatives; Antifungal activity; Pathogenic fungi; Structure–activity relationships.

Fig. 1

Chemical structures of containing benzoxazole skeleton

Scheme 1

General synthetic rout of target compounds

Fig. 2

Structure–activity relationship of the target compounds

Fig. 3

Effects of compound 3d on the growth of FS and FO at different concentrations (CK: blank control group)

Fig. 4

The effects of compound 3a on the growth of FS and AS at 25 μg/mL (FS-CK and AS-CK represented the normal mycelium morphology of FS and AS, and FS-3a and AS-3a represented the mycelium morphology of FS and AS after treatment with compound 3a)

Fig. 5

In vivo antifungal activity of compounds against Botrytis cinerea

Fig. 6

The binding models of the test compounds into the lipid binding pocket of Sec14p from S. cerevisiae. a Overlay of the six test compounds into the active site of Sec14p: 3a (gray), 3b (blue), 3d (orange), 3h (light blue), 3m (peach) and 3u (yellow)