Design, Synthesis, and Bioactivities of Phthalide and Coumarin Derivatives Based on the Biosynthesis and Structure Simplification of Gossypol

Abstract

Because gossypol and hemigossypol show antiviral activity but are structurally complex, we designed and synthesized a series of structurally simpler phthalide and coumarin derivatives. The phthalide derivatives were synthesized by opening the naphthalene ring of hemigossypol, and the coumarin derivatives were synthesized by ring-opening reactions of the phthalide derivatives with the goal of investigating the effect of the lactone ring size on bioactivity. The bioassay results showed that the two series of target compounds possessed moderate to good activities against tobacco mosaic virus, One of the compounds showed in vivo inactivation, curative, and protection activities of 50 ± 1, 53 ± 3, and 48 ± 2% at 500 mg/L, values which are higher than those of gossypol (32 ± 1, 35 ± 1, 29 ± 1%, respectively) and comparable to those of hemigossypol (55 ± 1, 49 ± 1, and 48 ± 1%, respectively) and the commercial antiviral agent ningnanmycin (56 ± 2, 54 ± 1, 58 ± 1%) at the same dose. Thus, this compound is a promising candidate for the development of new anti-plant-virus agents. In addition, most of the synthesized compounds showed broad-spectrum activity when tested against 14 kinds of phytopathogenic fungi and showed selectivity against Sclerotinia sclerotiorum, Physalospora piricola, and Rhizoctonia cerealis. Moreover, some of the compounds exhibited activity against Plutella xylostella larvae; the two most active compounds exhibited larvicidal activities (LC50) of 4.10 and 5.47 mg/L, respectively. Further studies showed that these compounds also exhibited insecticidal activities against Mythimna separata, Helicoverpa armigera, and Pyrausta nubilalis larvae.