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 (LC 50 ) 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.

Recent Achievements in Antiviral Agent Development for Plant Protection

“…Based on this study, Wang and co-workers 119 further designed and synthesized a series of phthalide and coumarin derivatives based on the multicyclic structure of Gossypol. Compound 88 was figured out as a promising antiviral agent with similar bioactivity to commercial antiviral agent ningnanmycin against TMV.…”

An Overview of Natural and Synthetic Phthalides Involved in Cancer Studies: Past, Present, and Future

“…[79] The structural characterizations of phthalides are accomplished frequently by the analysis of Infrared (IR) spectroscopy, mass spectrometry (MS), GC coupled to selective mass detectors (GC-MS) and high-resolution mass spectrometry (HR-MS), high-performance liquid chromatography (HPLC), and 1D and 2D Nuclear Magnetic Resonance (NMR), electronic circular dichroism (ECD) and X-ray crystallographic data, or frequently a combination of them has been applied. [80][81][82][83][84][85][86][87]…”

Discovery of Novel α-Methylene-γ-Butyrolactone Derivatives Containing Vanillin Moieties as Antiviral and Antifungal Agents

“…As a versatile pharmacophore, the γ-butyrolactone moiety widely exists in natural products, bioactive molecules, and drugs, many of which have a broad range of agricultural biological activities, such as antibacterial, insecticidal, herbicidal, and antiviral properties . For instance, the γ-butyrolactones derived from natural products incrustoporin, , gossypol, and hemigossypol , have showed high anti-TMV and antifungal activities.…”