Research Progress on Phthalide Compounds and Their Biological Activities
Phthalide compounds refer to a class of aromatic ester compounds with a benzopentacyclic lactone ring nucleus structure. The structural feature is that the hydroxyl and carboxyl groups in ortho hydroxymethylbenzoic acid undergo intramolecular acylation reactions, losing one unit of water molecule and forming a benzopentacyclic lactone ring structure. Phthalide compounds are widely present in plants of the Umbelliferae family. In addition, a small amount of benzophenone compounds are also distributed in plants of the families Cymbiaceae, Asteraceae, Piperaceae, and Corydalis. There is also a portion of phthalein compounds distributed in the secondary metabolites of microorganisms such as bacteria and fungi. Phthalide compounds are extremely unstable and susceptible to structural transformation due to factors such as light and temperature, which is also one of the main reasons for the structural diversity of phthalide compounds. Based on the structural characteristics of phthalein compounds, simple phthalides, polymeric phthalides, and phthalein alkaloid hybrids have been discovered. Simple benzophenones are mostly oily substances, with a small amount being crystals, and have a low melting point. Some low polarity benzophenone compounds can be detected in volatile oil extracts. Most of the polymerized benzophenones are easy to crystallize, and are mostly polymers of ligustilide or hybrids of ligustilide and isoquinoline skeleton or nitrogen-containing compounds. According to the number and type of polymers, they are further divided into dimers, trimers, poly (phenylphthalein) and benzophenone alkaloids. Phthalide compounds have diverse biological activities, such as cardiovascular and cerebrovascular activity, antibacterial, anti-tumor, anti-inflammatory, analgesic, and insecticidal effects. Especially in recent years, it has been discovered that benzophenone compounds can promote cerebral vascular microcirculation and protect brain nerves, with potential activity in preventing and treating Alzheimer’s disease (AD). For example, Enbipol capsules, whose main active ingredient is butylphthalein, have the effects of improving microcirculation in ischemic brain areas, increasing cerebral blood flow in ischemic areas, and protecting the blood-brain barrier. They are important clinical drugs for treating neurological dysfunction after cerebral infarction and cerebral thrombosis. Moreover, the combination of butylphthalein and hyperbaric oxygen can improve cognitive function and life ability in elderly patients with vascular dementia (VD). Therefore, phthalein compounds have always been one of the research hotspots. Previous literature has summarized the research progress of phthalein compounds and their biological activities, but currently there is no literature summarizing the research progress of phthalein compounds in the past five years. Therefore, this article summarizes the research work on phthalein compounds from 2015 to 2021 in terms of their sources, skeletal characteristics, and biological activities, in order to provide reference for the development and utilization of phthalein compounds, especially in the development and utilization of elderly vascular dementia.

 

Phthalide compounds are an important and unique type of backbone in secondary metabolites, with a wide range of pharmacological activities, and are also one of the main active ingredients in important traditional Chinese medicine and medicinal plants. For example, the traditional Chinese medicine Angelica sinensis has the effects of nourishing blood and promoting blood circulation, regulating menstruation and relieving pain, moistening intestines and promoting bowel movements. As the most important fat soluble effective component of Angelica sinensis, the volatile oil of Angelica sinensis and its phthalides (ligustilide, butylphthalide, butylphthalide, etc.) have obvious pharmacological activity on reducing blood lipids and blood pressure, inhibiting atherosclerosis, expanding blood vessels, protecting nerve cells, alleviating cerebral infarction and other diseases related to cardiovascular and cerebrovascular smooth muscle. In addition, traditional Chinese medicine Chuanxiong is often used to dispel wind and relieve pain, promote blood circulation and qi circulation. Among them, phthalide compounds (ligustilide, yangchuanxiong lactone A, yangchuanxiong lactone I, etc.) are the main active ingredients of Chuanxiong, which have pharmacological activities such as anti atherosclerosis, protecting damaged cerebral nerves, and enhancing drug absorption in the brain. Therefore, it is speculated that phthalide compounds are the main material basis of Chuanxiong’s significant regulatory effect on nervous system diseases and cardiovascular and cerebrovascular diseases.
The chemical properties of phthalein compounds are very active, and these molecules can polymerize themselves or with alkaloids to form structurally novel molecules. In recent years, many new types of phthalein based polymers have been reported, advancing the research on phthalein molecules. Phthalide compounds have significant activity against various diseases such as cardiovascular and cerebrovascular diseases, especially with potential therapeutic effects on Alzheimer’s disease. However, the origin pathway of phthalein molecules is unclear, and it is uncertain whether polymerized phthalein is a natural or artificial product. In addition, the study of the structure-activity relationship of phthalein compounds is not systematic and in-depth enough, especially the lack of research on the effect of phthalein molecule polymerization on activity. So far, there has been no systematic and in-depth explanation of the targets and mechanisms of action of phthalein compounds. Therefore, it is necessary to conduct in-depth and systematic research on phthalein compounds based on activity, interdisciplinary approaches, and explore from multiple perspectives such as source pathways, structure-activity relationships, targets, and mechanisms of action. This will provide scientific basis for the research and development of such compounds and lay the foundation for the modernization of traditional Chinese medicine.