Parkinson's disease (PD) is the second most common neurodegenerative disorder. According to the statistics of the World Parkinson Disease Association, there are globally 5.7 million patients with PD at present. It is estimated that the population of PD patients will reach to 13 million in 2040 [1], which will bring heavy burden for society and families. PD patients are characterized by involuntary tremor, muscle weakness, myotonia and postural balance disorder [2]. The major pathologies of PD are degeneration and death of dopaminergic neurons in the midbrain substantia nigra [3]. Multiple factors have been identified as contributing to the decline and death of dopaminergic cells, including environment factors, genetics and ageing process [4]. However, the formation of intracellular Lewy body inclusions, which consist of aggregates of α-synuclein (α-Syn), may have a more significant impact.

α-Syn, a soluble presynaptic protein, is composed of 140 amino acids encoded by SNCA gene on chromosome 4q21-q2 [5]. Structurally, α-Syn contains three domains including an N-terminus (residues 1–60) domain, a non-amyloid component (residues 61–95) and a C-terminus (residues 96–140) domain [6]. Under physiological circumstances, α-Syn functions in regulating synaptic maintenance, chaperone activities, proteasome functions, dopamine metabolism and mitochondrial homeostasis [7]. However, due to the hydrophobicity of the non-amyloid domain, the misfolded α-Syn monomers are prone to assemble into various aggregates including oligomers, protofibrils and fibrils [8]. The accumulation of α-Syn aggregates in specific brain regions leads to neuronal cell death, ultimately preluding to the development of PD. In addition, α-Syn aggregates may induce mitochondrial dysfunction and oxidative stress in PD patients [9]. The direct interactions between pathological α-Syn and mitochondrial membrane proteins mediate oxidative stress, which is reflected in the defect of mitochondrial electron transfer chain and excessive production of reactive oxygen species (ROS) in cells [10]. The production of ROS, which is a byproduct of regular oxygen metabolism, plays an indispensable role in cell signaling and regulation of homeostasis. However, when the electron transfer chain in mitochondria is disrupted, it can result in an overproduction of ROS, which is detrimental to cells [11]. The accumulation of free radicals can also cause irreversible damage to polysaccharides, nucleic acids [12], membrane lipids [13] and proteins [14], ultimately causing in oxidative stress. Therefore, inhibiting the aggregation of α-Syn and disaggregating the preformed α-Syn fibrils have become effective strategies for the treatment of PD.

Recently, the development of inhibitors against α-Syn aggregation has made encouraging progress, and a large number of inhibitors have been discovered, including natural compounds [15], nanoparticles [16], polypeptides [17] and antibodies [18]. Especially, the effect of natural products including alkaloids [19], polysaccharides [20], saponins [21] and polyphenols [22] on inhibiting α-Syn aggregation has been reported massively. Brazilin, a natural phenolic compound, is mainly extracted from traditional herbal plant Caesalpinia sappan and exhibits a range of biological properties such as anti-inflammatory [23], anti-cancer [24] and antioxidant [25] effects. Our previous studies have proven that brazilin can inhibit fibrillogenesis of various amyloid proteins, including amyloid β [26], human islet amyloid polypeptide [27] and α-Syn [28]. The aggregation of α-Syn was inhibited due to the hydrogen bonds between α-Syn and brazilin disrupted the intermolecular hydrogen bonds among α-Syn monomers of its pentamer state. Nevertheless, the non-specific side effects of brazilin as well as its high toxicity at concentration equal to or greater than 50 μM greatly limit its practical application in medicine [[28], [29], [30]]. This is due to the oxidative damage induced by the hydroxyl groups of brazilin [31,32]. In addition, hydroxyl groups of brazilin enhance the hydrophobicity between α-Syn and brazilin, but they chelate easily with metal ions including Cu(II) [33] and Zn(II) [34] and weaken the hydrophobicity to reduce the inhibitory effect on α-Syn aggregation. Of them, 7-hydroxy group is more unstable and easily oxidized to carbonyl group in vitro [35]. Therefore, the toxicity of brazilin probably is reduced and its inhibitory effect may be stronger after 7-hydroxy group is modified.

In this study, to obtain agents with lower toxicity and stronger inhibitory ability, brazilin derivatives were synthesized and examined for their effect on inhibiting the aggregation of α-Syn and brazilin-7-acetate (B-7-A) was lower toxic than brazilin. Thus, B-7-A was selected as the potential agent for the following studies. Then, the data showed that B-7-A inhibited α-Syn aggregation and depolymerized mature α-Syn fibrils. It also inhibited the conformational transition of α-Syn. Moreover, it alleviated cytotoxicity and reduced the ROS level of PC12 cell line. The protective effects of B-7-A against damage and oxidative stress generated by α-Syn aggregation were verified by using the transgenic Caenorhabditis elegans (C. elegans). In summary, B-7-A is a good candidate to treat PD.