The maintenance of an inflammatory response is associated with the pathogenesis of chronic inflammatory diseases [1], including metabolic syndrome [2], colitis, cardiovascular disease [3], neurodegenerative diseases [4], and cancer [5]. Chronic inflammatory diseases are slowly emerging as the dominant diseases in terms of morbidity and mortality, and the number of patients continues to increase each year [6]. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the predominant drugs currently used to treat inflammation [7]. However, NSAIDs can cause gastrointestinal and cardiovascular complications, and overdose can cause nephrotoxicity and eventually kidney failure [8,9]. As such, the development of alternative anti-inflammatory drugs with fewer toxic side effects and suitable for long-term use in chronic inflammatory diseases is urgently needed. Mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) are two classical signaling pathways that have been well-studied in inflammation [[10], [11], [12]]. In classical cellular or animal models of inflammation stimulated by endotoxin (LPS), both two signaling pathways are activated, ultimately resulting in the release of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and NO, leading to an inflammatory response [[13], [14], [15]].

Marine natural products are an important source of drug discovery [16,17], including the identification of lead molecules with anti-inflammatory activity from marine organisms [[18], [19], [20], [21]]. Among them, marine-derived alkaloids are an important class of molecules with anti-inflammatory activity [22,23], inhibiting the expression of various pro-inflammatory factors and inflammation-associated pathways such as NF-κB and MAPK pathways [24,25]. Marine-derived alkaloids with anti-inflammatory activity have great potential for new drug development and clinical applications to be further explored.

In our previous research, two fumiquinazolines, (±)-17-hydroxybrevianamide N (1) and (±)-N2-methyl-17-hydroxybrevia-namide N (2) were isolated from an Aspergillus sp. strain isolated from soft coral Sinularia sp. collected from the South China Sea in April 2015 [26]. Fumiquinazolines are a class of alkaloids derived from marine fungi containing the pyrazino[2,1-b]quinazoline-3,6-dione skeleton. Natural products containing residues of 2-amino-3-(2-hydroxyphenyl) propionic acid are exceedingly rare, with only eight peptides reported [27,28]. Nowadays, approximately 80 natural fumiquinazolines alkaloids have been isolated from fungi (mainly Penicillium, Aspergillus, and Neotrichum) collected from diverse environments globally [29]. More recent studies on the antibacterial, antiviral, and antitumor properties of fumiquinazolines are available [30,31]. However, research on the anti-inflammatory activity of natural fumiquinazolines with very rare o-hydroxyphenylalanine residues and an imide subunit is rare [29,32]. In this study, to solve the issue of limited availability of natural product sources, the fermentation conditions of Aspergillus sp. (CHNSCLM-0151) were systematically optimized for a high yield of (±)-1 and (±)-2 (Fig. 1). Compounds (±)-1 and (±)-2 were isolated as racemates owing to their propensity for racemization during the extraction and isolation processes [26]. Based on the structural feature of natural product (±)-1, a series of derivatives (±)-2−(±)29 were synthesized by structural modification. The chiral resolution of active derivatives (±)-4, (±)-6, (±)-9, (±)-22, (±)-23, and (±)-24 were performed to obtain six pairs of enantiomerically pure chiral derivatives. The anti-inflammatory activity of all compounds was studied.