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Anti-phytopathogen, multi-target acetylcholinesterase inhibitory and antioxidant activities of metabolites from endophytic Chaetomium globosum

Abstract Fourteen metabolites with various structure types were isolated from endophytic Chaetomium globosum. Five compounds were separated from genus Chaetomium for the first time. Some compounds exhibited remarkable inhibition against phytopathogenic fungi causing root rot of Panax notoginseng. Compounds 1–5 had significant DPPH-free radical-scavenging activity. Compounds 3 and 5 indicated significant inhibitions against the acetylcholinesterase (AChE). From preliminary structure–activity relationship, it was found that the oxygenic five-membered ring of 3 and 5 was crucial in the anti-AChE activity. These structures provide new templates for the potential treatment and management of plant diseases and Alzheimer disease.


Introduction
Endophytes are a special micro-organism group inhabiting the healthy tissues of plants. And many of the compounds from these endophytes may be of interest pharmaceutically (Debbab et al. 2012;Tanvir et al. 2014). As part of our ongoing research on active constituents from microbes, 14 compounds were isolated from the fermentation broth of Chaetomium globosum from the seeds of Panax notoginseng, and their structures were determined as flavipin (1) (Nitao et al. 2002), epicoccone (2) (Lee et al. 2007), 3-methoxyepicoccone (3) (El Amrani et al. 2014), epicoccolides A (4) (Talontsi et al. 2013), and B (5) (Talontsi et al. 2013), ABSTRACT Fourteen metabolites with various structure types were isolated from endophytic Chaetomium globosum. Five compounds were separated from genus Chaetomium for the first time. Some compounds exhibited remarkable inhibition against phytopathogenic fungi causing root rot of Panax notoginseng. Compounds 1-5 had significant DPPH-free radical-scavenging activity. Compounds 3 and 5 indicated significant inhibitions against the acetylcholinesterase (AChE). From preliminary structure-activity relationship, it was found that the oxygenic fivemembered ring of 3 and 5 was crucial in the anti-AChE activity. These structures provide new templates for the potential treatment and management of plant diseases and Alzheimer disease. chaetomugilins A (6) ) and D (7) (Yasuhide et al. 2008), chaetoglobosins A (8) (Ni et al. 2008), B (9) (Ni et al. 2008), E (10) (Li et al. 2014), F (11) (Li et al. 2014) and F ex (12) (Oikawa et al. 1993), penochalasins F (13) (Iwamoto et al. 2001) and G (14) (Iwamoto et al. 2001) (Figure 1). Among them, compounds 2, 3, 4, 5 and 14 were separated from genus Chaetomium for the first time. We tried to screen their activities in order to explore the new activities of these compounds.

Results and discussion
The anti-phytopathogen activities of some compounds against evaluated. These pathogens could cause root rot disease of pseudo-ginseng in our previous works (Miao et al. 2014). The MICs for compounds are listed in Table 1. The anti-acetylcholinesterase (AChE) activities of representative compounds，including 1, 3, 4, 5, 6 and 8 were tested. Compound 5 indicated significant inhibition against AChE with IC 50 at 5.55 μM. Compound 3 showed inhibition against AChE with the ratio of inhibition at 72.6% for a concentration at 50 μM. In consideration of the experiment, 3 and 5 were novel AChE inhibitors with high antioxidant activity, so these compounds might have the potential to be multi-target agents which could be used in the therapy of Alzheimer disease, a kind of disease caused by diverse factors including oxidative stress and reduced AChE levels (Zhang et al. 2006). The rest of the compounds didn't show obvious anti-AChE activity with the ratios of inhibition <10% at 50 μM. From structure-activity relationship, compounds 1 and 4 have no obvious activity in AChE inhibition assays, but 3 and 5 were AChE inhibitors, the structure difference between them was the five-membered ring, so this structure was important to the activity. Previous research was reported about huperzine A, a natural acetylcholinesterase inhibitors production by an endophytic fungus isolated from Huperzia serrata (Su &Yang 2015).
The 2,2-diphenyl-1-picrylhydrazyl (DPPH) method indicated that compounds 2, 3, 5 were antioxidants comparable with ascorbic acid. Compounds 1 and 4 have stronger antioxidant activities than positive control ascorbic acid (Table 2). It was the first time to report the antioxidant activities about 3, 4 and 5. So, 3 and 5 were multi-target acetylcholinesterase inhibitors.

Conclusion
Five compounds were separated from genus Chaetomium for the first time, and some molecules were found first to have remarkable anti-phytopathogen, multi-target acetylcholinesterase inhibitory and antioxidant activities.  (2) - Table 2. the ec 50 in dPPh free radical-scavenging activity of compounds 1-14 isolated from C. globosum.

Disclosure statement
No potential conflict of interest was reported by the authors.