Discovery of Two New Neuroprotective Isocoumarin Dimers From the Dendrobium huoshanense-derived Streptomyces sp. AHMU XC001.

Dendrobium-derived actinomycetes represent a promising source of bioactive natural products with potential applications in pharmaceutical chemistry. In this study, a rhizosphere soil-derived actinomycete strain, Streptomyces sp. AHMU XC001, isolated from Dendrobium huoshanense, displayed moderate neuroprotective activity and was selected for further secondary metabolite isolation. Bioassay-guided fractionation of the crude extract led to the discovery of two new compounds, designated strepisocoumarins A and B (1 and 2), along with two known analogs, 6,8-dihydroxy-3-methylisocoumarin (3) and 6,8-dihydroxy-3-hydroxymethyl-isocoumarin (4). Their structures were elucidated by comprehensive nuclear magnetic resonance spectroscopic and mass spectrometric analyses. Compounds 1 and 2 were characterized as 5-5' and 5-7' heterodimers of compounds 3 and 4, respectively. Compounds 1-4 showed no antimicrobial activity against Bacillus subtilis 1064, Staphylococcus aureus ATCC 29213, MRSA 669, and Acinetobacter baumannii ATCC 19606. Furthermore, they exhibited no cytotoxic effects on various human cancer cell lines, including CNE2, MCF-7, HepG2, and ECA109. Notably, compounds 1-4 effectively inhibited Aβ1-42-induced reduction in cell viability and alleviated cytotoxicity in the human neuroblastoma SH-SY5Y cell line. These findings pave the way for further investigation of compounds 1-4 as potential lead molecules for the development of neuroprotective agents targeting Alzheimer's disease.