Bioassay-Directed Isolation of Antibacterial Metabolites from an Arthropod-Derived Penicillium chrysogenum

Bioassay-directed isolation of secondary metabolites from an extract of Penicillium chrysogenum TJ403-CA4 isolated from the medicinally valuable arthropod Cryptotympana atrata afforded five new and 10 known compounds (1–15). All the compounds (except 14) belong to a minor class of highly rigid 6–5–5–5-fused tetracyclic cyclopiane-type diterpenes known to be exclusively produced by members of the Penicillium genus. The structures and absolute configurations of the new compounds (1–5) were elucidated by extensive spectroscopic analyses, including HRESIMS and 1D and 2D NMR, single-crystal X-ray diffraction, and comparison of the experimental electronic circular dichroism data. Compounds 1 and 2 represent the first examples of cyclopianes bearing a C-20 carboxyl group; compound 3 represents the first example of a cyclopiane with a gem-hydroxymethyl group; compound 4 represents the second example of a cyclopiane bearing a hydroxy group at C-7; compound 5 represents the first example of a cyclopiane bearing a hydroxy group at C-8. Compounds 2 and 3 exhibited activity against MRSA, with MIC values of 4.0 and 2.0 μg/mL, respectively. In addition, the structure–antibacterial activity relationship (SAR) of compounds 1–15 is discussed.