Roseoglobuloside A, a Novel Nonanolide, and Identification of Specialized Metabolites as hPTP1B1 – 400 Inhibitors from Mangrove-Dwelling Aspergillus spp

Abstract An approach combining enzymatic inhibition and untargeted metabolomics through molecular networking was employed to search for human recombinant full-length protein tyrosine phosphatase 1B (hPTP1 B1 – 400) inhibitors from a collection of 66 mangrove-associated fungal taxa. This strategy prioritized two Aspergillus strains (IQ-1612, section Circumdati, and IQ-1620, section Nigri) for further studies. Chemical investigation of strain IQ-1612 resulted in the isolation of a new nonanolide derivative, roseoglobuloside A (1), along with two known metabolites (2 and 3), whereas strain IQ-1620 led to the isolation of four known naphtho-γ-pyrones and one known diketopiperazine (4–8). Of all isolates, compounds 2, 3, and 7 showed a marked inhibitory effect on hPTP1B1 – 400 with an IC50 value < 20 µM, while 6 showed moderate inhibition with IC50 of 65 µM. Compounds 1 and 8 were inactive at a concentration of 100 µM, whereas 4 and 5 demonstrated significant inhibition at 20 µM. The structure of 1 was established by comprehensive spectroscopic analysis, and its relative and absolute configuration was assigned based on NOE correlations and by comparison of calculated and experimental ECD curves. Molecular docking indicated that these molecules primarily bind to two different allosteric sites, thereby inducing conformational changes that impact enzymatic activity.