Research on protein tyrosine phosphatase (PTP) 1B inhibitors from terrestrial and marine natural resources identified N-isobutyl-2E-decenamide (1) and 3,4,5-tri-O-caffeoylquinic acid (2) as PTP1B inhibitory substances together with a new N-alkylamide (3) and two known congeners (4 and 5) from the aerial parts of Indonesian Spilanthes paniculata. The structure of 3 was elucidated as (2E, 7Z)-6,9-endoperoxy-N-2-methylbutyl-2,7-decadienamide based on its spectroscopic data. Compound 3 is a rare N-alkylamide derivative with an endoperoxide bridge, and only three natural products have been reported in this class. Compound 1 inhibited PTP1B activity with an IC50 value of 24 μM, whereas compound 2 exerted an inhibitory effect of 35% at 15 μM. This is the first study to report the inhibitory effects of an N-alkylamide derivative (1) on PTP1B activity.