Tamanu oil from Calophyllum inophyllum L. has long been used in traditional medicine. Ethanol extraction was found the best strategy for recovering bioactive compounds from the resin part of Tamanu oil, yielding two neutral and acidic resins fractions with high phenolics, flavonoids and pyranocoumarins concentrations. A further cascade of LPLC/HPLC separations of neutral and acidic resin fractions allowed identifying fifteen metabolites, and among them, calanolide D and 12-oxocalanolide A (both in neutral fraction) were first identified from a natural source. All these extracts, subfractions and isolated metabolites demonstrated increased free radical scavenging, antioxidant, anti-inflammatory, antimicrobial and antimycobacterial activity compared to Tamanu oil and its de-resinated lipid phase. Overall, these results could promote resinous ethanol-soluble Tamanu oil extracts as a useful multifaceted and renewable medicinal resource.

Glioblastoma is one of the most highly aggressive types of brain tumor in adults. With limited treatment options, current therapies remain insufficient due to its invasiveness and immune evasion, highlighting the urgent need for new treatments. Bifunctional molecules targeting multiple aspects of the disease could be promising to overcome drug resistance and tumor heterogeneity. Metformin has demonstrated protective effects against brain tumors but requires high doses for efficacy, making it of great interest for molecular optimization. In this context, we synthesized a series of nine metformin–phenolic molecules, combining the metformin guanidine framework with phenolic acids, which have well-established properties in inhibiting cancer cell migration and adhesion. Their impact on cytotoxicity, reactive oxygen species inhibition, and signaling pathways was investigated for glioma cell lines and stem cells. Two of these hybrids, 5a and 5h, particularly enhanced cytotoxicity in glioblastoma cells, selectively targeting cancer cells while sparing healthy ones. Their mechanism of action differed significantly from metformin. Unlike metformin, which mainly triggers metabolic stress, the hybrids broadly inhibit RTK–MAPK–PI3K signaling, leading to cell cycle arrest and apoptosis. The results suggest that these compounds could offer a more effective and synergistic approach for glioblastoma treatment.