Brazilian biodiversity is a powerful source of small bioactive molecules, which are valuable lead compounds for the development of new drugs. In this sense, two rare lignoids, dehydrodieugenol B (1) and methyldehydrodieugenol B (2), formed by oxidative coupling of eugenol, were isolated as main metabolites from twigs of Nectandra leucantha (Lauraceae)1 Antitumoral activity against murine melanoma cells (B16F10Nex2) was detected to compound 1 (IC50 = 78.8 ± 2.8 M) while 2 was inactive (IC50 > 300 M). Additionally, compound 1 was prodigious in the induction of morphological, biochemical and enzymatic features of the intrinsic apoptosis against tested cell lines. These results lead to the preparation of 16 different semi-synthetic derivatives of 1, proposed as showed in Figure 1 aiming to establish structure-activity relationships (SAR). After preparation and chemical characterization, compounds 1a – 1r were evaluated against murine melanoma cell lines and the IC50 were determined. The obtained results indicated that 1b and 1c (figure 1) were the most active semisynthetic derivatives displaying IC50 values of 53.3 ± 2.4 and 51.8 ± 1.6 M, respectively, suggesting that hydrogenation (1b) and hydrogenation/acetylation (1c) cause a increment in the antitumoral potential of natural product 1. These compounds were applied to a rational approach for designing novel candidates based on Multivariate Statistical Analysis (PLS-DA – R2Y: 0.703), and Machine Learning Techniques. This strategy consisted in the development of a QSAR method based on Artificial Neural Networks resulting in higher parameters than the minimum required for this analysis (Table 1) [1-3]. The most important position and groups were elected by their statistical weights for cytotoxicity. To the selected position, bioisosteres substituents were applied aiming to improve the pharmacological profile of this series of compounds. The results suggested that some designed neolignans reached lower IC50 than the semi-synthetic derivatives pointing to promising candidates for synthesis (Table 2).