Eg5 is a kinesin essential in bipolar spindle formation, overexpressed in tumours, thus representing a new target in cancer therapy. We aimed at evaluating the anti-cancer activity of Eg5 thiadiazoline inhibitors 2 and 41 on gastric adenocarcinoma cells (AGS), focusing on the modulation of angiogenic signalling. Docking studies confirmed a similar interaction with Eg5 to that of the parent compound K858. Thiadiazolines were also tested in combination with Hesperidin (HSD). Cell cycle analysis reveals a reduction of G1 and S phase percentages when 41 is administered as well as HSD in combination with K858. Western blot reveals Eg5 inhibitors capability to reduce PI3K, p-AKT/Akt and p-Erk/Erk expressions; p-Akt/Akt ratio is even more decreased in HSD+2 sample than the p-Erk/Erk ratio in HSD+41 or K858. VEGF expression is reduced when HSD+2 and HSD+41 are administered with respect to compounds alone, after 72 h. ANGPT2 gene expression increases in cells treated with 41 and HSD+2 compared to K858. The wound-healing assay highlights a reduction in the cut in HSD+2 sample compared to 2 and HSD. Thus, Eg5 inhibitors appear to modulate angiogenic signalling by controlling VEGF activity even better if combined with HSD. Overall, Eg5 inhibitors can represent a promising starting point to develop innovative anti-cancer strategies.