In silico design, synthesis and biological evaluation of 2-benzyl-5-(2-methoxybenzyl)-1,3,4-oxadiazole derivates as allosteric deoxyhypusine synthase (DHPS) inhibitors for melanoma treatment

Melanoma, a highly aggressive skin Cancer, presents significant therapeutic challenges owing to its metastatic potential. Targeting deoxyhypusine synthase (DHPS), a pivotal enzyme in the activation of eukaryotic translation initiation factor 5A (eIF5A), emerges as a promising therapeutic strategy for melanoma. In this study, we designed and synthesized a series of 2-benzyl-5-(2-methoxybenzyl)-1,3,4-oxadiazole derivatives as novel allosteric DHPS inhibitors. Through molecular docking, dynamics simulations, scaffold screening, and comprehensive biological evaluations, we identified 7C16 as the most potent compound, demonstrating superior enzymatic inhibition (IC₅₀ = 0.07 μM) and anti-proliferative activity against melanoma cells (IC₅₀, _A375 = 4.00 μM). Notably, 7C16 significantly suppressed melanoma cell migration and invasiveness in vitro and exhibited potent anti-tumor efficacy in an A375 cell zebrafish xenograft model. These findings highlight 7C16 as a promising candidate for developing targeted anti-melanoma therapies.

1,3,4-Oxadiazole derivatives; Allosteric inhibitors; Deoxyhypusine synthase; Zebrafish xenograft model.