E ‐Stilbene‐Based Hydrazide‐1,3,4‐Oxadiazole Hybrids as Potential Anticancer Dual Carbonic Anhydrase‐I and Thymidine Phosphorylase Inhibitors: In Vitro and In Silico Studies

ABSTRACT A series of E ‐stilbene‐based hybrid structures were synthesized via a multistep route using the Mizoroki–Heck reaction to install the E ‐stilbene core. The compounds, structurally confirmed by FT‐IR, 1 H NMR, 13 C NMR, and mass spectrometry, were evaluated as dual inhibitors of carbonic anhydrase‐I (CA‐I) and thymidine phosphorylase (TPase), enzymes pivotal in tumor survival and progression. Among the synthesized series, the compounds 4a and 5a showed remarkable biological activity against TPase, while compounds 3b and 3c showed strong CA‐I inhibition in in vitro assays. Overall, the synergistic inhibitory activity of compounds 3a , 3c , 5a , and 5b against CA‐I and TPase suggests a coordinated dual enzyme targeting strategy capable of perturbing tumor homeostasis and impairing DNA synthesis pathways. This study underscores the potential of E ‐stilbene‐hybrid structures to disrupt tumor, pH regulation and nucleotide metabolism, offering a strategy to combat cancer progression by crippling dual enzymatic pathways critical for malignancy treatment. Molecular docking revealed binding affinities and molecular dynamics simulations highlighted interactions with catalytic residues of both enzymes, rationalizing the observed potency.