Green Efficient Synthesis of [1,3,4]Thiadiazole-Tethered Alkoxyaryl Hydrazones: Evaluation of Antitumor Activities and Molecular Docking Studies

Hydrazono-[1,3,4]-thiadiazoles have a prominent position among the heterocyclic compounds due to their broadening aspects of biological activities. In the current study, a neoteric series of [1,3,4]-thiadiazoles tethered to alkoxyaryl hydrazone has been formulated via the treatment of methyl 2-[3-(pentyloxy)-benzylidene]-hydrazine-1-carbodithioate and hydrazonoyl chlorides in ethanolic solution under thermal conditions. DABCO, as an environmentally nontoxic material, was utilized as a superior basic catalyst for the latter reaction. The structures of the isolated products were explicated by spectral (IR, NMR, and MS) and elemental analysis tools. The antitumor activity of the synthesized products was assessed against the breast cancer MCF-7 cell line. The results displayed that compounds <b>5a</b> and <b>5f</b> have highly selective inhibition profiles related to doxorubicin as a reference drug. The molecular docking analysis was performed using the Molecular Operating Environment (MOE) software through the interaction with the VEGFR-2 protein (PDB: 2OH4) and revealed that compounds <b>5a</b> and <b>5f</b> are linked with the same amino acid (GLU883), similar to the reference antibiotic doxorubicin. Also, these compounds exhibited higher binding affinities (-7.86 and -8.47 kcal/mol, respectively) than the reference compound (-6.68 kcal/mol), which supported their antitumor efficacy against the MCF-7 cell line. Moreover, confirmation of the drug-like properties and toxicity predictions of the newly synthesized compounds (<b>5a</b>-<b>m</b>) was achieved via in silico ADME.