Novel Hydrazone Derivatives of 3-Bromopyruvate: Synthesis, Evaluation of the Cytotoxic Effects, Molecular Docking and ADME Studies.

A series of 3-bromopyruvate (3-BP) derivatives were synthesized to develop new potent anticancer agents. The chemical structures of the compounds were characterized using FT-IR, 1 H-, 13 C-NMR spectroscopy, and elemental analysis (CHN). Their cytotoxic activities were investigated against four cancer cell lines, including colon (SW1116), breast (MDA-MB-231), lung (A549), and liver (HepG2) cancer cell lines. Among the synthesized compounds, 3b showed promising cytotoxic activity compared to 3-BP, with IC50 values of 16.3 µM, 19.1 µM, 27.8 µM, and 14.5 µM against A549, MDA-MB-231, SW1116 and, HepG2 cell lines, respectively. Furthermore, the effect of these compounds on MCF-10A (a normal breast cell lines) was investigated to determine their selectivity between tumorigenic and non-tumorigenic cells. Since the 3-BP inhibits hexokinase II (HK II), molecular docking of 3-BP derivatives was carried out using AutoDock 4.2. The binding energies of these derivatives were greater than 3-BP, indicating that they had a higher affinity for HK II. For validation of docking, a 40 ns MD simulation was performed. SwissADME was used to predict pharmacokinetics, drug-likeness, and ADME parameters of the screened compounds. The results demonstrated that these derivatives are suitable candidates for developing orally potent HK II inhibitors.