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Pyrazinoic acid or pyrazine-2-carboxylic acid (PA), due to its nitrogenous heteroaromatic ring, can be explored as an anticancer agent. Here, a series of twenty novels PA derivatives have been synthesized and characterized using IR, NMR, and mass spectrums. Their cytotoxic activity was evaluated against three different cancer cell lines, including lung (A549), breast (MCF-7), and colon (HT-29). P16, the most potent compound, showed moderate cytotoxicity with IC 50 of 6.11 μM, 10.64 μM, and 14.92 μM, against the A549, MCF-7, and HT-29 cell lines, respectively. Furthermore, the effect of this compound against MRC5 as a non-tumoral lung cell line, exhibited a selectivity index of 9.02. The apoptotic induction activity of P16 was also performed on the A549 cell line. The results showed that as the concentration of the compound increases (from 3 to 6 μM), the percentage of induction of apoptosis increases from 8.54% to 72.4%. Electrophoretic gel mobility shift assays showed that P16 was also able to ROS induce DNA cleavage in the presents of H 2 O 2 (1.0 mM) in dose-dependent manner. Molecular docking was also applied to anticipate the binding locations and the binding of the synthesized compound with Bcl-2 apoptosis regulator and DNA as their proposed targets.

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, 1H‐, 13C‐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.

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