Synthesis, anticancer and antioxidant activities of novel heterocyclic phenolic hydrazone based derivatives: Investigation of DFT calculation, molecular docking and drug-likeness studies

In this research, the anticancer and antioxidant activities of a novel class of heterocyclic phenolic hydrazone derivatives were investigated. The structure determination of the synthesized compounds was carried out through nuclear magnetic resonance spectroscopy, high-resolution mass spectrometry and infrared spectroscopy. The antiproliferative activities of the synthesized compounds were examined against three cancer cell lines (BGC823, MCF-7 and A549). Specifically, L3 showed better antiproliferative activity against these three cancer cell lines than standard 5-FU, but had no toxic effect on normal human liver cell line (HL-7702). In addition, DPPH and ABTS methods were used to evaluate the antioxidant activity of the synthesized compounds. Compound L3 was more effective in scavenging free radicals than the antioxidant BHT. The results of the structure-activity relationship study revealed that the rules governing anticancer and antioxidant activities of these compounds were similar. Specifically, the introduction of hydroxyl groups, quinoline and benzothiazole ring usually had a positive effect on activities, while the electron-withdrawing group (F) at the C5-position of the pyrimidine ring linked to imine bond were not favorable. The DFT computations were carried out using the B3LYP functional with def2-SVP basis set and calculation was executed via Gaussian 16 software. Frontier molecular orbital (FMO) analysis showed that high chemical potential highlighted the stronger binding affinity of compounds L3 and L4, indicating stronger potential interactions with amino acids. The electrophilic and nucleophilic reaction sites of these molecules were identified using molecular electrostatic potential (MEP). In addition, molecular docking studies were conducted to gain a deeper understanding of the interactions between 2CDU and 4AGM proteins and these compounds. Compared with the reference drugs, the studied compound showed higher binding affinity. Furthermore, the bioavailabilities of the synthesized compound have been established by the study of drug-likeness. The high human intestinal absorption (HIA) value indicated that compound L3 exhibited excellent oral efficacy. The above results indicated that the synthesized heterocyclic phenolic hydrazone derivatives may be effective pharmaceutical compounds and could be used as anticancer and antioxidant agents.