Synthesis And Bioactive Evaluation Of Chalcone Thiosemicarbazide And Aminoguanidine Derivatives

The fact that many compounds containing chalcone skeleton have biological activities, such as anti-tumor, anti-bacterial, anti-parasitic and so on, makes them arouse wide attention in chemical, medicinal and pharmaceutical research. Among these activities, the anti-tumor activity of chalcone shows the most attractive prospects for development, the mainly mechanisms are anti-angiogenic and antitubulin polymerization. Similarly, thiosemicarbazide and aminoguanidine compounds have low toxicity to humans and potent biological activity, which has become a hot topic in drug research. Herein, in continuation to extend our research on compounds with antitumor activity, we reported in the present work the synthesis and structure-activity relationships of two series of chalcone with thiosemicarbazide and aminoguanidine basic skeleton as potential EGFR inhibitor and antitubulin agent. According to the principle of structure-based design and molecular simulation techniques, a total of46new compounds were firstly designed, synthesized and tested their biological activity. The results were summarized below.(1) We synthesized24chalcone thiosemicarbazide derivatives (4a-4x) and measured their EGFR inhibitory activity. Firstly, different substituted chalcone compounds performed molecular docking simulation with EGFR protein molecular by the means of Autodock software. Then we can get the combination energy andinhibition constant, and analysis the molecular mechanism of interaction based on their interaction force docking conformation. According to the calculation results,24compounds were screened out. Secondly, the compounds were synthesized by a two-step chemical synthesis. The first step was the synthesis of a series of different substituted chalcone compounds, then grafted with thiosemicarbazide to form the target product. Certainly, the structure identify of all compounds were also performed, including1H NMR, ESI-MS, elemental analysis and crystal structure determination. Finally, biological activity of this series of compounds were measured, including anti-HepG2proliferation assay, EGFR inhibition assay and flow experimental tests. Given the combination of molecular modeling and biological activity screening results, we found that compound4r showed best EGFR inhibition activity, with IC50value of0.35μM, which is equal to the positive control Erlotinib.(2) We synthesized22chalcone aminoguanidine derivatives (5a-5v) and determined their antitubulin polymerization activity. Firstly, different substituted chalcone compounds performed molecular docking simulation with tubulin protein molecular by the means of Autodock software. Then we can get the combination energy and inhibition constant, and analysis the molecular mechanism of interaction based on their interaction force docking conformation. According to the calculation results,22compounds were screened out. Secondly, the compounds were synthesized by a two-step chemical synthesis. The first step was the synthesis of a series of different substituted chalcone compounds, then grafted with aminoguanidine to form the target product. Certainly, the structure identify of all compounds were also performed, including1H NMR, ESI-MS, elemental analysis and crystal structure determination. Finally, biological activity of this series of compounds were measured, including anti-MCF-7proliferation assay, tubulin polymerization activity assay, DAPI staining and cell cycle analysis experiments. Given the combination of molecular modeling and biological activity screening results, we found that compound5q showed best tubulin polymerization inhibition activity, with IC50value of8.4±0.6μM, which is equal to the positive control colchicine.