Design, Synthesis, and Biological Evaluation of Novel Trifluoromethoxy Substituted Pyrazolines as Potential Tubulin Assembling Inhibitors

Abstract

Breast cancer is a major health problem with an increasing number of cases over the years. Few classes of anticancer agents have been developed but they established toxic effects on normal cells. Despite the availability of many effective drugs to treat different types of cancers, chemotherapeutic drugs are unable to distinguish between healthy and cancerous cells, resulting in the risk of side effects and drugs resistance. There is a continuous effort to find new agents to help bring this disease under control. In this study, novel fluorinated pyrazolines derivatives (2a-c) were designed and synthesized via cyclo-condensation reaction of commercially available trifluoromethoxy phenylhydrazine with a series of chalcone derivatives (1a-c). These pyrazoline compounds, 2a-c exhibited inhibitory activity against MCF-7 cell lines with the IC50 values of 7.62 ± 0.69, 29.61 ±1.60 and 14.38 ± 0.69 μM, respectively. These values are comparable to the positive control, Doxorubicin (IC50 of 17.44 ± 5.32 μM). Pyrazoline 2a exhibited the best free binding energy of-10.8 kcal/mol compared to pyrazoline 2b and 2c which showed the free binding energy of-8.6 and-9.5 kcal/mol, respectively. Molecular docking results of pyrazoline 2a exhibited good interaction between OCF3 moiety with EGFR active site, forming three π bonds which enhanced the anticancer activity. Therefore, pyrazoline 2a would provide promising access to future studies as a potential antitumor agent. Keywords: Fluorinated compounds, trifluoromethoxy, pyrazoline derivatives, molecular modelling, anticancer activity