Synthesis of novel (S)-flurbiprofen-based esters for cancer treatment by targeting thymidine phosphorylase via Biomolecular Approaches

Abstract

The current work is based on the synthesis of novel ester derivatives (1–17) of commercially available drug flurbiprofen by using two methods. In the first method, CDI (1,1-carbonyldiimidazole) as a coupling reagent was used to stimulate the acid of flurbiprofen then various substituted phenols were added to the reaction mixture in the presence triethylamine in acetonitrile solvent. While in the second method, different alkyl halides were directly treated with the acid of flurbiprofen in the occurrence of potassium carbonate as a base in DMF solvent. The reactions direction was checked through thin layer chromatography. Modern spectroscopic techniques like, HR-ESI-MS, 1H- and 13C NMR were used for structural elucidation and finally these compounds were subjected for their thymidine phosphorylase inhibitory potential. Eight compounds (1, 5, 7, 2, 12, 6, 17, and 8) amongst the series were found potent inhibitors having IC50 values of 2.3 ± 0.6 to 14.9 ± 0.3 µM better than standard 7-deazxanthine = 15.1 ± 0.1 µM. Similarly, eight compounds showed significant to less activity while compound 15 was found inactive. The docking analysis reflects excellent binding of the active molecules at the predicted allosteric site of TP and the docking results correlates well with the experimental findings.