Synthesis, COX-2 inhibition and Metabolic Stability Studies of 6-(4-fluorophenyl)-pyrimidine-5-carbonitrile derivatives as Anticancer and Anti-inflammatory agents

Abstract In continuation of previous work on cyanopyrimidine derivatives for cancer and inflammation, eighteen novel amino containing cyanopyrimidine derivatives (4a-p) bearing secondary or tertiary amines and alkyl-thio substitution were synthesized by Biginelli condensation reaction followed by nucleophilic substitution reaction. Two compounds 4 g (NSC: 795754) and 4o (NSC: 798988) showed excellent anticancer potency against most of the cell lines. Compound 4 g was selected for five dose-assays and the result of tested compound was given by three response parameters i.e. GI50, TGI and LC50 for each cell line. Compound 4 g exhibited superior anticancer activity against ovarian cancer with GI50-value of 0.33 μM and selectivity index of 4.84 in comparison to 5-fluoro uracil (5-FU) which exhibited GI50-value 4.43 μM. During in-vivo anti-inflammatory study, compound 4 g exhibited 87% inhibition of inflammation at 3 h which was found superior to the standard drugs ibuprofen (78%) and celecoxib (52%). The compounds 4 g and 4o exhibiting both anticancer and anti-inflammatory potential were further studied for their biological target studies and in-vitro metabolic stability assessment. The result showed that compounds 4 g and 4o displaying broad anticancer activity were more selective towards COX-2 as compared to COX-1.