Synthesis, in vitro and in silico evaluation of new flavonoids-trifluoroacetylated amino acid conjugates as anti-acetylcholinesterase and anti-proliferative agents

A series of halogenated 3-hydroxyflavones (3HFs) ( 3a-3f ) and their conjugates with two trifluoroacetylated amino acids, namely glycine and L-alanine, were synthesized and characterized by 1 H NMR, 13 C NMR and ESI-HRMS. All the compounds were evaluated for their ability to inhibit the acetylcholinesterase enzyme and for their anti-proliferative effect against MCF-7, HCT-116 and OVCAR-3 cancer cell lines by standard MTT assay. Most of 3HFs-amino acids conjugates demonstrated promising cytotoxic activities, significantly higher than the corresponding 3HFs. Among them, compounds 8f and 9a showed the best cytotoxic activity against MCF-7 (IC 50  = 5.5 and 5.3 µM, respectively), HCT-116 (IC 50  = 6.2 and 5.5 µM, respectively) and OVCAR-3 (IC 50  = 9.2 and 8.9 µM, respectively). The derivatives 9c and 9b exhibited the highest anti-acetylcholinesterase activity with IC 50 values of 50.1 and 55.2 µM, respectively. The structure-activity relationship (SAR) is discussed based on molecular docking simulations.