A set of hydroxamate derivatives of folic acid and methotrexate (MTX) was synthesized and evaluated for the
inhibitory activity against histone deacetylase (HDAC) and dihydrofolate reductase (DHFR), two enzymes overexpressed
in metastasizing tumors. The synthesized compounds were further screened for their antiproliferative activity in two human
cancer cell lines, A549 (non-small cell lung carcinoma) and PC-3 (prostate adenocarcinoma). All derivatives showed
significant inhibitory activity against HDACs (micromolar range) while only the MTX derivative was reasonably effective
in DHFR inhibition. A docking study provided insight into the binding mode of the most potent inhibitor in the active
sites of the enzymes, allowing rationalization of the bioassays. The MTX-based compound could be of interest for testing
against metastasizing tumors in an animal model. The studied derivatives represent promising molecular templates for further
development of dual activity anti-cancer drugs