Design and campaign synthesis of pyridine-based histone deacetylase inhibitors.

A lead benzamide, bearing a cyanopyridyl moiety (3), was identified as a potent and low molecular weight histone deacetylase (HDAC) inhibitor. Various replacements of the cyano group were explored at the C3-position, along with the exploration of solubility-enhancing groups at the C5-position. It was determined that cyano substitution at the C3-position of the pyridyl core, along with a methylazetidinyl substituent at the C5-position yielded optimal HDAC1 inhibition and anti-proliferative activity in HCT-116 cells.