Synthesis and Anti-Proliferative Activity of 5-Benzoyl and 5-Benzylhydroxy Derivatives of 3-Amino-2-Arylcarboxamido-Thieno[2-3-b]Pyridines

Abstract

3-Amino-2-arylcarboxamido-thieno[2-3-b]pyridines have been previously described as having potent anti-proliferative activity against MDA-MB-231 and HCT116 cancer cell lines. The mechanism by which these molecules prevent cancer cell growth is proposed to be through interfering with phospholipid metabolism via inhibition of PI-PLC, along with other cellular processes. Previously, 5-cinnamyl derivatives of these thieno[2-3-b]pyridines have been shown to have enhanced anti-proliferative activity compared to compounds lacking this moiety, indicating a tethered aromatic ring is important for this western region of the pharmacophore. Herein, we report the synthesis and biological evaluation of a library of 40 novel thieno[2-3-b]pyridine analogues containing shorter benzoyl or secondary benzyl alcohol tethers at the 5-position, in addition to various substituents on the two phenyl rings present on the molecule. Compounds bearing alcohol functionality had improved efficacy compared to their benzoyl counterparts, in addition to a 2-methyl-3-halogen substitution on the 2-arylcarboxamide ring being important for maximising anti-proliferative activity. The most potent molecules 7h and 7i demonstrated IC50 concentrations of 25–50 nM against HCT116 and MDA-MB-231 cells, a similar level of activity as previous thienopyridine compounds bearing cinnamyl moieties, suggesting that these novel derivatives with shorter tethers were able to maintain potent anti-proliferative activity, while allowing for a more concise synthesis.