Synthesis and cytotoxicity of thieno[2,3-b]pyridine and furo[2,3-b]pyridine derivatives

•Synthesis of 47 thieno- and furo[2,3-b]pyridines prepared and biologically assessed.•Polyhalogenated furo[2,3-b]pyridines found to be unstable.•Tetrahydrothieno[2,3-b]quinolones most active with GI50 in low nanomolar range.•Biological results correlate well with predicted binding of the ligands with PLC.

Forty seven thieno[2,3-b]pyridines-2-carboxamides, furo[2,3-b]pyridines-2-carboxamides and tetrahydrothieno[2,3-b]quinolones-2-carboxamides derivatives were synthesized and tested for their antiproliferative activity against the NCI-60 cell lines. The 5-keto-tetrahydrothieno[2,3-b]quinolones-2-carboxamides (series 17) were found to have the greatest activity, with the compound containing a 3-methoxyphenylcarboxamide (compound 17d) being the most active, with GI50 values in the low nanomolar range against a range of cell lines, in particular the melanoma cell line MDA-MD-435 (GI50 – 23 nM) and the breast cancer cell line MDA-MB-468 (GI50 – 46 nM). Molecular modelling of series 17 against phosphoinositide specific-phospholipase C reveals that the side chains of the amino acids His356, Glu341, Arg549 and Lys438 are involved in hydrogen bonding with the ligands as well as a lipophilic pocket is occupied by the phenyl carboxamide moiety.

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