Design, Synthesis and Biological Evaluation of 2-(naphthoyl) iminothiazolidin-4-ones as Potential Anticancer Agents

A library of novel naphthyl bearing 2-iminothiazolidin-4-ones (2-ITZDs) (2 a-2 q) was designed and synthesized through a facile route involving regioselective heterocyclization of unsymmetrical thioureas (1 a-1 q). The synthesis was achieved at ambient temperature in good to excellent yields under catalyst free conditions. The molecular structures of 2-ITZDs were elucidated by spectroscopic techniques such as FT-IR, H-1-NMR and C-13-NMR. X-ray structural data was used to establish the structure (2 o) unequivocally and to define the geometry of exo double bond. The in vitro anticancer activity of 2-ITZDs (2 a-2 q) was investigated in several human cancer cell lines (A549, LNCap, PC-3, MDA-MB-231, BxPC3, MIA PaCa2). All compounds showed cytotoxicity with IC50 values ranging from 6-23 mu M in the tested cancer cell lines except MDA-MB-231. Compound 2 k (IC50=7 mu M) and the homologous analog 2 q (IC50=6 mu M) were found to be equipotent to 2 k and showed moderate cytotoxicity against human breast cell line (DA-MB-231). Furthermore, compound 2 k exhibited a medium permeability, enough metabolic stability and no significant inhibition of hERG channel. Compound 2 k inhibited cytochrome P450 activity below 50 % in 1 A2, 3 A4 and 2 C19, but not in 2 C9 and 2D6 at 10 mu M. Structure-activity relationships (SAR) provided useful insights towards this class of compounds and tiled a way to design novel analogues with increased potency.