Novel Substituted Benzothiophene and Thienothiophene Carboxanilides and Quinolones: Synthesis, Photochemical Synthesis, DNA-Binding Properties, Antitumor Evaluation and 3D-Derived QSAR Analysis

A series of new <i>N</i>,<i>N</i>-dimethylaminopropyl- and 2-imidazolinyl-substituted derivatives of benzo­[<i>b</i>]­thienyl- and thieno­[2,3-<i>b</i>]­thienylcarboxanilides and benzo­[<i>b</i>]­thieno­[2,3-<i>c</i>]- and thieno­[3′,2′:4,5]­thieno­[2,3-<i>c</i>]­quinolones were prepared. Quinolones were prepared by the reaction of photochemical dehydrohalogenation of corresponding anilides. Carboxanilides and quinolones were tested for the antiproliferative activity. 2-Imidazolinyl-substituted derivatives showed very prominent activity. By use of the experimentally obtained antitumor measurements, 3D-derived QSAR analysis was performed for the set of compounds. Higly predicitive 3D-derived QSAR models were obtained, and molecular properties that have the highest impact on antitumor activity were identified. Carboxanilides <b>6a</b>–<b>c</b> and quinolones <b>9a</b>–<b>c</b> and <b>11a</b> were evaluated for DNA binding propensities and topoisomerases I and II inhibition as part of their mechanism of action assessment. The evaluated differences in the mode of action nicely correlate with the results of the 3D-QSAR analysis. Taken together, the results indicate which modifications of the compounds from the series should further improve their anticancer properties