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

Abstract

A series of new N,N-dimethylaminopropyl- and 2-imidazolinyl-substituted derivatives of benzo[b]thienyl- and thieno[2,3-b]thienylcarboxanilides and benzo[b]thieno[2,3-c]- and thieno[3',2':4,5]thieno[2,3-c]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. Highly predictive 3D-derived QSAR models were obtained, and molecular properties that have the highest impact on antitumor activity were identified. Carboxanilides 6a-c and quinolones 9a-c and 11a 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.

Synthesis, Molecular Docking and Biological Evaluation of Quinolone Derivatives as Novel Anticancer Agents

“…It is noted that the substitution R 2 at the 2-position of phenyl (8i) exhibiting better biological activities than the substitution R 2 at the 3-position of phenyl (8j), which may be due to steric-hindrance effect. Docking Study Docking was performed against DNATop I because it is reported as possible anticancer target of [16][17][18][19] In order to understand the binding conformation of the most potent cytotoxic activity of the compound 8i, its flexible molecular docking was carried out into the Top I (PDB code: 1K4T) active site using CDOCKER protocol of Discovery Studio 2.1.…”

Comparison of Antitumor Activity of Some Benzothiophene and Thienothiophene Carboxanilides and Quinolones in 2D and 3D Cell Culture System

“…[14][15][16][17] CHROM logD DETERMINATION Chrom logD values were determined from the following equation: chrom logD = 0.0857 x CHI -2 (ref. Chromatographic Hydrophobic Index (CHI) values have been determined from gradient retention times (tR) as described by Valkó and Slegel.…”

“…As a part of our continuing search for potential anticancer agents structurally related to heterocyclic quinolones, we have previously reported synthesis and strong inhibitory activities on several human tumor cell lines of versatile benzothiophene and thienothiophene carboxanilides and quinolones, thus confirming the anticancer potential of this class of compounds. [14][15][16][17] In general, amidino-substituted benzo [b]thieno [2,3-c]quinolones, strong ds-DNA/RNA intercalators, showed in general stronger and more selective antitumor activity than acyclic precursors. Also, we have shown that replacement of the acyclic amidino groups with cyclic amidino 2-imidazolinyl group, respectively, resulted with increased antitumor activity.…”

“…Furthermore, compounds with high DNA binding capacity were identified as the most promising inhibitors of tumor growth and of topoisomerase activity. [14][15][16][17] Guided by all above mentioned compounds, we have chosen selected benzo[b]thiophene, thieno [2,3-b]thiophene and thieno [3,2-b]thiophene-2-carboxanilides and their cyclic derivatives [2,3-c]quinolones as potential anticancer agents for further biological evaluation. The screened compounds were used as a small platform to compare potential antitumor activity in 2D and 3D cancer cell culture system.…”

“…were previously synthesized and characterized in our research group. [14][15][16] Starting from corresponding carbonyl-chlorides and substituted anilines, 2-carboxanilides 1-5, 7 and 18-19 were prepared. Amidino substituted derivatives 1-4 and 14-17 were prepared by Pinner reaction from cyano substituted precursors.…”