Activity profile analysis of carboxamides of 2-aryl-3- hydroxyquinolin-4(1H)-one

Introduction

Carboxamides of 2-aryl-3-hydroxyquinolin-4(1H)-one represent an attractive group of compounds with different biological activities, displaying especially antiprotozoal, anticancer and immunosuppresive effects. 102 compounds were tested against several normal and tumor cell lines and for flow cytometric profiling. The goal of the study was to identify structure-property relationships using chemoinformatics approaches and select most promising candidates for further developments.

Materials/methods Commonly and widely used MTT test of cytotoxicity was applied in order to obtain IC50 values for compounds against normal and daunorubicin-resistant CEM, normal and paclitacxel-resistant K562, wild and mutated HCT116p53, A549, MRC-5 and BJ. Information about cell cycle alterations was obtained by propidium iodide staining. For analysis of DNA and RNA synthesis, the cells were treated by 5-bromo-2‘-deoxyuridine and 5-bromouridine, correspondingly. Statistical analysis and visualization of found structureactivity relationships was performed using R.

Results and conclusions The results are good demonstration of efficiency of chemoinformatics approaches for structure-activity relationship analysis. Analysis of anti-tumor activity showed that compounds bearing carboxamide moiety at different position of 2-aryl-3-hydroxyquinolin-4(1H)-one core leaded to different anti-tumor profiles of compounds. In general a good correlation between activity against different tumor cell lines is observed (R > 0.6). However for derivatives bearing carboxamide group at position 8 of quinolinone cycle the activity against mutated HCT116p53 doesn‘t correlate with activities against other cell lines. It was found that position of carboxamide moiety significantly influences cell cycle profile and DNA/RNA production. Compounds having carboxamide moiety at position 6 produced higher levels G0G1 phase and lower levels of S phase cells relative to control. At the same time compounds with carboxamide at position 8 demonstrated significantly higher levels of RNA synthesis. As a result three most promising compounds were chosen.