Amino- and fluoro-substituted quinoline-4- carboxylic acid derivatives: MWI synthesis, cytotoxic activity, apoptotic DNA fragmentation and molecular docking studies

Abstract

In continuation of our research work on amino substituted quinoline-4-carboxylic acid derivatives, microwave irradiated and conventional heating methods were used for synthesis of target compounds. Benzaldehyde, pyruvic acid, and 3-chloro-4-fluoroaniline in absolute ethanol media reacted, condensed, and cyclized to form intermediate 7-chloro-6-fluoro-2-phenyl-quinoline-4-carboxylic acid. This intermediate reacted with various substituted amines attaining desired products 6-fluoro-2- phenyl-7-substitutedamino-quinoline-4-carboxylic acid derivatives (7a–7l). Products obtained by microwave synthesizer showed short reaction time of 110–210 s and yield of 91–96 %, demonstrating advantages of the said method. All synthesized compounds were identified and characterized by FT-IR, 1H and 13C NMR, Mass spectroscopy, and Elemental analysis. Synthesized compounds were tested for their effect on cellular viability against various carcinoma cell lines viz. MCF-7, HELA, Hep-2, NCI, HEK-293, and VERO by XTT bioassay at 24 h of drug exposure using doxorubicin and methotrexate as standard drugs. Majority of the compounds proved to be more potent than doxorubicin and compounds 7a, 7c, 7d, and 7i exhibited significant anticancer activity Apoptotic DNA fragmentation was carried out on MCF-7 and HEK-293 cell lines and found that few compounds exhibited excellent DNA fragmentation pattern confirming apoptosis. Docking study was performed by Surflexdock to establish probable mechanism of action of synthesized compounds using X-ray crystallographic structure of the ATPase domain of hTopoIIa. Docking experiments confirmed good correlation between calculated interactions with the hTopoIIa and the observed IC50 values. The present study of quinoline-4-carboxylic acid derivatives may be considered as promising lead for future design of potent hTopoIIa inhibitors as novel anticancer agents.