Molecular hybridization-based design, PASE three-component synthesis, antiproliferative activity and molecular modelling studies of N,N-dimethylaminophenyl substituted 5H-chromeno[2,3-b]pyridine analogs

Abstract

A series of N,N-dimethylaminophenyl substituted 5H-chromeno[2,3-b]pyridine derivatives were designed using molecular-hybridization strategy and synthesised using a pot, atom and step economy (PASE) approach. The synthesis involves the one-pot three component reaction of salicyaldehydes, 3-(dimethylamino)phenol and 2-aminopropene-1,1,3-tricarbonitrile catalyzed by triethylamine as a catalyst in ethanol at reflux. This methodology has many beneficial features, including a broad substrate range, easy work up, non-column chromatographic separation, and high product yield. All newly synthesized compounds were screened for their antiproliferative activity towards several human cancer cell lines such as PC3 (prostate), MDA-MB-231 (breast cancer), MIA Paca-2 (pancreatic), HEK293 (hypotriploid) and CHO (Chinese hamster ovary). The SAR identified the compounds 4e and 4k as the most potent analogs in the series, while 4c and 4d demonstrated moderate antitumoral activities. Molecular docking studies revealed that the lead compounds selectively occupy the colchicines binding site of tubulin. Molecular dynamics simulation results supported anticancer efficacy of the synthesized compounds with high molecular stability in binding pocket of heterodimer.