New Coumarin Derivatives: Design, Synthesis And Biological Activity

Coumarins are class of compounds with multiple biological activities such as antitumor, anti-inflammatory, antivirus, and antibacterial properties. Coumarins and its derivatives are kind of organic heterocyclic compounds, which exhibit extensive aplications and development foreground. Structure-based design principles, by means of molecular simulation techniques, a total of 28 novel compounds, that 4 novel series of 2H-chromene-3-carboxamide, 2H-chromene-3-carbothioate and dihydropyrazole containing coumarin moiety were designed 、 synthesized and screened structure-activity relationship in this paper. All of the compounds were characterized by 1H-NMR, 13C-NMR, elemental analysis and other modern means of physical analysis, among them, 4 compounds were provided with single crystal X-ray structural analysis. Many of which compounds have good anti-cancer activity and MAO selectivity. The results were concluded as follows.(1) A series new 2H-chromene-3-carboxamides(4a–4i) and S-2H-chromene-3-carbothioates(5j–5t) were synthesized and evaluated as monoamine oxidase A and B inhibitors. Among them, compound 5k(IC50=0.21 mM, IC50 iproniazid= 7.65 mM) showed the most activity and higher MAO-B selectivity(189.2-fold vs 1-fold) with respect to the MAO-A isoform. The need to clarify at a 3D level some important molecular aspects of discussed SAR, we undertaked a number of docking simulations to better assess. The steric effect was analyzed interms of both posing and scoring by investigating the nature of the binding interactions. The docking results of active compound 5k with h MAO-B complex indicated that conserved residue ILE 199 was important for ligand binding via Sigma–Pi interaction.(2)A series of novel dihydropyrazole derivatives linked with 2H-chromen were designed and synthesized. All of the compounds have been screened for their antiproliferative activity against MGC-803, Hep3 b, SMMC-7721 and Hep G2 cell lines in vitro. The results revealed that compounds 4 and 5 exhibited strong inhibitory activity against Hep G2 cell and manifested obvious un-toxic effect on GES-1 and L-02 cell lines. Some title compounds were tested against telomerase, compound 5 showed the most potent inhibitory activity with IC50 value at 0.98±11?M, it could fit well into the active site of TERT. The further molecular mechanism of antiproliferation was explored, the data suggested that compound 5 could inhibit h TERT expression and Wnt/β-catenin signaling.