This work was supported by the Foundation for Science and Technology (FCT), Portugal (projects PTDC/QUI-QUI/113687/2009 and PEst-C/QUI/UI0081/2013). A.G. (SFRH/BD/43531/2008) and M.J.M. (SFRH/BD/61262/2009) thank FCT for grants.

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Chromone: A Valid Scaffold in Medicinal Chemistry

A series of N-methyl-3-nitro-4-(nitromethyl)-4H-chromen-2-amine derivatives 8 were synthesized from 2-((E)-2-nitrovinyl)phenol 7 and ((E)-N-methyl)-1-(methylthio)-2-nitroethenamine 5. The cytotoxic activity of these molecules was tested against two cancer cell lines namely HeLa (cervical cancer) and HEp-2 (epidermoid laryngeal carcinoma). Among them, two molecules (4H-chromenes 8h and 8i) displayed potent anti-proliferative activity with IC50 values of 115.04 and 18.96 μM for HeLa and 86.94 and 25.08 μM for Hep-2 cell lines, respectively. Morphological evaluation of the cell lines revealed that both 8h and 8i induce the apoptotic process. Molecular docking studies of all the 4H-chromenes 8 with anti-apoptotic Bcl-2, Bcl-w, and Bcl-xL proteins revealed that the 4H-chromenes 8h and 8i have good docking score and thus corroborated in vitro studies. Furthermore, evaluation of Lipinski and ADMET properties revealed their drug-like pharmacokinetic profiles. Thus, 4H-chromenes 8h and 8i exhibit promising anti-cancer properties and can be used as lead compounds for further development.

Design, synthesis, molecular docking, and biological evaluation of N -methyl-3-nitro-4-(nitromethyl)-4 H -chromen-2-amine derivatives as potential anti-cancer agents

A number of flavone and xanthone derivatives bearing some characteristic features of fluoroquinolones such as the fluorine atom and an ortho piperazine ring are described The new compounds have been tested for possible cytotoxic and antimicrobial activities Cytotoxicity of both groups of compounds is rather poor, while the antibacterial activity is restricted to xanthones

Flavone and xanthone derivatives related to fluoroquinolones.

A combinatorial library of eighteen C4-active methine-substituted 4H-chromenes were synthesized, and their anti-cancer properties were evaluated against four human cancer cell lines, namely laryngeal carcinoma (Hep2), lung adenocarcinoma (A549), colon carcinoma (HT-29) and cervical cancer (HeLa). Out of them, six displayed significant anti-proliferative activity. The best among them, the 4H-chromene with C4-malononitrile substitution, was selected for further structure–activity relationship studies. Six analogues were synthesized and subjected to in vitro studies on above four cancer cell lines. The best among them was subjected to detail in silico studies by binding with Bcl-2 protein, and the results corroborated those obtained from in vitro studies. Our findings show that the C4-malononitrile and C2-N-phenyl-substituted 4H-chromene are the most promising lead molecules for treatment of cancer.

Design, synthesis, in vitro and in silico anti-cancer activity of 4H-chromenes with C4-active methine groups

Anticonvulsant evaluation of aminoalkanol derivatives of 2- and 4-methylxanthone.

Chromone, flavone and xanthone analogues of geiparvarin (1) are described. Compounds 2a and 2b are more active in inhibiting the proliferation of F10 metastatic murine melanoma cells. In particular, 2a is 13 times more active at microM concentration after 48 h exposure.

Benzo-gamma-pyrone analogues of geiparvarin: synthesis and biological evaluation against B16 melanoma cells.

By appropriate superimposing of fenofibrate and fenofibric acid molecules, two xanthone derivatives (closed models) may be obtained. These compounds as well as their four chlorine-free isomers were prepared and tested on adrenaline- and theophylline-induced lipolysis in rat fat cells in comparison with ethyl 2-(4-chlorophenoxy)-2-methylpropionate (clofibrate). Some of these new derivatives besides being good inhibitors of adrenaline effect, as clofibrate is, were also very active in reducing theophylline-induced lipolysis. Very promising for further studies is the chlorine-free 3-isomer (3e). The possible difference in the action mechanism of these compounds as compared with clofibrate and the structure-activity relationships are briefly discussed.

Montanari P

Papers

Benzo-gamma-pyrone analogues of geiparvarin: synthesis and biological evaluation against B16 melanoma cells.

Xanthone analogues of clofibrate / Synthesis and biological evaluation as antagonists of lipolysis in vitro.