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标题：Computational study and in vitro evaluation of the anti-proliferative activity of novel naproxen derivatives
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作者：Abdullah G. Al-Sehemi ; Abdullah G. Al-Sehemi ; Ahmad Irfan 等
期刊名称：Journal of King Saud University - Science
印刷版ISSN：1018-3647
出版年度：2017
卷号：29
期号：3
页码：311-319
DOI：10.1016/j.jksus.2017.01.003
语种：English
出版社：Elsevier
摘要：Graphical abstract Display Omitted Highlights • Naproxen derivatives were synthesized and characterized by FTIR, 1H and 13C NMR. • SAR, QSAR, FMO, MEP and reactivity descriptors were studied by DFT methods. • The in vitro cytotoxic screening was performed. • The effect of electron donating and withdrawing groups was studied. • Compound c showed strong antiproliferative activity against MCF-7 cells. Abstract In the present work, five naproxen derivatives, i.e., 3-amino-(4E)-5-imino-1-[2-(6-methoxy-2-naphthyl)propanoyl]-4-(benzylidene)-4,5-dihydro-1H-pyrazole (a), 3-amino-(4E)-5-imino-1-[2-(6-methoxy-2-naphthyl)propanoyl]-4-(4-bromobenzylidene)-4,5-dihydro-1H-pyrazole (b), 3-amino-(4E)-5-imino-1-[2-(6-methoxy-2-naphthyl)-propanoyl]-4-(4-methoxybenzylidene)-4,5-dihydro-1H-pyrazole (c), 3-amino-(4E)-5-imino-1-[2-(6-methoxy-2-naphthyl)propanoyl]-4-(4-methylbenzylidene)-4,5-dihydro-1H-pyrazole (d), 3-amino-(4E)-5-imino-1-[2-(6-methoxy-2-naphthyl)propanoyl]-4-(4-nitrobenzylidene)-4,5-dihydro-1H-pyrazole (e) were synthesized then characterized by FTIR, 1H and 13C NMR techniques. The ground state geometries were optimized by B3LYP functional of density functional theory (DFT) with three different basis sets (6-31G∗, 6-31G∗∗ and 6-31+G∗∗). The absorption wavelengths, oscillator strengths and major transitions were calculated using time dependent DFT. The effect of electron withdrawing groups (–NO2 and –Br) and electron donating groups (–CH3 and –OCH3) was intensively studied with respect to structure–activity relationship (SAR), quantitative structure–activity relationship (QSAR), frontier molecular orbitals (FMOs), molecular electrostatic potentials (MEP) and global reactivity descriptors. By the analysis of molecular docking work, it was found that pure hydrophobic substitution at position 4 of aldehyde part is more favorable than hydrophilic one. Compound c showed strong anti-proliferative activity against MCF-7 cells with IC50 value of 1.49μM, and compound d showed moderate activity. The docking studies revealed that normal alkane chain is improving the biological activity in compound c, which endorsed to bury well in the active site resulting to enhance the hydrophobic interactions. The newly synthesized compounds against tested cell lines showed stronger antiproliferative activity as compared to the naproxen.
关键词：Biological active compounds;Naproxen derivatives;Quantitative structure–activity relationship;Electro-optical properties;Antiproliferative activity