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Design and Synthesis of Novel <i>N</i>-Benzylidene Derivatives of 3-Amino-4-imino-3,5-dihydro-4<i>H</i>-chromeno[2,3-<i>d</i>]pyrimidine under Microwave, <i>In Silico</i> ADME Predictions, <i>In Vitro</i> Antitumoral Activities and <i>In Vivo</i> Toxicity

The synthesis of a series of new <i>N</i>-benzylidene derivatives of 3-amino-4-imino-3,5-dihydro-4<i>H</i>-chromeno[2,3-<i>d</i>]pyrimidine <b>10(a-l)</b> bearing two points of molecular diversity is reported. These new compounds were synthesized in fi...

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Bibliographic Details
Main Authors:	Sirine Karoui (Author), Marwa Dhiabi (Author), Mehdi Fakhfakh (Author), Souhir Abid (Author), Emmanuelle Limanton (Author), Rémy Le Guével (Author), Thierry D. Charlier (Author), Anthony Mainguy (Author), Olivier Mignen (Author), Ludovic Paquin (Author), Houcine Ammar (Author), Jean-Pierre Bazureau (Author)
Format:	Book
Published:	MDPI AG, 2024-04-01T00:00:00Z.
Subjects:	article
Online Access:	Connect to this object online.
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Summary:	The synthesis of a series of new <i>N</i>-benzylidene derivatives of 3-amino-4-imino-3,5-dihydro-4<i>H</i>-chromeno[2,3-<i>d</i>]pyrimidine <b>10(a-l)</b> bearing two points of molecular diversity is reported. These new compounds were synthesized in five steps including two steps under microwave dielectric heating. They were fully characterized using <sup>1</sup>H and <sup>13</sup>C NMR, FTIR and HRMS. The <i>in silico</i> physicochemical properties of compounds <b>10(a-l)</b> were determined according to Lipinski's rules of five (RO5) associated with the prediction of their bioavailability. These new compounds <b>10(a-l)</b> were tested for their antiproliferative activities in fibroblasts and eight representative human tumoral cell lines (Huh7 D12, Caco2, MDA-MB231, MDA-MB468, HCT116, PC3, MCF7 and PANC1). Among them, the compounds <b>10h</b> and <b>10i</b> showed sub-micromolar cytotoxic activity on tumor cell lines (0.23 < IC<sub>50</sub> < 0.3 μM) and no toxicity on fibroblasts (IC<sub>50</sub> > 25 μM). A dose-dependent inhibition of Store-Operated Ca<sup>+2</sup> Entry (SOCE) was observed in the HEK293 cell line with <b>10h</b>. <i>In vitro</i> embryotoxicity and angiogenesis on the mCherry transgenic zebrafish line showed that <b>10h</b> presented no toxic effect and no angiogenic effect on embryos with a dose of 5 μM at 72 hpf.
Item Description:	10.3390/ph17040458 1424-8247