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

The synthesis of a series of new N -benzylidene derivatives of 3-amino-4-imino-3,5-dihydro-4 H -chromeno[2,3- d ]pyrimidine 10(a-l) 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 1 H and 13 C NMR, FTIR and HRMS. The in silico physicochemical properties of compounds 10(a-l) were determined according to Lipinski's rules of five (RO5) associated with the prediction of their bioavailability. These new compounds 10(a-l) 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 10h and 10i showed sub-micromolar cytotoxic activity on tumor cell lines (0.23 < IC 50 < 0.3 μM) and no toxicity on fibroblasts (IC 50 > 25 μM). A dose-dependent inhibition of Store-Operated Ca +2 Entry (SOCE) was observed in the HEK293 cell line with 10h . In vitro embryotoxicity and angiogenesis on the mCherry transgenic zebrafish line showed that 10h presented no toxic effect and no angiogenic effect on embryos with a dose of 5 μM at 72 hpf.