12th International Conference of Pharmaceutical Sciences

The present study aims to synthesize novel double PI3K/mTOR inhibitors that act on PI3K/Akt/mTOR pathway. In silico and in vitro assays were proposed in order to evaluate the affinity of obtained molecules on both enzymes, their mode of interaction and possible cytotoxicity. The synthetic strategy was based on the method described by LIU et al1, which comprised a three component reaction in one pot procedure. In general, this involved the treatment of 2-aminonicotinic acid with anhydrous pyridine, triphenyl phosphate, an amine-protected amino acid and microwave irradiation. Then, the mixture was treated with the second carboxyl-protected amino acid and heated in microwave again. The best conditions were determined for both steps after some attempts. Therefore, the synthesis of 13 new compounds was achieved, giving pyrazino[1,2-a]pyrido[2,3-d]pyrimidine-5,7-dione products in moderate yields (22-74%). These were properly characterized by 1H NMR , 13C, gCOSY, gHMQC, gHMBC and ESI-MS techniques after purification by CCC and HPLC. Modeling studies were also accomplished by using LigPrep, Maestro and Glide programs, which confirmed the affinity of the compounds for mTOR target. In vitro assays on two different cell lines (SH-SY5Y and HepG2) showed that all compounds were not cytotoxic (Figure 1).