Design, synthesis and biological evaluation of novel morpholinopyrimidine-5-carbonitrile derivatives as dual PI3K/mTOR inhibitors.

In this study, novel morpholinopyrimidine-5-carbonitriles were designed and synthesized as dual PI3K/mTOR inhibitors and apoptosis inducers. The integration of a heterocycle at position 2, with or without spacers, of the new key intermediate 2-hydrazinyl-6-morpholinopyrimidine-5-carbonitrile (5) yielded compounds 6-10, 11a-c and 12a-h. The National Cancer Institute (USA) tested all compounds for antiproliferative activity. Schiff bases, 12a-h analogs, were the most active ones. The most promising compounds 12b and 12d exhibited excellent antitumor activity against the leukemia SR cell line, which is the most sensitive cell line, with IC50 0.10 ± 0.01 and 0.09 ± 0.01 µM, respectively, along with significant effects on PI3Kα/PI3Kß/PI3Kδ with IC50 values of 0.17 ± 0.01, 0.13 ± 0.01 and 0.76 ± 0.04 µM, respectively, for 12b and 1.27 ± 0.07, 3.20 ± 0.16 and 1.98 ± 0.11, respectively, for 12d compared to LY294002. Compared to Afinitor, these compounds inhibited mTOR with IC50 values of 0.83 ± 0.05 and 2.85 ± 0.17 µM, respectively. Annexin-V and propidium iodide (PI) double labeling showed that compounds 12b and 12d promote cytotoxic leukemia SR apoptosis. Compounds 12b and 12d also caused a G2/M cell cycle arrest in the leukaemia SR cell line. The findings of this study indicate that the highest effect was observed for 12b, which was supported by western blot and docking analysis.

Synthesis, biological evaluation and molecular docking studies of some pyrimidine derivatives.

Some novel pyrimidine-5-carbonitrile derivatives bearing various substituent have been synthesized. The structures of target compounds were confirmed by elemental analysis and spectral data. Some selected members of the newly synthesized compounds were investigated for their cytotoxic potency against certain human tumor cell lines. Five representative active anticancer compounds 6a, 6c, 6d, 17a and 18a were subjected to docking using MOE program on the 3D structure of two enzymes, namely; thymidylate synthase and dihydrofolate reductase. The antimicrobial activities of the synthesized compounds were tested against Staphylococcus aureus, Pseudomonas aeruginosa, Shigella flexneri and Candida albicans. Compounds 2c, 7a and 9c showed broad spectrum antimicrobial activity.