Synthesis of Heterocyclic Compounds Derived From Dimedone and their Anti-tumor and Tyrosine Kinase Inhibitions.

The reaction of dimedone with arylaldehydes gave the benzylidene derivatives 3a-c, the latter underwent a series of heterocyclization reactions to give fused thiophene, pyrazole isoxazole and pyridazine derivatives. The synthesized compounds were evaluated against different kinds of cancer cell lines together tyrosine kinases and Pim-1 kinase inhibitions. All the synthesized compounds were assessed for the inhibitory activities against A549 (non-small cell lung cancer), H460 (human lung cancer), HT-29 (human colon cancer) and MKN-45 (human gastric cancer) cancer cell lines together with foretinib as the positive control by a MTT assay. The promising compounds were 3c, 5b, 5e, 5f, 7c, 7f, 9c, 11b, 12c, 12d, 13b, 13d, 14b, 16c and 16d among the tested compounds. On the other hand, compounds 5b, 5e, 5f, 7c, 11b, 12c, 12d, 13d, 14b, 16c and 16d were the most effective inhibitors against tyrosine kinases and compounds 5b, 11b, 12d, 13d, 14b and 16c were the most potent against Pim-1 kinase.

1,2,4-Trisubstituted imidazolinones with dual carbonic anhydrase and p38 mitogen-activated protein kinase inhibitory activity.

Various 1,2,4 trisubstituted imidazolin-5-one derivatives were synthesized and evaluated for their inhibitory activity against p38 mitogen-activated protein kinase (p38MAPK) and carbonic anhydrase (CA) enzymes aiming to explore potential dual inhibitors. Results revealed that compounds 3c, 3g, 3h, 4a, 6c and 6d were the most effective derivatives against p38αMAPK (IC50 = 0.14, 0.14, 0.056, 0.14, 0.13 and 0.14 µM, respectively) compared to sorafenib (IC50 = 1.58 µM) as standard drug. On the other hand, compound 4a revealed the best inhibitory activity against all the tested carbonic anhydrase isoforms CA I, II, IV and IX with Ki values of 95.0, 0.83, 6.90 and 12.4 nM, respectively compared to acetazolamide with Ki values 250, 12.1, 74 and 12.8 nM, respectively. Therefore, compound 4a can be considered as a potent dual p38αMAPK/CA inhibitor.