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Objective: Conjugating quinolones with different bioactive pharmacophores to obtain potent anticancer active agents. Methods: Fused pyrazolopyrimidoquinolines 3a-d, Schiff bases 5, 6a-e, two hybridized systems: pyrazolochromenquinoline 7 and pyrazolothiazolidinquinoline 8, different substituted thiazoloquinolines 13-15 and thiazolo[3,2-a]pyridine derivatives 16a-c were synthesized. Their chemical structures were characterized through spectral and elemental analysis, cytotoxic activity on five cancer cell lines, caspase-3 activation, tubulin polymerization inhibition and cell cycle analysis were evaluated. Results: Four compounds 3b, 3d, 8 and 13 showed potent activity than doxorubicin on HCT116 and three compounds 3b, 3d and 8 on HEPG2. These promising derivatives showed increase in the level of caspase-3. The trifloromethylphenyl derivatives of pyrazolopyrimidoquinolines 3b and 3d showed considerable tubulin polymerization inhibitory activity. Both compounds arrested cell cycle at G2/M phase and induced apoptosis. Conclusion: Compounds 3b and 3d can be considered as promising anticancer active agents with 70% of colchicine activity on tubulin polymerization inhibition and represent hopeful leads that deserve further investigation and optimization.

The targeted approach of protein kinases (PKs), as PKs are the main regulators of cell survival and proliferation, has been a promising strategy for treatments for cancer. Here we analyze the potential of quinoline-carboximide derivatives for four cell lines: MCF-7, CACO, HepG-2 and HCT-116 as anticancer agents. 3e, 4b, 11b and 13d derivatives showed good anti-proliferative activities in comparison to the reference standard Doxorubicin, against the four cell lines tested. They have been chosen for further studies. First of all, the IC50 value surveys were carried out to ensure the protection of our hits and demonstrate that the cytotoxic effect (IC50 > 113 μM) is highly selective on normal human cells (WI-38). Secondly, apoptosis was accomplished by down-regulation of Bcl-2 and up-regulation of BAX and Caspase-3 by these active compounds. Also, the Pim-1 inhibitory activity of the active hybrids was done, which indicate that compound 3e was the most active with percentage of inhibition 82.27% and IC50 equal 0.11 when compaired to SGI-1776 as a reference standered. In addition, the in silico assessment of ADME properties, all of the strongest compounds are orally bioavailable without blood brain barrier penetration.

Die Reaktion der Stickstoff‐Agenzien (I) mit den ungesättigten Ethoxyketoestern (II) verläuft unter Cyclisierung zu den Pyrimidinen (III); wenn (IIb) von seiner Darstellung her mit dem Vinyldiether (IV) verunreinigt ist, entstehen bei der obigen Kondensation neben (IIIb) in Spuren die entsprechenden Pyrimidine (V), die spektroskopisch nachgewiesen werden.

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