An efficient synthesis of substituted pyrido[2,3-d]pyrimidines was carried out and evaluated for in vitro anticancer activity against five cancer cell lines, namely hepatic cancer (HepG-2), prostate cancer (PC-3), colon cancer (HCT-116), breast cancer (MCF-7), and lung cancer (A-549) cell lines. Regarding HepG-2, PC-3, HCT-116 cancer cell lines, 7-(4-chlorophenyl)-2-(3-methyl-5-oxo-2,3-dihydro-1H-pyrazol-1-yl)-5-(p-tolyl)- pyrido[2,3-d]pyrimidin-4(3H)-one (5a) exhibited strong, more potent anticancer (IC50: 0.3, 6.6 and 7 µM) relative to the standard doxorubicin (IC50: 0.6, 6.8 and 12.8 µM), respectively. Kinase inhibitory assessment of 5a showed promising inhibitory activity against three kinases namely PDGFR β, EGFR, and CDK4/cyclin D1 at two concentrations 50 and 100 µM in single measurements. Further, a molecular docking study for compound 5a was performed to verify the binding mode towards the EGFR and CDK4/cyclin D1 kinases.

A new series of pyrido[2,3-d]pyrimidin-4(3H)-one derivatives having the essential pharmacophoric features of EGFR inhibitors has been designed and synthesised. Cell viability screening was performed for these compounds against A-549, PC-3, HCT-116, and MCF-7 cell lines at a dose of 100 μM. The highest active derivatives ( 8a, 8 b, 8d, 9a, and 12b ) were selected for IC 50 screening. Compounds 8a, 8 b, and 9a showed the highest cytotoxic activities and were further investigated for wild EGFR WT and mutant EGFR T790M inhibitory activities. Compound 8a showed the highest inhibitory activities against EGFR WT and EGFR T790M with IC 50 values of 0.099 and 0.123 µM, respectively. In addition, it arrested the cell cycle at pre-G1 phase and induced a significant apoptotic effect in PC-3 cells. Furthermore, compound 8a induced a 5.3-fold increase in the level of caspase-3 in PC-3 cells. Finally, docking studies were carried out to examine the binding mode of the synthesised compounds against both EGFR WT and EGFR T790M .

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Pyrido[2,pyrimidines and thiazolo based scaffold were reported to exhibit valuable anticancer activity and inhibit EGFR tyrosine kinase receptors wild and mutant types as well. So a new series of 6,8-diaryl pyrido [2,3-d]thiazolo[3,2-a]pyrimidinones 2a-c was synthesized and their confirmed chemical structures were established through various spectral analyses including IR, 1 HNMR, 13 CNMR and mass spectroscopy. Anticancer evaluation was performed through screening for these compounds against MCF-7, PC-3, HCT-116 and A-549 cancerous cell lines at a dose of 100 in comparison with erlotinib. The antiproliferative activity revealed that compound 2a was excellent and approximately equipotent with the reference (IC50= 13.25 and 11.05 μM) which implicated that substitution at position 6 and 8 greatly affect the cytotoxic activity. Furthermore, the promising compound 2a was subjected to molecular docking analysis against EGFR WT and EGFR T790M kinases to examine the binding mode and elucidate the mechanism of the promising cytotoxic activity. Finally compound 2a has been shown to be good candidate that deserve further investigation.