Discovery of novel pyrazole based Urea/Thiourea derivatives as multiple targeting VEGFR-2, EGFR(WT), EGFR(T790M) tyrosine kinases and COX-2 Inhibitors, with anti-cancer and anti-inflammatory activities.

A novel series of pyrazole derivatives with urea/thiourea scaffolds 16a-l as hybrid sorafenib/erlotinib/celecoxib analogs was designed, synthesized and tested for its VEGFR-2, EGFRWT, EGFRT790M tyrosine kinases and COX-2, pro-inflammatory cytokines TNF-α and IL-6 inhibitory activities. All the tested compounds showed excellent COX-2 selectivity index in range of 18.04-47.87 compared to celecoxib (S.I. = 26.17) and TNF-α and IL-6 inhibitory activities (IC50 = 5.0-7.50, 6.23-8.93 respectively, compared to celecoxib IC50 = 8.40 and 8.50, respectively). Screening was carried out against 60 human cancer cell lines by National Cancer Institute (NCI), compounds 16a, 16c, 16d and 16 g were the most potent inhibitors with GI% ranges of 100 %, 99.63-87.02 %, 98.98-43.10 % and 98.68-23.62 % respectively, and with GI50 values of 1.76-15.50 µM, 1.60-5.38 µM, 1.68-7.39 µM and 1.81-11.0 µM respectively, in addition, of showing good safety profile against normal cell line (F180). Moreover, compounds 16a, 16c, 16d and 16 g had cell cycle arrest at G2/M phase with induced necrotic percentage compared to sorafenib of 2.06 %, 2.47 %, 1.57 %, 0.88 % and 1.83 % respectively. Amusingly, compounds 16a, 16c, 16d and 16 g inhibited VEGFR-2 with IC50 of 25 nM, 52 nM, 324 nM and 110 nM respectively, compared to sorafenib (IC50 = 85 nM), and had excellent EGFRWT and EGFRT790M kinase inhibitory activities (IC50 = 94 nM, 128 nM, 160 nM, 297 nM), (10 nM, 25 nM, 36 nM and 48 nM) respectively, compared to both erlotinib and osimertinib (IC50 = 114 nM, 56 nM) and (70 nM, 37 nM) respectively and showed (EGFRwt/EGFRT790M S.I.) of (range: 4.44-9.40) compared to erlotinib (2.03) and osmertinib (1.89).

Fadaly WAA ，Nemr MTM ，Kahk NM 《-》

Optimization of pyrazole/1,2,4-triazole as dual EGFR/COX-2 inhibitors: Design, synthesis, anticancer potential, apoptosis induction and cell cycle analysis.

A novel series of pyrazol-4-yl-1,2,4-triazole-3-thiol derivatives 14a-l was designed, prepared and characterized by many spectroscopic techniques. All the novel compounds were screened for their anti-proliferative activity towards breast cancer cell line (MCF-7), colon cancer cell line (HT-29) and lung cancer cell line (A-549) utilizing celecoxib, erlotinib and osimertinib as standards. Compounds 14b, 14g and 14k were the most active towards HT-29, MCF-7 and A-549 cell lines, sequentially with IC50 = 1.20-2.93 μM compared with celecoxib (IC50 = 16.47-41.45 μM), erlotinib (IC50 = 1.95-33.57 μM) and osimertinib (IC50 = 0.75-3.45 μM). These most active derivatives 14b, 14g and 14k were further investigated for their inhibitory potential against COX and EGFR enzymes. These compounds 14b, 14g and 14k suppressed COX-2 (IC50 = 0.560-4.692 μM), EGFRWT (IC50 = 0.121-0.423 μM) and EGFRT790M (IC50 = 0.076-0.764 μM) enzymes. Compounds 14b, 14g and 14k displayed apoptosis induction by up-regulating Bax and down-regulating Bcl-2 protein levels. Cell cycle analysis recorded that exposure of MFC-7 cells to compound 14g resulted in a significant increase in the percentage of cells at the G2/M to 39.15 % compared to the standard erlotinib (9.87 %). Docking study of the most potent candidates 14b, 14g and 14k within COX-2, EGFRWT and EGFRT790M active regions was conducted to suggest the binding mode of these compounds inside these target enzymes.

Kahk NM ，Mohamed FEA ，Abdelhakeem MM ，Bakr RB ... -  《-》

Design, Synthesis, Docking Studies, and Investigation of Dual EGFR/VEGFR-2 Inhibitory Potentials of New Pyrazole and Pyrazolopyridine Derivatives.

The anticancer potential of certain newly synthesized pyrazole and pyrazolopyridine derivatives has been estimated. NCI 60 cancer cells cytotoxic screening pointed out compounds 3e and 3f as the highest cytotoxic agents with % mean growth inhibition of 67.69% and 87.34%, respectively. The five dose outcomes outlined 3f as the most potent cytotoxic agent with promising MG-MID GI50 = 3.3 µM when compared to erlotinib (MG-MID GI50 = 7.68 µM). In the in vitro assays, compounds 3d, 3e, 3f, and 4a demonstrated dual inhibitory potential on EGFRWT and VEGFR-2 with IC50 range of 0.066-0.184 µM and 0.102-0.418 µM, respectively. The best dual EGFR/VEGRF-2 inhibitory effect was shown by the compound 3f. Moreover, the latter compound stopped the cell cycle at the G1/S phase. Also, it greatly boosted total apoptosis, including early and late apoptosis, by 54.5- and 84.7-fold, respectively, which supposes HCT-116 cell death via inducing apoptosis. This was confirmed by the elevation of the BAX and caspase-3 levels, and the decreased BCL-2 level. Moreover, the safety of the most active compound 3f was assessed and the results showed promising selectivity of compound 3f toward HCT-116 over FHC (selectivity index [SI]: 20.84) when compared to erlotinib (SI: 3.42). Finally, compound 3f demonstrated efficient binding to both EGFR and VEGFR-2 enzymes, which could explain the sufficient inhibition level of each enzyme.

Alhamaky SM ，Khalil NA ，Bass AKA ，Osama N ，Hassan MSA ... -  《-》

Discovery of new pyrimidine-5-carbonitrile derivatives as anticancer agents targeting EGFR(WT) and EGFR(T790M).

Nasser AA ，Eissa IH ，Oun MR ，El-Zahabi MA ，Taghour MS ，Belal A ，Saleh AM ，Mehany ABM ，Luesch H ，Mostafa AE ，Afifi WM ，Rocca JR ，Mahdy HA ... -  《-》

Computational Design, Synthesis, and Bioevaluation of 2-(Pyrimidin-4-yl)oxazole-4-carboxamide Derivatives: Dual Inhibition of EGFR(WT) and EGFR(T790M) with ADMET Profiling.

Raghunath Khedkar N ，Sindkhedkar M ，Joseph A 《-》