Design, synthesis, and in silico insights of novel N'-(2-oxoindolin-3-ylidene)piperidine-4-carbohydrazide derivatives as VEGFR-2 inhibitors.

Eldehna WM ，Habib YA ，Mahmoud AE ，Barghash MF ，Elsayed ZM ，Elsawi AE ，Maklad RM ，Rashed M ，Khalil A ，Hammad SF ，Ali MM ，El Kerdawy AM ... -  《-》

Discovery of Novel Pyrimidine Based Small Molecule Inhibitors as VEGFR-2 Inhibitors: Design, Synthesis, and Anti-Cancer Studies.

Dhawale SA ，Mokale SN ，Dabhade PS 《-》

Discovery of novel diaryl urea-oxindole hybrids as BRAF kinase inhibitors targeting BRAF and KRAS mutant cancers.

In the current study, a novel series of diaryl urea incorporating oxindole moiety was rationally designed as type II BRAF inhibitors targeting BRAF and KRAS mutant cancers. Molecular hybridization between the diaryl urea scaffold which binds to the inactive conformation of protein kinases on one side and the oxindole core which exhibit adenine mimic properties to be settled in the hinge region on the other side was performed. Studying the antiproliferative activity of the synthesized candidates 9a-t on NCI cancer cell lines showed that they exhibit potent and broad spectrum of antiproliferative activity on the tested cancer cell lines with compounds 9c, 9p, 9q, 9s, and 9t demonstrating potent GI50 reaching 0.01 µM. Noteworthy, compound 9s demonstrated a potent GI50 on cell lines expressing mutant KRAS and those express BRAFV600E with GI50 ranges of 1.79 and 7.94 µM and 1.68 to 2.0 µM, respectively. Further analysis on A375 and Mel501 cell lines expressing BRAFV600E revealed that compound 9s has a potent growth inhibitory activity with IC50 of 0.7 and 1.5 µM, respectively, in reference to sorafenib (IC50 = 8.7 and 0.3 µM, respectively). Additionally, nearly all the target candidates did not show any cytotoxic effect on the normal fibroblast cell line BJ-1 with compound 9s showing IC50 of 20.2 µM in reference to sorafenib (IC50 = 6.1 µM). Further cellular assays on A375 cell line, revealed the ability of compound 9s to halt the cell cycle progression at the G2 phase besides its ability to induce apoptosis. In parallel, all the synthesized candidates 9a-t were biochemically evaluated for their inhibitory activity on BRAFWT and compounds 9b, 9c, and 9n revealed a sub-micromolar IC50 of 0.11, 0.84 and 0.80 µM, respectively. Further investigation of selected compounds on BRAFV600E showed that compounds 9c, 9n, 9s, and 9t exhibit a sub-micromolar IC50 range of 0.17 to 0.89 µM. Noteworthy, the examined candidates demonstrated a higher selectively towards BRAFV600E over BRAFWT highlighting their promising optimization for treating BRAFV600E expressing cancers. Molecular docking and molecular dynamics simulations in the inactive DFG-out kinase domain of BRAFWT/V600E protein kinases confirmed the planned design strategy.

Ghannam IAY ，El Kerdawy AM ，Mounier MM ，Abo-Elfadl MT ，Abdel-Mohsen HT ... -  《-》

Synthesis of S-alkylated oxadiazole bearing imidazo[2,1-b]thiazole derivatives targeting breast cancer: In vitro cytotoxic evaluation and in vivo radioactive tracing studies.

Mohammed ER ，Abdel Fattah Ezzat M ，Seif EM ，Essa BM ，Abdel-Aziz HA ，Sakr TM ，Ibrahim HS ... -  《-》

Anti-proliferative 2,3-dihydro-1,3,4-thiadiazoles targeting VEGFR-2: Design, synthesis, in vitro, and in silico studies.

In this study, we present the design, synthesis, and evaluation of six new thiadiazole derivatives designed as VEGFR-2 inhibitors. The most promising compound, 18b, demonstrated promising inhibitory activity against VEGFR-2, with an IC50 value of 0.165 µg/mL. The in vitro assessments on MCF-7 and HepG2 cell lines revealed the superior anti-proliferative effects of compound 18b, exhibiting IC50 values of 0.06 and 0.17 µM, respectively. Further investigations into the cell cycle distribution of compound 18b on MCF-7 cells exhibited a cell cycle arrest at the S phase (52.96 %) and significantly reducing the percentage of cells in the G0-G1 and G2/M phases. Additionally, compound 18b demonstrated a remarkable pro-apoptotic effect, with 45.29 % total apoptosis, characterized by both early and late apoptosis, and minimal necrosis. These findings were corroborated by RT-PCR analysis, revealing a significant downregulation of the anti-apoptotic gene Bcl2 and upregulation of the pro-apoptotic gene BAX in compound 18b-treated cells compared to control MCF-7 cells. Moreover, in silico studies involving molecular docking, Density Functional Theory (DFT) calculations, Molecular Dynamics (MD) simulations, MM-GBSA, Principle Component Analysis of Trajectories (PCAT), in addition to Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) predictions underscored the molecular interactions, energetics, and pharmacokinetic properties of compound 18b and the other derivatives further supporting its potential. Our integrated approach, combining in vitro experimens with in silico predictions provides valuable insights into the therapeutic potential of compound 18b as a robust VEGFR-2 inhibitor and lays the groundwork for future optimization.

Elkady H ，Elgammal WE ，Mahdy HA ，Zara S ，Carradori S ，Husein DZ ，Alsfouk AA ，Ibrahim IM ，Elkaeed EB ，Metwaly AM ，Eissa IH ... -  《-》