Discovery of New Quinolone-Based Diarylamides as Potent B-RAF V600E /C-RAF Kinase Inhibitors Endowed with Promising In Vitro Anticancer Activity.

The emergence of cancer resistance to targeted therapy represents a significant challenge in cancer treatment. Therefore, identifying new anticancer candidates, particularly those addressing oncogenic mutants, is an urgent medical demand. A campaign of structural modifications has been conducted to further optimize our previously reported 2-anilinoquinoline-diarylamides conjugate VII as a B-RAFV600E/C-RAF inhibitor. Considering the incorporation of a methylene bridge between the terminal phenyl and cyclic diamine, focused quinoline-based arylamides have been tailored, synthesized, and biologically evaluated. Among them, the 5/6-hydroxyquinolines and stood out as the most potent members, with IC values of 0.128 µM, 0.114 µM against B-RAF, and 0.0653 µM, 0.0676 µM against C-RAF. Most importantly, elicited remarkable inhibitory potency against the clinically resistant B-RAF mutant with an IC value of 0.0616 µM. The putative binding mode of and were studied by molecular docking and molecular dynamics (MD). Moreover, the antiproliferative activity of all target compounds has been examined over a panel of NCI-60 human cancer cell lines. In agreement with cell-free assays, the designed compounds exerted superior anticancer impact over the lead quinoline against all cell lines at a 10 µM dose. Notably, both and showed highly potent antiproliferative activity against melanoma cell lines with growth percent under -90% (SK-MEL-29, SK-MEL-5, and UACC-62) at a single dose, while maintained potency with GI values of 1.60-1.89 µM against melanoma cell lines. Taken together, , a promising B-RAF and C-RAF kinase inhibitor, may serve as a valuable candidate in the arsenal of anticancer chemotherapeutics.