New pyrazolylindolin-2-one based coumarin derivatives as anti-melanoma agents: design, synthesis, dual BRAF^V600E/VEGFR-2 inhibition, and computational studies

Malignant melanoma is the most invasive skin cancer with the highest risk of death. The inhibition of BRAF(V600E) appears relevant for overcoming secondary resistance developed during melanoma treatment. BRAF(V600E) triggers angiogenesis via modification of the expression of angiogenic inducers, which play a crucial role in the metastasis of melanoma. Accordingly, the dual inhibition of the BRAF(V600E)/VEGFR-2 signaling pathway is considered a rational approach in the design of anti-melanoma candidates. In this study, a new class of pyrazolylindolin-2-one linked coumarin derivatives as dual BRAF(V600E)/VEGFR-2 inhibitors targeting A375 melanoma cells was designed. Target compounds were tailored to occupy the pockets of BRAF(V600E) and VEGFR-2. Most of the synthesized compounds demonstrated potent mean growth inhibitory activity against A375 cells. Compound 4j was the most active cytotoxic derivative, displaying an IC50 value at a low micromolar concentration of 0.96 mu M with a significant safety profile. Moreover, 4j showed dual potent inhibitory activity against BRAF(V600E) and VEGFR-2 (IC50 = 1.033 and 0.64 mu M, respectively) and was more active than the reference drug sorafenib. Furthermore, derivative 4j caused significant G0/G1 cell cycle arrest, induced apoptosis, and inhibited the migration of melanoma cells. Molecular docking showed that compound 4j achieved the highest Delta G value of -9.5 kcal mol(-1) against BRAF(V600E) and significant Delta G of -8.47 kcal mol(-1) against VEGFR-2. Furthermore, the structure-activity relationship study revealed that TPSA directly contributed to the anticancer activity of the tested compounds.