Naturally based pyrazoline derivatives as aminopeptidase N, VEGFR2 and MMP9 inhibitors: design, synthesis and molecular modeling

Aminopeptidase N (APN) is regarded as an attractive target for cancer treatment due to its overexpression in various types of malignancies and its close association with cancer angiogenesis, metastasis and invasion. Herein the authors describe the design, synthesis and biological evaluation of some naturally based pyrazoline derivatives. Among these compounds, the diphenylpyrazole carbothioamide 8 showed significant activity and selectivity index (SI = 4.7) on breast (MCF-7) human cancer cell line and was capable of inhibiting APN with pIC 50 value of 4.8, comparable to the reference standard. Further evaluation of derivative 8 against VEGFR2 and MMP9 as biomarkers for angiogenesis and invasion showed that the selected compound had an inhibitory activity on both proteins with pIC 50 values of 6.7 and 6.4, respectively. Additionally, the migration ability of cells following treatment with the diphenylpyrazole derivative decreased to record a percentage wound closure of 57.77 for compound 8 versus 97.03 for the control. The promising derivative arrested cell growth at the G1 phase inducing early and late apoptosis. Finally, docking and ADMET in silico studies were performed. New naturally based pyrazoline derivatives were investigated as anti-breast cancer agents targeting APN, VEGFR2 and MMP9. The effects on wound healing, cell cycle and apoptosis were evaluated. Docking and ADMET studies were performed as well.