Synthesis of Some New Phthalazine piperazine pyrazole Conjugates; In vitro Anti-Cancer, ADMET And Molecular Docking Studies

摘要

A new series of phthalazine piperazine pyrazole conjugates were synthesised and evaluated for their in vitro anticancer activity against three human cancer cell lines including MCF-7 (breast), A549 (lung) and DU-145 (prostate). The result data showed that compound 2-((3-(3,5-dimethoxyphenyl)-1H-pyrazol- 5-yl)methyl)-4-(piperazin-1-yl methyl)phthalazin-1(2H)-one (5 i) showed comparable activity against all the cell lines with the standard drug Etoposide. As well, compounds 2-((3-(3- methoxyphenyl)-1H-pyrazol-5-yl) methyl)-4-(piperazin-1- ylmethyl) phthalazin-1(2H)-one (5 j) and 2-((3-(3,5-dimethylphenyl)- 1H-pyrazol-5-yl) methyl)-4-(piperazin-1-ylmethyl) phthalazin-1(2H)-one (5l) exhibited promising activity against three cancer cell lines as compared to Etoposide. Three potent compounds (5i, 5j, and 5l) were examined against the normal breast cell line in a cell viability assay (MCF-10A), but none of them showed any apparent cytotoxicity with IC50 values above 78 μM. In addition, compounds 5i, 5j, and 5l were screened for the VEGFR-2 tyrosine kinase inhibitory activity using sorafenib as the standard drug and found that compound 5i exhibited more potency in inhibiting the VEGFR-2 tyrosine kinase as compared to sorafenib. Finally, molecular docking studies of compounds 5i, 5j and 5l were also revealed that these compounds showed more binding interactions with VEGFR-2 than VEGFR-1. In accumulation to this, in silico pharmacokinetic profile was carried out for the potent compounds 5i, 5j and 5l by SWISS/ADME and pkCSM. Whereas, 5i, 5j and 5l compounds followed Lipinski, Veber, Egan, and Muegge rules without any deviation.