Synthesis of Some New Phthalazine−piperazine−pyrazole Conjugates; In vitro Anti‐Cancer, ADMET And Molecular Docking Studies
Vinitha Badithapuram, Satheesh Kumar Nukala, Gouthami Dasari, Narasimha Swamy Thirukovela, Srinivas Bandari
Abstract
Abstract 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)‐1 H ‐pyrazol‐5‐yl)methyl)‐4‐(piperazin‐1‐yl methyl)phthalazin‐1(2 H )‐one (5 i) showed comparable activity against all the cell lines with the standard drug Etoposide. As well, compounds 2‐((3‐(3‐methoxyphenyl)‐1 H ‐pyrazol‐5‐yl) methyl)‐4‐(piperazin‐1‐ylmethyl) phthalazin‐1(2 H )‐one (5 j) and 2‐((3‐(3,5‐dimethylphenyl)‐1 H ‐pyrazol‐5‐yl) methyl)‐4‐(piperazin‐1‐ylmethyl) phthalazin‐1(2 H )‐one ( 5 l) exhibited promising activity against three cancer cell lines as compared to Etoposide. Three potent compounds ( 5 i , 5 j , and 5 l ) were examined against the normal breast cell line in a cell viability assay (MCF‐10A), but none of them showed any apparent cytotoxicity with IC 50 values above 78 μM. In addition, compounds 5 i , 5 j , and 5 l were screened for the VEGFR‐2 tyrosine kinase inhibitory activity using sorafenib as the standard drug and found that compound 5 i exhibited more potency in inhibiting the VEGFR‐2 tyrosine kinase as compared to sorafenib. Finally, molecular docking studies of compounds 5 i , 5 j and 5 l 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 5 i , 5 j and 5 l by SWISS/ADME and pkCSM. Whereas, 5 i , 5 j and 5 l compounds followed Lipinski, Veber, Egan, and Muegge rules without any deviation.