One-Pot Synthesis of Some New Phthalazine-Piperazine-1,2,4-Oxadiazole Hybrids: Anticancer Evaluation, Molecular Docking and ADMET Studies

We herein, described the synthesis of some new phthalazine-piperazine-1,2,4-oxadiazole hybrids (4a-n). All the synthesized compounds were evaluated for their in vitro anti-cancer activity against three human cancer cell lines including MCF-7 (breast cancer), A549 (lung cancer) and DU-145 (prostate cancer). In this study, Etoposide was used as a positive control. The results revealed that the compounds 4d, 4e, 4c, and 4h exhibited promising activity against three cancer cell lines. Predominantly, compound 4d displayed greater activity than the standard drug etoposide (with IC50 value 0.92 mu M against MCF-7) on MCF-7, A549 and DU-145 with IC50 values of 0.90 +/- 0.02, 1.40 +/- 0.06, and 2.16 +/- 0.02 mu M, respectively. The cell viability assay carried out toward a normal breast cell line (MCF-10A) for four potent compounds 4d, 4e, 4c, and 4h did not exhibit significant cytotoxicity with IC50 values above 97.74 mu M for all compounds. Furthermore, the compounds 4d, 4e, 4c, and 4h displayed promising inhibitory activity over tyrosine kinase EGFR when compared with the standard erlotinib. Molecular docking studies of potent compounds 4d, 4e, 4c, and 4h on EGFR receptor recommended that the more potent compound 4d strongly binds to protein EGFR (pdb id: 4HJO). The compound 4d is excellent for all tumor cells due to presence of nitro group in it comparable with 4e and it confirmed in docking analysis. In addition to this, in silico pharmacokinetic profile was achieved for the potent compounds 4d, 4e, 4c, and 4h using SWISS/ADME and pk CSM, whereas 4e, 4c, and 4h compounds followed Lipinski, Veber, and Muegge rules without any deviation.