Chimeric pyrrolodiketo-pyrrolidine-phthalazine - triazole derivatives: synthesis, structure, stereochemistry, and anticancer activity.

We present herein a detailed study concerning the design, synthesis, structure, stereochemistry, and anticancer activity of a new class of chimeric pyrrolodiketo-pyrrolidine-phthalazine-triazole (PPPT) derivatives. The design of the chimeric PPPT molecules integrated the biological potential of phthalazine, pyrrolidine, and triazole scaffolds using the Multiple Targeting Ligands (MTL) / molecular hybridization (MH) strategy, along with bioisosteric modifications of existing drugs. The synthesis of our chimeric PPPT derivatives was efficient and straightforward in two steps: a Huisgen 3 + 2 dipolar cycloaddition reaction of ylides with a symmetrically substituted cyclic Z-alkene, followed by a click copper-catalysed reaction. The cycloaddition reactions proceed with high stereospecificity, and NMR and single-crystal X-ray diffraction studies unambiguously established the stereochemistry of the obtained compounds. The anticancer assay reveals that the newly obtained compounds 1, 4a,b, and 6a-j have low or no cytotoxicity toward normal cells and exhibit very good to moderate activity against breast adenocarcinoma and osteosarcoma cancer cell lines. The most active compounds were proved to be the chimeric derivatives 6c, 6d, and 6j, with IC50 values close to those of the standard drug doxorubicin on the MCF7 and MG-63 cancer cell lines, and with selectivity index values also indicating a good cytotoxic profile. Notable SAR correlations have been observed. The in silico Swiss-ADME evaluation indicates that our chimeric PPPT derivatives exhibit good ADME, drug-likeness, and medicinal chemistry properties. The in silico computational Swiss-Target Prediction tool predicts that our chimeric PPPT compounds will most likely act as Multiple Targeting Ligands, primarily as tyrosine kinase and PARP-1 inhibitors. The in silico molecular docking studies confirm VEGFR-2 and PARP-1 as possible binding sites for our compounds. Both the experimental anticancer assay and the in silico computational studies suggest that our chimeric pyrrolodiketo-pyrrolidine-phthalazine-triazole derivatives 6c, 6d, and 6j are promising drug candidates.