Design and Synthesis of Novel Phthalazine Scaffolds Linked to 1,3,4–oxadiazolyl–1,2,3–triazoles as Potent Anticancer Agents: A Computational Docking Analysis

A study on the chemical and biological properties of molecules simultaneously comprising various heterocycles, such as fused 1,3,4–oxadiazole and 1,2,3–triazoles, has been conducted as part of our ongoing research in the field of medicinal and organic chemistry. In the present study, novel 1,3,4-oxadiazoles and 1,2,3-triazoles incorporating a phthalazine ring have been synthesized and evaluated for their anticancer activity and docking analysis. In this study, we performed ligand–based pharmacophore modeling as a promising design strategy of substituted phthalazin–1(2H)–one–1,3,4–oxadiazole acetamides (4); 1,2,3–triazole–1,3,4–oxadiazolyl)phthalazin-1(2H)-one (5) were synthesized from key intermediate 2-((5-mercapto-1,3,4-oxadiazol-2-yl)methyl)-4-methylphthalazin-1(2H)-one 2. The prepared compounds were characterized by proton and carbon nuclear magnetic resonance spectroscopy, infrared, elemental analysis, and mass spectroscopy. Synthesized scaffolds were screened for their anticancer activity against three cell lines, MCF-7, T-47D, and MDA-MB-231, by MTT assay. The prepared ligands were docked by using the input protocols, like RCSB, AutoDock 4.2, ACD ChemSketch, Open Babel, and SwissADME. The final compound 5f exhibited excellent activity (IC50 = 10.21 ± 2.2, 7.53 ± 0.1 µM) against T-47D and MCF-7 cancer cell lines, respectively, and compounds 4b and 5b showed the highest % growth of inhibition (61.25 ± 0.52, 62.48 ± 0.20 µg/mL) against T-47D and MCF-7 cell lines, which has been found to be equivalent to that reported by the standard cisplatin. The prepared ligand 5f exhibited greatest bonding with amino acids AlaX:191, MetX:193, ValX:196, ThrX:140, PheX:192, TyrX:155, AsnX:90, LysX:159, LeuX:95, and IleX:14, with a docking score of –11.53 Kcal/mol, respectively. These compounds were further evaluated for their ADMET and physicochemical properties by using SwissADME. Phthalazine with 1,3,4–oxadiazole substituents and 1,2,3–triazoles containing 1,3,4–oxadiazole ring displayed excellent anticancer activity; some interesting relationship has also been evidenced between the synthesised structures and their antimicrobial activity and docking studies. In light of all the above findings, it can be concluded that these molecules may serve as lead molecules for further synthetic and biological evaluation.