Novel hybrid motifs of 4-nitroimidazole-piperazinyl tagged 1,2,3-triazoles: Synthesis, crystal structure, anticancer evaluations, and molecular docking study

4-((4-(1-benzyl-2-methyl-4-nitro-1H-imidazole-5-yl)piperazine-1-yl)methyl)-1-substituted-1H-1,2,3-triazole motifs are designed and synthesized via click chemistry. The reaction of 1-(N(1)-benzyl- 2-methyl-4-nitro-1H-imidazole- 5-yl)-4-(prop-2-yn-1-yl) piperazine 5 as new scaffold with diverse primary azides to selectively produce 1,4-disubstituted-1,2,3-triazoles 9a–k, 10a–c and 11a–q. Physicochemical methods: when (1)H NMR, (13)C NMR, and HRMS are utilized to fully characterize all synthesized compounds. X-ray structural determination and analysis for compound 9a is also performed. The newly designed chromophores are assessed for their anti-proliferative potency against three selected human cancer cell lines (MCF-7, HepG2, and PC3), and one normal cell line (Dermal/Fibroblast). Compounds 9g and 9k have shown potent activities against the MCF-7 cell line with IC(50) values of (2.00 ± 0.03 μM) and (5.00 ± 0.01 μM) respectively. ADMET studies and Molecular docking investigations are performed on the most active hybrid nitroimidazole derivatives 9g and 9k with 4-hydroxytamoxifen (4-OHT) at the human estrogen receptor alpha (hER) during binding active sites to study the ligand–protein interactions and free binding energies at atomic levels. The triazole ring in the 9g derivative forms a hydrogen bond with Asp58 with distance 3.2 Å. And it is found that polar contact with His231 amino acid residue. In silico assessment of the compounds showed very good pharmacokinetic properties based on their physicochemical values, also the ADMET criteria of the most active hybrid systems are within the acceptable range.