Novel niclosamide-derived Schiff bases as a dual-targeted anticancer agents

Abstract

Nicosamide (NIC), an approved anthelmintic medication, has demonstrated encouraging antitumor action. To enhance NIC’s pharmacokinetic and pharmacodynamic characteristics and make it a potential anticancer drug, thirteen NIC-Schiff bases were created by condensation reaction of NIC-amine 2 with various monocyclic/bicyclic/tricyclic aromatic aldehydes/acetophenone in absolute ethanol. Several spectroscopic methods, such as elemental analysis, IR, ¹H NMR, and MS, were used to determine the structures of these novel synthesized compounds. MTT assay was used to assess the target compounds’ activity against prostate cancer cell line (PC-3) and two breast cancer cell lines (MCF-7) and (MDA-MB-231). IC50 was determined for the most promising compounds using doxorubicin and NIC as reference standards. Among the compounds examined, the noteworthy compound 11 exhibited IC50 values of 2.85, 4.61, and 7.69 µM against MCF-7, MDA-MB-231, and PC-3, respectively, whereas, compound 8 displayed IC50 values of 8.70 and 8.20 µM against MCF-7 and MDA-MB-231, respectively. Using NIC as a reference standard, a mechanistic analysis of the interesting compounds 8 and 11 revealed dual inhibitory effect on JAK1 and CDK7 enzymes. They elicited greater amounts of JAK1 inhibition in MCF-7 and MDA-MB-231 (81-85.5%, 53.6-69.18%) than NIC (75.6% and 36.6%, respectively). Surprisingly, compound 11 inhibits CDK7 more than NIC does on MCF-7 (80.7%) and PC-3 (83.4%) cells. Additionally, compound 11 produced cell cycle arrest at G2/M (35.03%) with overexpression of pre-G (20.68%) in contrast to the control (20.95%) and (0.31%), respectively. With respect to the control, compound 11 performed better than NIC in raising the levels of apoptosis mediators, caspases 1, 3, and 9, in MDA-MB-231 cells by 4.60, 3.03, and 2.69 times, respectively. Like NIC, it also activates caspase 1 in PC-3 cells 3.5 times more than control. According to flow cytometry results, 11 significantly increased apoptotic cell death from 1.34% to 10.92% and necrotic cell death from 1.05% to 3.47% in comparison to control MCF-7 cells. The docking results of NIC-Schiff bases 8 and 11 confirmed the combined in vitro inhibitory effects of the JAK1 and CDK7 enzymes. Compound 11 establishes a more stable, tightly bound complex with JAK1, as indicated by molecular dynamics.