Exploring Novel Niclosamide Derivatives for Enhanced Efficacy in Human Glioblastoma U-87 MG Cells: A SAR Investigation

Glioblastoma, often referred to as glioblastoma multiforme (GBM), is the most aggressive and malignant type of primary brain tumor in adults. Glioblastoma is notoriously difficult to treat due to several inherent characteristics, such as its aggressiveness, heterogeneity, compartmentalization via the blood-brain barrier, resistance to most conventional therapies like chemotherapy and radiation, its location, and limited treatment options. Consequently, despite significant advancements in pharmacotherapies over the past 30 years, there has been only relatively minimal improvement in prognosis. Recent research into the effectiveness of niclosamide, an antihelminth drug, has yielded encouraging findings regarding its potential as a treatment for glioblastoma. Our research aims to improve the efficacy of niclosamide through derivative analogs to better treat glioblastoma. This study employed phosphorus trichloride (PCl3) to facilitate the coupling of salisylic acid and analine, each at 2 mmol, to synthesize novel analogs of niclosamide. NMR spectroscopy was conducted to confirm the structures of the resulting compounds, ensuring the integrity of the synthesized derivatives. The synthesized analogs were evaluated by MTT assay for their efficacy in comparison to the parent compound, with preliminary results indicating promising enhancements in activity profiles. In this study, niclosamide derivatives were synthesized and evaluated for their anti-glioblastoma activity. The Western blot analysis confirmed findings from the MTT cell viability assay. Previous research indicated that the phenol OH group at position R1 is crucial for anti-glioblastoma activity. Additionally, chlorine substitutions at R2 or R3, or both, demonstrated comparable efficacy to niclosamide, but complete removal of these substitutions reduced bioactivity compared to niclosamide. Substituents such as NO2, N3, or CF3 at the R4 position exhibited similar effects to niclosamide possibly due to their electron removing properties disrupting key signaling pathways, whereas NH2 at R4 diminished bioactivity. Building on the previous research, bromine at R2 exhibited the most promising results, though not as potent as the stock niclosamide. At R3, substitution with a methoxy group demonstrated a significant increase in IC50, similar to the results obtained when replacing R4 with chlorine. Additionally, replacing R4 with a trifluoromethyl group resulted in the highest increase in IC50 among the tested compounds. Further studies on different derivatives are essential to improving the efficacy of niclosamide in glioblastoma treatment. Nevertheless, these findings suggest that niclosamide and its derivatives could serve as promising therapeutic agents for treating human glioblastoma and potentially other cancers in the future.