A series of novel 1-naphthol derivatives—4a–f, 5a,f, 6a, and 7a,b—were synthesized through a three-step synthetic strategy involving Diels-Alder cycloaddition between furan and in situ-generated benzyne intermediates, Cu(OTf)₂-catalyzed aromatization to form naphthol cores, and controlled bromination to introduce halogen substituents. The resulting compounds were purified via silica gel chromatography and rigorously characterized using ¹H NMR, ¹³C NMR, FTIR, and HRMS, confirming their molecular identity and high purity. Spectroscopic analysis revealed distinct features: bridgehead protons appeared at δ 5.65–6.02 ppm, while phenolic –OH signals resonated between δ 5.26 and 5.96 ppm. Notably, the presence of multiple halogens induced significant downfield shifts in –OH protons (e.g., 4c at δ 8.09 ppm, 4d at δ 8.21 ppm), indicating strong electron-withdrawing effects that influence redox behavior.
Biological evaluation focused on antioxidant capacity and inhibition of key enzymes linked to neurodegeneration—human carbonic anhydrase I and II (hCA I, hCA II)—and acetylcholinesterase (AChE). Antioxidant activity was assessed using DPPH·, ABTS·⁺, FRAP, CUPRAC, and Fe³⁺ reduction assays.5-tert-Butylisophthalic acid Cancer Compounds bearing methoxy (4b, 4f) and dioxole (4f) groups exhibited superior radical scavenging ability, with 4f showing IC₅₀ values of 18.886 µg/mL (DPPH) and 5.484 µg/mL (ABTS), outperforming standard antioxidants such as BHA, Trolox, and tocopherol. This enhanced activity is attributed to resonance stabilization of the phenoxyl radical, facilitated by electron-donating oxygen-containing groups and extended π-conjugation.
In enzyme inhibition studies, all compounds demonstrated potent activity against hCA I and II. Ki values ranged from 0.034 ± 0.54 to 0.724 ± 0.18 µM for hCA I and 0.172 ± 0.02 to 0.562 ± 0.21 µM for hCA II. Compound 4c emerged as the strongest inhibitor of hCA I (Ki = 0.034 ± 0.54 µM), while 5a and 6a showed the highest potency against hCA II (Ki = 0.172 ± 0.02 µM). Inhibition occurs via coordination of the phenolic oxygen with the catalytic Zn²⁺ ion, hydrogen bonding with Thr199, and hydrophobic interactions within the active site pocket.Temozolomide Apoptosis Halogen atoms enhance binding affinity through increased lipophilicity and favorable van der Waals contacts.PMID:34764459
AChE inhibition was also highly effective, with Ki values spanning 0.096 ± 0.01 to 0.177 ± 0.02 µM. Compound 4a was the most potent inhibitor (Ki = 0.096 ± 0.01 µM), surpassing tacrine (Ki = 0.109 ± 0.01 µM). This suggests that specific substitution patterns improve interaction with the catalytic anionic site, likely through enhanced π-stacking and electrostatic complementarity.
Structure-activity relationship analysis confirmed that methoxy and dioxole groups are essential for optimal antioxidant performance, while halogenation enhances enzyme inhibition. However, excessive halogenation reduced antioxidant efficacy due to decreased electron density and destabilization of the radical intermediate. Compounds 4b, 4f, 5a, and 6a consistently ranked among the top performers across all assays.
Statistical analysis confirmed high significance (p < 0.01), with R² values exceeding 0.90 in all biological tests. These findings demonstrate that the 1-naphthol scaffold, when functionalized with strategic substitutions, can serve as a powerful platform for designing dual-action agents capable of simultaneously combating oxidative stress and inhibiting neurodegeneration-associated enzymes. This multi-target approach holds significant promise for the development of next-generation therapeutics for Alzheimer’s disease and related disorders.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com