Zhang_2025_Bioorg.Chem_160_108430

In this study, nine novel carvacrol/thymol derivatives incorporating carbamate groups were designed, synthesized, and evaluated as multifunctional anti-AD agents. These derivatives displayed superior BuChE inhibitory and anti-inflammatory characteristics compared to the parent compounds. While the derivatives exhibited AChE IC(50) values exceeding the detectable limit (>100 microM), they demonstrated high potency as BuChE inhibitors, with IC(50) values ranging from 0.05 to 9.62 microM. In an inflammation model of BV2 microglial cells induced by lipopolysaccharide (LPS), the derivatives effectively reduced the levels of the pro-inflammatory cytokine interleukin-1beta (IL1beta), with inhibition rates of IL1beta exceeding 50 % at 10 microM. Notably, compound SXF3 attained the highest BuChE inhibition efficacy (eqBuChE IC(50) = 0.05 +/- 0.003 microM, hBuChE IC(50) = 0.04 +/- 0.001 microM), the highest selectivity for BuChE (with a selectivity index, SI, exceeding 2000, calculated as the ratio of eeAChE IC(50) to eqBuChE IC(50)) and high anti-inflammatory activity (inhibition of IL1beta, IC(50) = 8.33 +/- 0.08 microM). In a scopolamine-induced AD mouse model, SXF3 (15 mg/kg) significantly reduced the latency to the platform and attenuated memory deficits. Biochemical analysis confirmed that SXF3 significantly increased acetylcholine (ACh) levels in the mice hippocampus, primarily due to the inhibition of BuChE rather than AChE, and that SXF3 significantly reduced IL1beta levels to normal, further confirming its anti-inflammatory activities. Hence, the selective BuChE inhibitory properties and anti-inflammatory attributes of SXF3 render it a promising candidate for further investigation in the treatment of AD.