Background: Several human diseases like Parkinson’s, Alzheimer’s disease, and systemic amyloidosis are associated with the misfolding and aggregation of protein molecules.

Objective: The present study demonstrated the comparison of 4-methyl coumarin and 4-methylthiocoumarin derivative for their anti-amyloidogenic and disaggregation activities. The hen egg-white lysozyme is used as a model system to study protein aggregation and disaggregation under in vitro conditions.

Methods: Techniques used in the study were Thioflavin T fluorescence assay, intrinsic fluorescence assay, circular dichroism, transmission electron microscopy, and molecular dynamics.

Results: Fifteen compounds were screened for their anti-amyloidogenic and disaggregation potential. Six compounds significantly inhibited the fibril formation, whereas ten compounds showed disaggregation property of pre-formed fibrils. Under in vitro conditions, the compound C3 and C7 showed significant inhibition of fibril formation in a concentration-dependent manner as compared to control. C3 and C7 demonstrated 93% and 76% inhibition of fibril formation, respectively. Furthermore, C3 and C7 exhibited 83% and 76% disaggregation activity, respectively, of pre-formed HEWL fibrils at their highest concentration. These anti-amyloidogenic and disaggregation potential of C3 and C7 were validated by intrinsic fluorescence, CD, molecular dynamics, and TEM study.

Discussion: 4-methylthiocoumarins derivatives have shown better anti-amyloidogenic activity as compared to 4-methylcoumarin derivatives for both amyloid formation as well as disaggregation of preformed amyloid fibrils. Structurally, the derivatives of 4-methylthiocoumarins (C3 and C7) contain thio group on 2nd position that might be responsible for anti-amyloidogenic activity as compared to 4- methylcoumarin derivatives (C2 and C4).

Conclusion: C3 and C7 are novel 4-methylthiocoumarin derivatives that can be used as a lead for alleviation and symptoms associated with protein aggregation disorders.

背景：帕金森氏病，阿尔茨海默氏病和系统性淀粉样变性等几种人类疾病与蛋白质分子的错误折叠和聚集有关。

目的：本研究证明了4-甲基香豆素和4-甲基硫代香豆素衍生物的抗淀粉样蛋白生成和分解活性。鸡蛋清溶菌酶被用作研究体外条件下蛋白质聚集和解聚的模型系统。

方法：本研究使用的技术为硫黄素T荧光测定，固有荧光测定，圆二色性，透射电子显微镜和分子动力学。

结果：筛选了15种化合物的抗淀粉样蛋白生成和解聚潜力。六种化合物显着抑制了原纤维的形成，而十种化合物显示了预形成的原纤维的解聚性能。在体外条件下，与对照相比，化合物C3和C7以浓度依赖的方式显示出对原纤维形成的显着抑制。C3和C7分别抑制了93％和76％的原纤维形成。此外，在最高浓度下，C3和C7分别显示了预形成的HEWL原纤维的83％和76％的分解活性。这些C3和C7的抗淀粉样蛋白产生和解聚的潜力已通过固有荧光，CD，分子动力学和TEM研究得到了验证。

讨论：与4-甲基香豆素衍生物相比，对于形成淀粉样的淀粉样蛋白以及分解淀粉样原纤维，4-甲基硫代香豆素衍生物具有更好的抗淀粉样生成活性。在结构上，与4-甲基香豆素衍生物（C2和C4）相比，4-甲基硫代香豆素衍生物（C3和C7）在2位上含有硫基，可能负责抗淀粉样蛋白生成活性。

结论：C3和C7是新型的4-甲基硫代香豆素衍生物，可以用作减轻与蛋白质聚集疾病有关的症状和症状的先导。