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.