Free drug concentration is the concentration of the unbound drug or compound. The free drug hypothesis is a widely accepted pharmacological norm that postulates that, in the absence of transporters, the free drug concentration is the same on both sides of the biological membrane at a steady-state, and the species that exerts pharmacological activity, such as in-vivo efficacy and toxicity, is the free drug or unbound concentration at the site of action. For the first part of the hypothesis, this may be true for the designed chalcones considering their high passive permeability and possible fast rate of permeation which can fasten the rate of reaching equilibrium across membranes. However, for the second part of the hypothesis, there are some exceptions that could apply to designed chalcones as do other drugs as follows.