Why can curcumin cross the blood-brain barrier, but not congo red?
Preface: both molecules could act as bidentate ligands but the &#x3b2;-diketo structure found in curcumin is typically a much better bidentate ligands — as the 2-oxophenol moieties would be. So I would expect curcumin to be a much better ligand than congo red.



The key difference between the two molecules is comparing the extent of their lipophilicity and their hydrophilicity. Curcumin has a rather low water solubility of $3.2~\mathrm{mg/l}$, in line with the fact that it has rather little features that can enhance solubility. Basically, it boils down to the two keto-groups and the phenol moiety.

Congo red has two sulphonic acid groups and two aromatic amino groups. This means that there is a much greater relative charge present, and indeed its solubility in water is reported to be $1.16 \times 10^{2}~\mathrm{g/l}$ — notice the different unit. So congo red is already much more hydrophilic than curcuminis.

In terms of lipophilicity, the sulphonic acid groups present in congo red reduce its lipophilicity while the amino groups themselves don’t have too strong an effect. On curcumin’s side, the phenol groups can comfortably hydrogen bond to the neighbouring methoxy residues and the &#x3B2;-diketo fragment can tautomerise to a keto-enol form and form another intramolecular hydrogen bond. Thus, curcumin is a lot more capable of coping with low-hydrogen bond solvents and is thus expected to have a high lipophilicity.

This is the edge that curcumin has over congo red to cross the blood-brain barrier.